[{"id":"idea-mfbg-pet-replaces-mibg","kind":"idea","name":"18F-MFBG PET replacing 123I-MIBG scintigraphy","aka":[],"tldr":"A same-day PET tracer could replace the two-day, low-resolution MIBG scan children now undergo repeatedly.","summary":"Children with neuroblastoma repeatedly undergo 123I-MIBG scintigraphy, a two-day, low-resolution scan, and this idea proposes replacing it with same-day 18F-MFBG PET. 18F-meta-fluorobenzylguanidine uses the same norepinephrine-transporter biology as MIBG but gains PET resolution and 18F logistics, needs no sedation across two days, and early data show higher lesion detection. The hypothesis is that MFBG PET/CT detects more lesions than MIBG SPECT with equal specificity, and that Curie-type scoring on MFBG predicts outcome at least as well. Prospective paired comparisons are under way at MSK and in COG imaging studies and an NDA is in progress; at an early clinical stage, it sits within the paediatric oncology roadmap alongside the MIBG theranostics and PET records.","asOf":"2026-09-07","links":[{"label":"Pandit-Taskar et al., Biodistribution and dosimetry of 18F-meta-fluorobenzylguanidine: a first-in-human PET study (Journal of Nuclear Medicine 2017)","url":"https://doi.org/10.2967/jnumed.117.193169"}],"tags":[],"related":["f-18","i-123"],"indications":["neuroblastoma"],"sections":[],"technologies":["mibg-theranostics","pet"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"18F-MFBG PET/CT detects more lesions than 123I-MIBG SPECT with equal specificity, and Curie-type scoring on MFBG predicts outcome at least as well.","rationale":"MFBG uses the same norepinephrine-transporter biology as MIBG but with PET resolution and 18F logistics.","test":"Paired prospective comparison in newly diagnosed and relapsed patients; response prediction analysis.","maturity":"early-clinical"},{"id":"idea-reg-medical-isotope-reactor-reserve","kind":"idea","name":"A coordinated reserve and shared schedule for the world's medical isotope reactors","aka":[],"tldr":"A handful of ageing research reactors make most cancer isotopes. Coordinating their maintenance and funding reserve capacity would prevent the shortages that stop treatments.","summary":"Lutetium-177, iodine-131 and molybdenum-99 depend on a few research reactors (HFR Petten, BR2, MARIA, SAFARI-1, OPAL, several in Russia and the US), most over 50 years old. The OECD Nuclear Energy Agency's High-Level Group on Medical Radioisotopes coordinated molybdenum-99 after the 2009-10 crisis. The proposal is to extend that model formally to therapeutic isotopes: shared outage scheduling, an agreed reserve capacity margin funded by a per-dose levy, and public co-financing of the next generation of producers (PALLAS in the Netherlands, accelerator-based SHINE, new irradiation positions in existing reactors).","asOf":"2026-09-08","links":[{"label":"OECD NEA medical radioisotopes","url":"https://www.oecd-nea.org/jcms/pl_26262/medical-radioisotopes"}],"tags":[],"related":["mo-99","lu-177","i-131"],"indications":[],"sections":[],"technologies":["radioligand-therapy"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-manufacturing-cell-therapy"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Coordinated scheduling and reserve capacity reduce clinic-reported therapeutic isotope shortage weeks by at least 80% and keep lutetium-177 spot prices stable during planned reactor outages.","rationale":"The molybdenum-99 experience showed that coordination, not new physics, ended a supply crisis; therapeutic isotopes now face the same concentration of supply with faster-growing demand.","test":"Publish a shared outage calendar and reserve-margin target for lutetium-177 producers within a year; track clinic-reported dose cancellations and prices against the prior three years.","maturity":"early-clinical","actor":"policy","cost":"large","horizonYears":5},{"id":"idea-reg-isotope-supply-observatory","kind":"idea","name":"A global medical isotope supply observatory with forecasts and shortage alerts","aka":[],"tldr":"Nobody publishes how much cancer isotope is made, where, or when supply will fall short. A public observatory would let hospitals and investors plan.","summary":"Supply and demand for lutetium-177, actinium-225, iodine-131 and their precursors are opaque; producers guard volumes, and shortages surface only when clinics cancel doses. The proposal is an observatory, hosted by the IAEA or OECD NEA with WHO, that collects confidential production and capacity data from producers under aggregation rules, publishes quarterly supply-demand balances and five-year forecasts, and issues shortage alerts to clinics and regulators. It would also track trial-stage demand so producers can invest ahead of approvals.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Manufacturing cost and time for living and radioactive medicines): Hernandez, Prasad & Gellad, Total costs of chimeric antigen receptor T-cell immunotherapy (JAMA Oncology 2018)","url":"https://doi.org/10.1001/jamaoncol.2018.0977"}],"tags":[],"related":["lu-177","ac-225","i-131"],"indications":[],"sections":[],"technologies":["radioligand-therapy","targeted-alpha-therapy"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-manufacturing-cell-therapy"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Publication of forecasts is followed by earlier capacity investment decisions (measured by announced projects relative to forecast shortfalls) and a fall in unanticipated clinic-level shortages within three years.","rationale":"Transparent supply data (as in energy and food markets) reduce boom-bust investment and allow health systems to plan; the molybdenum-99 experience showed that opaque supply led to repeated crises.","test":"Establish the observatory for lutetium-177 first, publish two years of quarterly balances, and evaluate accuracy of forecasts and changes in shortage reports.","maturity":"speculative","actor":"data","cost":"small","horizonYears":2},{"id":"idea-copper-theranostic-pair-standard","kind":"idea","name":"A single-molecule copper-64/copper-67 pair instead of switching ligands between scan and treatment","aka":[],"tldr":"Most PSMA treatments use one molecule to take the pre-treatment scan and a slightly different molecule for the actual treatment, so the scan is only an approximate guide. A copper-based pair uses the identical molecule for both steps, just with a different form of copper, so the scan should be a much truer preview of where the treatment radiation will go.","summary":"The standard PSMA theranostic workflow images patients with 68Ga-PSMA-11 or a related diagnostic ligand and then treats responders with 177Lu-PSMA-617, a chemically different molecule; differences in the two ligands' binding and pharmacokinetics mean the diagnostic scan is only an approximate predictor of the therapeutic biodistribution. Clarity Pharmaceuticals' SAR-bisPSMA programme instead uses one identical molecule labelled with two isotopes of the same element: copper-64 for PET imaging and copper-67 for beta-emitting therapy, so in principle the diagnostic scan should be a much closer match to the therapeutic distribution than a cross-ligand, cross-element approach.\n\nThe combination is being tested in the ongoing SECuRE trial (NCT04868604), a US multi-centre, single-arm phase I/IIa study in metastatic castration-resistant prostate cancer, aiming to enrol approximately 54 participants. Company-reported interim results (data cut-off 20 July 2026) from 19 participants treated at the 8 GBq 67Cu-SAR-bisPSMA dose level showed a PSA50 response rate of 63% and PSA90 of 26%, with 81% of radiographically evaluable participants achieving disease control, including 31% with a complete response or undetectable disease by RECIST, bone scan or PSA; no dose-limiting toxicities have been reported across dose-escalation cohorts up to 12 GBq, and the sponsor states registrational phase 3 planning is under way.\n\nThese results come from company press releases and conference-style updates rather than an independent peer-reviewed publication, and the trial is a single-arm study, so there is no direct comparison yet against 177Lu-PSMA-617 or another PSMA radioligand therapy to establish whether the same-molecule imaging/therapy matching translates into a measurable clinical advantage over the established gallium-68/lutetium-177 approach.","asOf":"2026-09-22","links":[{"label":"SECuRE update: 8 GBq Cu-67 SAR-bisPSMA dose level results (Clarity Pharmaceuticals, Aug 2026)","url":"https://www.claritypharmaceuticals.com/news/secure-update-05-08-26/"},{"label":"SECuRE trial update: another participant with undetectable disease (Clarity Pharmaceuticals, Feb 2026)","url":"https://www.claritypharmaceuticals.com/news/secure-undetectable/"},{"label":"64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA (SECuRE) (ClinicalTrials.gov, NCT04868604)","url":"https://clinicaltrials.gov/study/NCT04868604"}],"tags":["copper theranostics","prostate","same-molecule imaging"],"related":["nct04868604","psma","prostate-mcrpc","pluvicto","ga-68","cu-64","lu-177","cu-67"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Using the identical molecule for imaging (copper-64) and therapy (copper-67) in PSMA-targeted treatment, rather than switching between different ligands such as gallium-68-PSMA-11 for imaging and lutetium-177-PSMA-617 for therapy, will give a more accurate match between the pre-therapy scan and the actual therapeutic radiation distribution, improving patient selection and predicting toxicity more reliably.","rationale":"Because 64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA are the same molecule differing only in the copper isotope, the pre-therapy scan should in principle predict the therapeutic biodistribution more directly than the common practice of imaging with one ligand and treating with a different one. Interim company-reported results from the SECuRE trial (19 participants at the 8 GBq dose level) show promising PSA response and radiographic disease-control rates with no observed dose-limiting toxicity, but these are sponsor-reported interim data from a single-arm trial, not an independent peer-reviewed head-to-head comparison against 177Lu-PSMA-617.","test":"The ongoing SECuRE trial itself (NCT04868604, approximately 54 planned participants) reporting mature, independently peer-reviewed phase II data, followed by a randomised phase 3 (registrational planning reported by the sponsor as under way) comparing 67Cu-SAR-bisPSMA against 177Lu-PSMA-617 or standard of care in metastatic castration-resistant prostate cancer.","maturity":"early-clinical","actor":"industry","cost":"medium","horizonYears":6},{"id":"idea-fund-academic-radiopharma-pipeline","kind":"idea","name":"A university cyclotron network with shared regulatory files for new tracers","aka":[],"tldr":"Most new cancer imaging agents and radioactive drugs start in university hospitals. A network sharing production, quality files and regulatory paperwork would get them into multi-centre trials years faster.","summary":"Academic radiopharmacy has repeatedly produced the agents the field now runs on (PSMA ligands and FAPI tracers from Heidelberg, DOTATATE from Basel and Rotterdam) but each centre re-creates production, quality control and regulatory documentation. A funded network of university cyclotrons and radiopharmacies would share drug master files, validated synthesis modules, GMP quality systems and a common clinical trial application template, so a tracer validated in one centre can be adopted in ten within months. It would also provide isotope purchasing at scale (gallium-68 generators, lutetium-177, actinium-225 allocation) for academic trials.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (The valley of death between lab and product): Butler, Translational research: crossing the valley of death (Nature 2008)","url":"https://doi.org/10.1038/453840a"}],"tags":[],"related":["idea-fap-theranostics-pancancer","radiopharma-roadmap","ga-68","lu-177","ac-225"],"indications":[],"sections":[],"technologies":["psma-pet","fapi-pet","radioligand-therapy","targeted-alpha-therapy"],"targets":[],"drugs":[],"companies":[],"institutions":["heidelberg-nct","peter-mac"],"pathways":[],"terms":[],"trials":[],"people":["uwe-haberkorn","frederik-giesel","hofman-michael"],"bottlenecks":["b-manufacturing-cell-therapy"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"A shared network reduces the time from first-in-human of an academic tracer or radioligand to a five-centre trial from the current several years to under eighteen months, and doubles the number of academic radiopharmaceuticals entering multi-centre trials within four years.","rationale":"PSMA PET spread globally because academic centres shared precursors and methods informally; formalising that with shared regulatory files removes the largest delay. Germany's and the Netherlands' academic radiopharmacy networks demonstrate feasibility within a country.","test":"Fund a ten-centre network with a shared master file for two agents and measure time to multi-centre trial start and centres activated compared with agents developed without the network.","maturity":"early-clinical","actor":"research","cost":"medium","horizonYears":4},{"id":"idea-rlt-plus-checkpoint-inhibitor","kind":"idea","name":"Adding a checkpoint inhibitor to PSMA radioligand therapy","aka":[],"tldr":"Radiation from a targeted radioactive treatment can spill tumour debris that alerts the immune system. Giving an immunotherapy drug at the same time, to stop the immune system being switched off, is being tested to see if it makes the radioactive treatment work better.","summary":"Radiation-induced cell death can expose tumour antigens and trigger immune responses, but immune checkpoints such as PD-1 can suppress that response. The PRINCE trial (NCT03658447, Peter MacCallum Cancer Centre) tested whether adding the PD-1 inhibitor pembrolizumab to 177Lu-PSMA-617 could improve outcomes in metastatic castration-resistant prostate cancer, a disease in which checkpoint inhibitors alone have limited activity. In this single-arm phase 1b/2 study of 37 patients, up to six cycles of 177Lu-PSMA-617 were given with pembrolizumab every three weeks for up to 24 months. The trial reported a PSA50 response rate of 76% and PSA90 of 46%, notably higher than the roughly 46% (VISION) and 66% (TheraP) PSA50 rates reported with 177Lu-PSMA-617 alone in other trials, and median radiographic progression-free survival of 11.2 months with median overall survival of 17.8 months.\n\nThe combination was not free of added toxicity: 35% of patients experienced grade 3 treatment-related adverse events, including grade 3 immune-related events in 30% of patients (colitis, myasthenia gravis, acute kidney injury, oral mucositis among them), and 14% of patients discontinued pembrolizumab because of immune-related toxicity, though all patients were able to continue 177Lu-PSMA-617. Because PRINCE was single-arm with no concurrent comparator, the reported PSA response rates cannot be directly attributed to the addition of pembrolizumab rather than to differences in patient selection between trials. A second combination trial, testing the CTLA-4-directed antibody ONC-392 alongside 177Lu-PSMA-617 (NCT05682443), is exploring an alternative checkpoint target in the same disease setting.","asOf":"2026-09-22","links":[{"label":"177Lu-PSMA-617 in combination with pembrolizumab for treatment of mCRPC (PRINCE): phase 1b/2 study (PubMed, 2026)","url":"https://pubmed.ncbi.nlm.nih.gov/41926961/"},{"label":"PRINCE trial 12-month follow-up results (ASCO abstract, 2025)","url":"https://www.asco.org/abstracts-presentations/ABSTRACT383277"},{"label":"Lu-PSMA-617/Pembrolizumab Shows Early Efficacy in Metastatic CRPC (Cancer Network, summary of Lancet Oncology publication)","url":"https://www.cancernetwork.com/view/lu-psma-617-pembrolizumab-shows-early-efficacy-in-metastatic-crpc"},{"label":"PRINCE study (ClinicalTrials.gov, NCT03658447)","url":"https://clinicaltrials.gov/study/NCT03658447"}],"tags":["combination therapy","immunotherapy","prostate"],"related":["pluvicto","pembrolizumab","sandhu-shahneen","prostate-mcrpc","vision","therap","lu-177"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Combining lutetium-177-PSMA-617 with the PD-1 inhibitor pembrolizumab will produce a higher PSA response rate in metastatic castration-resistant prostate cancer than radioligand therapy alone, by exposing radiation-released tumour antigens to an immune system no longer blocked by PD-1 signalling.","rationale":"The single-arm PRINCE trial (37 patients) reported a PSA50 response rate of 76% and PSA90 of 46%, higher than the 46% (VISION) and 66% (TheraP) PSA50 rates reported for 177Lu-PSMA-617 monotherapy in other trials, but with no concurrent comparator arm the apparent improvement could reflect differences in patient selection rather than a true treatment effect. The trial also documented a meaningful immune-related toxicity burden, with 30% of patients experiencing grade 3 immune-related adverse events and 14% discontinuing pembrolizumab.","test":"A randomised phase 2 or 3 trial directly comparing 177Lu-PSMA-617 plus pembrolizumab against 177Lu-PSMA-617 alone in PSMA-positive metastatic castration-resistant prostate cancer, powered on PSA50 response rate or radiographic progression-free survival, roughly 150-250 patients, to confirm or refute the single-arm PRINCE signal and quantify the added immune-related toxicity against any efficacy gain.","maturity":"early-clinical","actor":"research","cost":"medium","horizonYears":5},{"id":"idea-rlt-plus-parp-inhibitor","kind":"idea","name":"Adding a PARP inhibitor to PSMA radioligand therapy","aka":[],"tldr":"A drug that blocks a cell's DNA-repair enzyme (PARP) is being added to PSMA-targeted radioactive treatment, on the theory that if a cell can't repair the small cuts radiation makes to its DNA, those cuts become fatal breaks that kill the cancer cell.","summary":"Lutetium-177-PSMA-617 kills cells mainly by causing single-strand breaks in DNA, which the cell can often repair using PARP-dependent base excision repair. PARP inhibitors such as olaparib block this repair pathway, and preclinical work has shown this can convert what would have been a survivable single-strand break into a lethal double-strand break, radiosensitising tumour cells.\n\nThe combination has been tested clinically in the LuPARP phase 1 trial (NCT03874884, Peter MacCallum Cancer Centre), which enrolled patients with metastatic castration-resistant prostate cancer who had progressed on an androgen receptor pathway inhibitor. Across ten dose-escalation cohorts of olaparib schedules combined with a fixed 7.4 GBq dose of 177Lu-PSMA-617 every six weeks for up to six cycles, no dose-limiting toxicities were reported; common adverse events were low-grade xerostomia, nausea and fatigue, with transient grade 1-3 cytopenias. Reported activity was promising: a PSA50 response rate of 62% and PSA90 of 48% were seen in an interim 29-patient analysis, and at the recommended phase 2 dose (an intermittent olaparib schedule starting four days before each lutetium cycle), the median radiographic progression-free survival was 12.8 months with a PSA90 response rate of 55%.\n\nA second, alpha-emitter version of this combination is now in trial: FPI-2265 (225Ac-PSMA-I&T) plus olaparib (NCT06909825) is testing whether the same DNA-repair rationale extends to alpha-particle radioligand therapy. Neither the beta nor the alpha combination has yet been tested in a randomised trial against radioligand therapy alone, so the magnitude of any added benefit over 177Lu-PSMA-617 or 225Ac-PSMA-I&T monotherapy is not yet established.","asOf":"2026-09-22","links":[{"label":"LuPARP: Phase 1 trial of 177Lu-PSMA-617 and olaparib in mCRPC (JCO, 2023)","url":"https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.5005"},{"label":"177Lu-PSMA-617 Therapy and Olaparib in Patients With mCRPC (LuPARP) (ClinicalTrials.gov, NCT03874884)","url":"https://clinicaltrials.gov/study/NCT03874884"},{"label":"Recent Advances in Radioligand Therapy: LuPARP recommended phase 2 dose results","url":"https://nuclide-hema.healthbooktimes.org/article/154290-recent-advances-in-radioligand-therapy"},{"label":"FPI-2265 and Olaparib for Patients With mCRPC (ClinicalTrials.gov, NCT06909825)","url":"https://clinicaltrials.gov/study/NCT06909825"}],"tags":["combination therapy","PARP","prostate"],"related":["radionuclide-parp-combination","pluvicto","olaparib","fpi-2265","sandhu-shahneen","prostate-mcrpc","lu-177","ac-225"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Adding the PARP inhibitor olaparib to lutetium-177-PSMA-617 will increase the objective response rate in metastatic castration-resistant prostate cancer compared with radioligand therapy alone, by converting radiation-induced DNA single-strand breaks into lethal double-strand breaks, without added toxicity that prevents patients completing a full course of treatment.","rationale":"177Lu-PSMA-617 predominantly causes DNA single-strand breaks repaired via PARP-dependent base excision repair; PARP inhibition is mechanistically expected to radiosensitise tumour cells by blocking this repair. The LuPARP phase 1 trial found the combination tolerable across ten olaparib dosing schedules with no dose-limiting toxicities, and reported PSA50 62% and PSA90 48% in an interim analysis of heavily pretreated patients, with median radiographic progression-free survival of 12.8 months at the recommended phase 2 dose — figures that compare favourably with historical 177Lu-PSMA-617 monotherapy series, though this was a single-arm study without a concurrent comparator.","test":"LuPARP (NCT03874884) has already generated phase 1 safety and preliminary activity data in a single-arm design; the next step is a randomised phase 2/3 trial of 177Lu-PSMA-617 with or without olaparib in metastatic castration-resistant prostate cancer, powered on radiographic progression-free survival, alongside the ongoing alpha-emitter analogue trial of FPI-2265 plus olaparib (NCT06909825).","maturity":"early-clinical","actor":"research","cost":"medium","horizonYears":5},{"id":"idea-ai-lesion-segmentation-dosimetry","kind":"idea","name":"AI segmentation to make voxel-level radioligand dosimetry practical at scale","aka":[],"tldr":"Working out how much radiation a patient's kidneys and tumours received after a radioactive treatment normally means a specialist spending hours tracing organ outlines by hand on a scan. Software that draws those outlines automatically using artificial intelligence can do the same job in minutes, making personalised dose tracking available everywhere, not just in a few specialist centres.","summary":"Personalised, voxel-level dosimetry after radioligand therapy requires segmenting organs and tumours on serial SPECT/CT or PET/CT scans, a step that traditionally takes a trained physicist or physician several hours per patient using manual contouring. Deep-learning segmentation models, typically convolutional neural networks such as U-Net or newer transformer architectures, have been developed to automate this step. A 2025 comparison of AI-based against fully manual kidney segmentation for single-time-point 177Lu-PSMA dosimetry, using 8 treatment cycles from 5 patients, found no statistically significant difference in mean absorbed dose between the two methods, with a Dice similarity coefficient of 0.898 between AI and manual contours, though the underlying kidney volumes did differ significantly between methods.\n\nA broader review of automated dosimetry pipelines reports that combining CNN-based organ segmentation with automated registration and dose-rate estimation can cut total per-patient processing time from 4-6 hours to 30-45 minutes, a 70-90% reduction, while achieving Dice similarity coefficients of 0.88-0.95 against expert manual contours for organ segmentation specifically. Performance for tumour lesion segmentation, as opposed to organ segmentation, is less mature: an external, held-out-centre test of an nnU-Net lesion segmentation model for PSMA PET/CT and post-therapy SPECT/CT reported lower Dice scores of 0.76-0.78, and the model's PET-derived tumour volume estimates were described as unstable in that external test.\n\nAn independent 2026 evidence review of AI in oncologic theranostics concludes that, despite this technical progress, no AI segmentation or dose-prediction model for PSMA or peptide receptor radionuclide therapy dosimetry has yet been validated in a prospective, multicentre trial demonstrating that AI-guided activity adaptation (continuing, delaying or stopping treatment based on the AI-derived dose) actually changes patient outcomes; the review explicitly calls this the priority next study for the field.","asOf":"2026-09-22","links":[{"label":"Single time-point kidney dosimetry in 177Lu-PSMA therapy: AI-based vs manual segmentation (2025)","url":"https://he01.tci-thaijo.org/index.php/bulletinAMS/article/view/279571"},{"label":"Radiomics and Artificial Intelligence in Radiotheranostics (PMC review, 2024)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10814892/"},{"label":"Towards Routine AI-Based PET/CT and SPECT/CT Lesion Segmentation and Tracking in PSMA Theranostics (arXiv, 2026)","url":"https://arxiv.org/abs/2603.22666"},{"label":"Artificial intelligence across oncologic theranostics: evidence review (Frontiers in Nuclear Medicine, 2026)","url":"https://www.frontiersin.org/journals/nuclear-medicine/articles/10.3389/fnume.2026.1935247/full"}],"tags":["artificial intelligence","dosimetry","segmentation"],"related":["radioligand-dosimetry","in-vivo-dosimetry","radiomics","mim-software","quantitative-imaging-biomarkers","lu-177"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Replacing manual contouring of organs and tumours on post-therapy SPECT/CT and PET/CT with deep-learning segmentation will cut per-patient dosimetry processing time from hours to minutes without a clinically meaningful loss of accuracy, making voxel-level personalised radioligand dosing practical to run routinely rather than only in specialist research centres.","rationale":"A direct comparison of AI-based versus manual kidney segmentation for 177Lu-PSMA dosimetry found no significant difference in mean absorbed dose (p=0.964) with Dice concordance of 0.898, and a broader review reports 70-90% reductions in total processing time using automated pipelines with Dice similarity of 0.88-0.95 for organ segmentation. However, tumour lesion segmentation specifically performs less well in external testing (Dice 0.76-0.78, unstable volume estimates in one held-out-centre study), and an independent 2026 evidence review states plainly that no prospective, multicentre, decision-impact trial has yet shown AI-guided dosing actually improves outcomes.","test":"A prospective, multicentre equivalence trial comparing AI-automated against expert-manual dosimetry-guided treatment decisions (continue, delay, or stop a treatment cycle) in patients receiving 177Lu-PSMA-617 or 177Lu-DOTATATE, with the primary endpoint being agreement between the AI and manual absorbed-dose estimates against a Monte Carlo reference standard, and a secondary endpoint of agreement in the resulting clinical decision, in roughly 100-150 patients across several centres.","maturity":"being-tested-at-scale","actor":"industry","cost":"small","horizonYears":4},{"id":"idea-alpha-after-adc","kind":"idea","name":"Alpha radioligands after ADC failure","aka":[],"tldr":"When ADCs against a surface protein stop working because the payload no longer kills, use the same protein to deliver radiation instead.","summary":"When ADCs against a surface protein stop working because the payload no longer kills, this idea uses the same protein to deliver radiation instead. Antigen often persists after ADC failure with resistance at the payload level, so a 225Ac- or 177Lu-labelled anti-TROP2 or anti-HER2 antibody would bypass efflux, TOP1 mutations and SLFN11 loss, and crossfire would cover antigen-heterogeneous neighbours. The test is a phase 1 of a HER2 or TROP2 radioimmunoconjugate in ADC-refractory breast cancer, with antigen PET selection and dosimetry. Speculative in maturity, it complements Payload-class switching as the rule for ADC sequencing and draws on radio-antibody and radio-ADC, targeted alpha therapy and TROP2 PET.","asOf":"2026-09-04","links":[],"tags":[],"related":["lu-177","ac-225"],"indications":[],"sections":[],"technologies":["radioimmunotherapy","targeted-alpha-therapy","trop2-pet"],"targets":["trop2","her2","b7h3"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"225Ac- or 177Lu-labelled anti-TROP2 or anti-HER2 antibodies produce responses in patients progressing on TROP2 or HER2 ADCs with retained antigen expression on PET.","rationale":"Radiation cytotoxicity is independent of drug efflux and payload-specific resistance; crossfire covers antigen-heterogeneous neighbours.","test":"Run a phase 1 of a HER2 or TROP2 radioimmunoconjugate in ADC-refractory breast cancer with antigen PET selection and dosimetry.","maturity":"speculative"},{"id":"idea-alpha-first-mhspc","kind":"idea","name":"Alpha-emitting PSMA therapy at first metastatic diagnosis","aka":[],"tldr":"If Pluvicto helps at first diagnosis, an alpha version might do more against microscopic disease, when tumour burden is smallest.","summary":"This speculative idea would give alpha-emitting PSMA therapy with actinium-225 at the first metastatic diagnosis of hormone-sensitive prostate cancer, alongside hormone therapy. Short-range alpha emission suits small-volume disease and is oxygen-independent, and early treatment avoids the PSMA heterogeneity of castration resistance; PSMAddition established beta-emitter therapy here. The hypothesis is deeper PSA nadirs and longer radiographic progression-free survival than lutetium-177 PSMA-617 at equal or lower salivary dose; salivary toxicity and actinium-225 supply are limiting. The test is a randomised phase 2 with PSMA PET-based dosimetry, salivary gland protection and the undetectable-PSA rate at one year as primary endpoint.","asOf":"2026-09-06","links":[{"label":"ClinicalTrials.gov NCT04720157: PSMAddition","url":"https://clinicaltrials.gov/study/NCT04720157"}],"tags":[],"related":["lu-177","ac-225"],"indications":["prostate"],"sections":[],"technologies":["targeted-alpha-therapy","radioligand-therapy"],"targets":[],"drugs":["ac225-psma","pluvicto"],"companies":[],"institutions":[],"pathways":[],"terms":["alpha-vs-beta","dosimetry"],"trials":["psmaddition"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"225Ac-PSMA added to ADT + ARPI in high-volume de novo mHSPC produces deeper PSA nadirs and longer rPFS than 177Lu-PSMA-617 at equal or lower cumulative salivary dose.","rationale":"Short-range alpha emission suits small-volume disease; early treatment avoids PSMA heterogeneity that develops under castration resistance.","test":"Phase 2 randomised 225Ac-PSMA vs 177Lu-PSMA-617 in mHSPC with PSMA PET-based dosimetry, salivary gland protection, and undetectable-PSA rate at 12 months as primary.","maturity":"speculative"},{"id":"idea-alpha-for-oligometastatic-disease","kind":"idea","name":"Alpha-emitting PSMA therapy for oligometastatic (few-lesion) prostate cancer","aka":[],"tldr":"When prostate cancer comes back in just a handful of spots, doctors already zap those spots with precision radiotherapy. Adding a single dose of an alpha-particle radioactive drug at the same time, instead of the more established beta-particle version, might mop up cancer cells too small to see on a scan, because alpha radiation travels a much shorter distance and hits harder in that short range.","summary":"Oligorecurrent prostate cancer, typically defined as one to five metastatic lesions visible on PSMA PET after initial treatment, is increasingly treated with metastasis-directed stereotactic body radiotherapy (SBRT) to the visible spots, sometimes combined with a radioligand. Beta-emitting 177Lu-PSMA-I&T has already been tested as monotherapy in this setting: the randomised BULLSEYE trial (NCT04443062, 58 patients) compared two cycles of 177Lu-PSMA-I&T against standard-of-care deferred hormone therapy in oligometastatic hormone-sensitive disease. Alpha emitters have a much shorter particle range (tens to about 100 micrometres versus roughly a millimetre for lutetium-177's beta particles), which is physically well suited to killing scattered single cells or micrometastases invisible on the pre-treatment scan, but this physical argument has not yet been tested head-to-head against beta therapy in oligometastatic disease.\n\nThat direct comparison is now the subject of an open randomised trial: ANDROMEDA (NCT07150715, UCLA, led by Amar Kishan) randomises patients with one to five oligorecurrent lesions to either two cycles of 177Lu-PSMA-617 plus SBRT or a single cycle of 225Ac-PSMA-617 plus SBRT, with progression-free survival at 24 months (defined by PSMA PET/CT or biochemical progression) as the primary comparison. Separately, the ACCEL trial (NCT06229366) is testing a next-generation alpha ligand, 225Ac-PSMA-62 (LY4181530), specifically designed with a different linker to reduce the xerostomia and marrow toxicity associated with first-generation 225Ac-PSMA-617 or 225Ac-PSMA-I&T, in both oligometastatic hormone-sensitive and castration-resistant cohorts.\n\nNo trial has yet reported a comparative result between alpha- and beta-emitter approaches in oligometastatic disease; the rationale rests on radiobiological principles and on a strong first-generation alpha-emitter side-effect profile (particularly xerostomia) that newer ligands like PSMA-62 aim to address.","asOf":"2026-09-22","links":[{"label":"ANDROMEDA: Alpha- or Beta-Emitting Radionuclide With Metastasis-Directed SBRT for Recurrent Oligometastatic Prostate Cancer (ClinicalTrials.gov, NCT07150715)","url":"https://clinicaltrials.gov/study/NCT07150715"},{"label":"ANDROMEDA (NCI trial listing)","url":"https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2025-05583"},{"label":"ACCEL: Ac-225-PSMA-62 phase Ia/Ib/II trial in oligometastatic and castration-resistant prostate cancer (ASCO abstract, 2025)","url":"https://ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.TPS282"},{"label":"Lutetium-177-PSMA-I&T as metastases-directed therapy in oligometastatic hormone-sensitive prostate cancer (BULLSEYE, BMC Cancer, 2020)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7490874/"}],"tags":["alpha therapy","oligometastatic","prostate"],"related":["ac225-psma","pluvicto","oligometastatic","idea-psma-pet-guided-mdt","lu-177","ac-225"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Treating oligometastatic (one-to-five lesion) recurrent prostate cancer with a single dose of an alpha-emitting PSMA radioligand alongside stereotactic body radiotherapy to each visible lesion will control disease for longer than the same regimen using the beta-emitter lutetium-177-PSMA-617, because the alpha particle's short range concentrates a lethal dose in micrometastases that are below the resolution of the pre-treatment scan.","rationale":"The rationale is grounded in the established physical difference between alpha and beta emitters (alpha's roughly 100-micron range is a better physical match for single cells and micrometastases than beta's roughly 1 mm range), but no completed clinical trial has yet compared the two approaches in oligometastatic disease. The randomised ANDROMEDA trial (NCT07150715) is specifically designed to test this comparison directly, and the BULLSEYE trial already established that beta-emitter 177Lu-PSMA-I&T monotherapy alone can be tested against standard of care (deferred androgen deprivation) in this setting, providing the methodological precedent.","test":"ANDROMEDA (NCT07150715), an open, randomised phase 2 trial at UCLA comparing two cycles of 177Lu-PSMA-617 plus SBRT against a single cycle of 225Ac-PSMA-617 plus SBRT in patients with one to five oligorecurrent lesions, with 24-month progression-free survival (by PSMA PET/CT or biochemical progression) as the primary comparison.","maturity":"early-clinical","actor":"research","cost":"medium","horizonYears":6},{"id":"idea-open-dosimetry-data-commons","kind":"idea","name":"An open data commons linking patient-level radiopharmaceutical dosimetry to outcomes","aka":[],"tldr":"Every hospital that treats patients with radioactive drugs measures how much radiation reached the tumour and healthy organs, but this data mostly stays locked in each hospital's own files. A shared, public library pooling that dosimetry data, with patient outcomes, would let researchers everywhere build and test better dosing rules, especially smaller centres that don't see enough patients alone.","summary":"Two open resources already exist but neither covers what is missing. OpenDose is a collaboration of 18 international teams that provides freely downloadable specific absorbed fractions and S-values for 1,252 radionuclides, generated and cross-checked using six different Monte Carlo radiation-transport codes; this is foundational physics reference data (how radiation deposits in standard geometries), not patient-level dosimetry from real treatments. The Cancer Imaging Archive (TCIA), and the NCI Imaging Data Commons that ingests it alongside other sources, hosts large public collections of clinical cancer imaging, including some radiotherapy dose and structure sets, under Creative Commons licences, but there is no dedicated TCIA-style collection pairing diagnostic and post-therapy radiopharmaceutical images with per-patient organ- and tumour-absorbed-dose calculations and clinical outcomes.\n\nThe practical consequence is that dose-response findings such as the LUMEN, LUTADOSE and University of Wisconsin dosimetry series described elsewhere in this graph are each built and validated on single-centre cohorts of a few dozen patients, because no shared, pooled, patient-level dataset exists to train or externally validate a dose-response or dose-toxicity model across institutions. This also limits how AI segmentation and dose-prediction models (see the AI dosimetry idea in this graph) can be externally validated, since most reported models are trained and tested within one centre's data.\n\nNo dedicated, open, patient-level radiopharmaceutical dosimetry-and-outcomes commons was found in this research; this is an idea rather than a project already under way, distinct from the isotope-supply observatory idea already in this graph, which tracks production and shortage data rather than dosimetry-and-outcome data.","asOf":"2026-09-22","links":[{"label":"OpenDose: open-access resources for radiopharmaceutical dosimetry","url":"https://www.opendose.org/"},{"label":"OpenDose: Open-Access Resource for Nuclear Medicine Dosimetry (Journal of Nuclear Medicine, PMC)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7539649/"},{"label":"Access the Data — The Cancer Imaging Archive (TCIA)","url":"https://www.cancerimagingarchive.net/access-data/"},{"label":"Imaging Data Commons (NCI Cancer Research Data Commons)","url":"https://datacommons.cancer.gov/repository/imaging-data-commons"}],"tags":["open data","dosimetry","data sharing"],"related":["tcia","radioligand-dosimetry","idea-reg-isotope-supply-observatory","idea-ai-lesion-segmentation-dosimetry"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"A shared, open repository of patient-level radiopharmaceutical dosimetry data (organ and tumour absorbed doses linked to clinical outcomes, pooled across treating centres) would let smaller nuclear medicine departments and AI developers build and externally validate dose-response and dose-toxicity models that no single centre currently has enough patients to construct or test alone.","rationale":"OpenDose demonstrates that an international, multi-team collaboration can successfully build and maintain a shared, open dosimetry resource, but its content is Monte Carlo reference physics data rather than patient-level clinical dosimetry. TCIA and the NCI Imaging Data Commons demonstrate that open, licensed sharing of clinical imaging data at scale is technically and legally workable, but no collection there currently pairs radiopharmaceutical dosimetry with clinical outcomes. The gap this idea addresses is the absence of any open resource combining these two proven capabilities for radioligand therapy specifically.","test":"A pilot data-sharing consortium of 5-10 treating centres pooling de-identified post-therapy SPECT/CT or PET/CT dosimetry data and matched clinical outcomes for patients treated with 177Lu-PSMA-617 or 177Lu-DOTATATE into a common, versioned schema, hosted alongside or modelled on TCIA, with success measured by whether a dose-response or dose-toxicity model trained on the pooled data from most centres externally validates against data from a held-out centre not used in training.","maturity":"speculative","actor":"data","cost":"small","horizonYears":5},{"id":"idea-bispecific-radioligands","kind":"idea","name":"Bispecific PSMA/GRPR radioligands for discordant prostate cancer lesions","aka":[],"tldr":"Not every prostate cancer cell carries the same marker: some show the PSMA protein that most scans target, others show a different marker called GRPR instead. A single tracer molecule built to stick to both markers at once could find and treat tumours that a PSMA-only or GRPR-only scan would miss.","summary":"PSMA and GRPR expression in prostate cancer are complementary rather than fully overlapping: GRPR tends to be higher in earlier, lower-grade disease and PSMA in more advanced disease, and a head-to-head comparison of 68Ga-PSMA-11 and 68Ga-RM2 (a GRPR ligand) PET found broadly similar overall detection rates but each tracer found lesions the other missed. This has motivated development of bispecific 'heterodimer' molecules that carry both a PSMA-binding urea-based inhibitor and a GRPR-binding bombesin-analogue peptide on a single scaffold, so that a lesion expressing either receptor (or both) would be detected or treated.\n\nSeveral such heterodimers have been synthesised and tested in mouse models. A DUPA-RM26 heterodimer (NOTA-DUPA-RM26) showed high affinity and specific binding to both PSMA-positive and GRPR-positive cell lines with only moderate affinity loss compared with the individual monomers; a related iPSMA-BN heterodimer reached a first-in-human PET imaging study reporting specific uptake in the pancreas (GRPR-expressing) and salivary glands (PSMA-expressing) of healthy volunteers; and a 2024 paper reported a DOTA-conjugated heterodimer combining PSMA-617 and the GRPR antagonist RM2, labelled with both gallium-68 and lutetium-177, which showed dual-receptor tumour targeting, faster pharmacokinetics and lower kidney uptake than either parent compound alone in mouse xenografts.\n\nDespite this preclinical progress, two independent reviews (2020 and 2025) both state that none of the described PSMA/GRPR bispecific radioligands has yet been evaluated in a clinical trial in patients; the concept remains preclinical, distinct from the closely related but separately developed GRPR-only and PSMA-only radioligands already in clinical use or trials.","asOf":"2026-09-22","links":[{"label":"Bispecific Radioligands (BRLs): Two Is Better Than One (PMC review, 2025)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12386959/"},{"label":"Current State of Radiolabeled Heterobivalent Peptidic Ligands in Tumor Imaging and Therapy (MDPI review, 2020)","url":"https://www.mdpi.com/1424-8247/13/8/173"},{"label":"Synthesis and Preclinical Evaluation of a Bispecific PSMA-617/RM2 Heterodimer (PMC, 2024)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11571012/"},{"label":"Gastrin Releasing Peptide Receptors-targeted PET imaging in prostate cancer (Erasmus MC review)","url":"https://pure.eur.nl/ws/portalfiles/portal/150811942/1-s2.0-S1556859824000191-main.pdf"}],"tags":["bispecific","prostate","molecular imaging"],"related":["psma","grpr","psma-pet","ga-68","lu-177"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"A single small-molecule radioligand that binds both PSMA and GRPR will detect and, in a therapeutic form, treat more prostate cancer lesions than a PSMA-only or GRPR-only agent, because it captures tumours regardless of which receptor they predominantly express, including cases with discordant single-tracer PET results.","rationale":"PSMA and GRPR expression patterns in prostate cancer are complementary across disease stages, and a head-to-head PET comparison found each single-target tracer detected lesions the other missed, supporting the rationale for a dual-target agent. Multiple PSMA/GRPR heterodimers have shown dual-receptor binding, tumour uptake and favourable biodistribution in mouse xenograft models, including one first-in-human imaging study of a related heterodimer in healthy volunteers, but two independent reviews confirm that no PSMA/GRPR bispecific radioligand has yet been tested in cancer patients.","test":"A first-in-human phase 0/1 imaging study of a PSMA/GRPR bispecific PET tracer in patients with biochemically recurrent prostate cancer and known discordant single-tracer PSMA and GRPR PET results, roughly 20-30 patients, comparing lesion detection rate against same-patient single-target PSMA and GRPR PET scans, as the precursor step before testing a therapeutic bispecific ligand.","maturity":"preclinical-evidence","actor":"research","cost":"medium","horizonYears":9},{"id":"idea-reg-yb176-enrichment-capacity","kind":"idea","name":"Build Western ytterbium-176 enrichment so lutetium-177 has more than one supplier","aka":[],"tldr":"The lutetium used in approved prostate and neuroendocrine cancer treatments is made from an enriched metal that comes mostly from Russia. Making it elsewhere would secure supply.","summary":"No-carrier-added lutetium-177 is produced by irradiating enriched ytterbium-176, most of which has historically come from Russian electromagnetic separators. Demand is rising steeply with Pluvicto, Lutathera and pipeline radioligands. Several companies (ASP Isotopes, ITM, SHINE and others) are developing laser or centrifuge enrichment in North America and Europe. The proposal is an advance market commitment by health systems and manufacturers to buy a guaranteed volume of Western-enriched ytterbium-176 at a floor price for ten years, with a strategic buffer stock, mirroring how vaccine advance commitments created capacity.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Manufacturing cost and time for living and radioactive medicines): Hernandez, Prasad & Gellad, Total costs of chimeric antigen receptor T-cell immunotherapy (JAMA Oncology 2018)","url":"https://doi.org/10.1001/jamaoncol.2018.0977"}],"tags":[],"related":["lu-177"],"indications":[],"sections":[],"technologies":["radioligand-therapy"],"targets":[],"drugs":["pluvicto","lutathera"],"companies":["itm","novartis"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-manufacturing-cell-therapy"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Advance commitments bring at least two non-Russian enrichment facilities to commercial output within four years, supplying more than half of global ytterbium-176 demand, and lutetium-177 supply interruptions to clinics fall to zero.","rationale":"Enrichment is a capital-intensive, low-margin step whose investors need demand certainty; the clinical demand is now visible and growing, and geopolitical risk to a single-source supply chain is evident.","test":"Model demand to 2035 with the major radioligand producers, structure a joint offtake agreement, and measure delivered enrichment capacity and supply-interruption reports over five years.","maturity":"early-clinical","actor":"industry","cost":"large","horizonYears":4},{"id":"idea-caix-theranostics","kind":"idea","name":"CAIX theranostics: 89Zr-girentuximab PET and 177Lu/225Ac-girentuximab therapy","aka":[],"tldr":"Almost every clear-cell kidney cancer carries the CAIX protein. Image it with one radioactive antibody, then treat with the same antibody carrying a therapeutic isotope.","summary":"Nearly every clear-cell renal cell carcinoma expresses carbonic anhydrase IX as a direct consequence of VHL loss, so the antigen is near-universal and stable. This theranostic idea images it with 89Zr-girentuximab PET, validated for diagnosis in ZIRCON, and then treats with the same antibody carrying 177Lu for beta emission or 225Ac for targeted alpha therapy. The rationale combines a stable target, the PSMA precedent in prostate cancer, and radiation-induced immunogenic cell death in a cancer that already responds to immunotherapy. STARLITE-1 and STARLITE-2 are testing 177Lu-girentuximab with nivolumab or cabozantinib, and the proposed test is a randomised phase 2 of 177Lu-girentuximab plus nivolumab versus nivolumab alone; Telix Pharmaceuticals is the linked company.","asOf":"2026-09-07","links":[{"label":"Shuch et al., ZIRCON: 89Zr-girentuximab PET-CT imaging of clear-cell renal cell carcinoma (Lancet Oncology 2024)","url":"https://doi.org/10.1016/S1470-2045(24)00402-9"}],"tags":[],"related":["zr-89","lu-177","ac-225"],"indications":["rcc"],"sections":[],"technologies":["caix-pet","radioligand-therapy","targeted-alpha-therapy","radioimmunotherapy"],"targets":[],"drugs":[],"companies":["telix"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"177Lu- or 225Ac-girentuximab produces objective responses in ≥25% of heavily pretreated clear-cell RCC patients selected by CAIX PET, and synergises with PD-1 blockade.","rationale":"Stable antigen, theranostic pairing proven in prostate cancer (PSMA), and radiation-induced immunogenic cell death in an immunotherapy-responsive tumour.","test":"Randomised phase 2 of 177Lu-girentuximab + nivolumab vs nivolumab after IO-TKI progression, PET-selected.","maturity":"early-clinical"},{"id":"idea-cd8-pet-io","kind":"idea","name":"CD8 PET to stop or switch immunotherapy early","aka":[],"tldr":"Scan for T cells inside the tumour a few weeks after starting immunotherapy. If they have not arrived, change course.","summary":"Scan for T cells inside the tumour a few weeks after starting immunotherapy, and change course if they have not arrived. Tracers such as 89Zr-crefmirlimab, a CD8 minibody, and 18F-AraG image T-cell infiltration and activation, and an early increase has tracked response in phase 2 studies. Response to checkpoint blockade requires T-cell infiltration, CT changes lag by months and pseudoprogression confounds RECIST, so an absent CD8 PET signal at week 4 could identify non-responders early. The test is a prospective trial in NSCLC or melanoma with week-4 CD8 PET, randomising PET non-responders to continue or switch. At early-clinical maturity it addresses the bottleneck No one can predict who responds to immunotherapy.","asOf":"2026-09-04","links":[{"label":"Farwell et al., CD8-targeted PET imaging of tumour-infiltrating T cells in patients with cancer: a phase 1 first-in-human study of 89Zr-Df-IAB22M2C (Journal of Nuclear Medicine 2021)","url":"https://doi.org/10.2967/jnumed.121.262485"}],"tags":[],"related":["f-18","zr-89"],"indications":[],"sections":[],"technologies":["immuno-pet"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Absence of CD8 PET increase at week 4 identifies non-responders with >85% specificity, enabling early switch to alternative therapy.","rationale":"Response to checkpoint blockade requires T-cell infiltration; CT changes lag by months; pseudoprogression confounds RECIST.","test":"Run a prospective trial in NSCLC or melanoma with week-4 CD8 PET; randomise PET-non-responders to continue vs switch.","maturity":"early-clinical"},{"id":"idea-net-dosimetry-prrt","kind":"idea","name":"Dosimetry-personalised PRRT instead of four fixed cycles","aka":[],"tldr":"Measure the radiation each patient's tumour and kidneys actually absorb and adjust the number and size of doses, instead of giving everyone four identical cycles.","summary":"The idea is to personalise peptide receptor radionuclide therapy with lutetium-177 dotatate or 177Lu-edotreotide by measuring the radiation each patient's tumour, kidneys and marrow actually absorb on SPECT/CT after each cycle, and adjusting the number and size of doses. The standard of 7.4 GBq for four cycles leaves many patients under-dosed relative to renal and marrow limits, uptake varies widely, and retrospective dosimetry shows tumour absorbed dose correlates with response. The hypothesis is that dosimetry-guided PRRT raises cumulative tumour dose and response rate without exceeding organ limits. The test is a randomised phase 2 of individualised versus fixed activity; P-PRRT in Canada is already testing this, and the idea addresses the wrong-doses bottleneck.","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT03049189: COMPETE","url":"https://clinicaltrials.gov/study/NCT03049189"}],"tags":[],"related":["lu-177"],"indications":["neuroendocrine"],"sections":[],"technologies":["prrt","spect"],"targets":[],"drugs":["lutathera","itm-11"],"companies":[],"institutions":[],"pathways":[],"terms":["dosimetry"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Dosimetry-guided PRRT increases cumulative tumour dose and response rate without exceeding renal/marrow limits, versus fixed dosing.","rationale":"Wide inter-patient variation in uptake; SPECT/CT after each cycle makes dosimetry feasible.","test":"Randomised phase 2 of individualised vs fixed activity with ORR and PFS endpoints.","maturity":"early-clinical"},{"id":"idea-fap-theranostics-pancancer","kind":"idea","name":"FAP theranostics as a pan-cancer stromal strategy","aka":[],"tldr":"Instead of finding a different target for each cancer, hit the scaffolding cells that almost all solid tumours share.","summary":"Rather than finding a different target for each cancer, this idea hits the cancer-associated fibroblasts that almost all solid tumours share. FAP-targeted alpha or beta radioligands such as FAP-2286 would be given to FAPI-PET-avid pancreatic, gastric and sarcoma patients irrespective of tumour-cell genotype, delivering radiation to the stroma with crossfire into adjacent tumour cells and depleting the fibroblasts that exclude T cells. Stroma is genetically stable, so resistance mutations are not expected. The test is phase 2 FAP-2286 cohorts selected by FAPI PET, with paired biopsies and a PD-1 combination in pancreatic cancer. At early-clinical maturity it addresses the bottleneck Cold tumours and the immunosuppressive microenvironment.","asOf":"2026-09-04","links":[{"label":"Kratochwil et al., 68Ga-FAPI PET/CT: tracer uptake in 28 different kinds of cancer (Journal of Nuclear Medicine 2019)","url":"https://doi.org/10.2967/jnumed.119.227967"}],"tags":[],"related":[],"indications":[],"sections":[],"technologies":["fapi-pet","radioligand-therapy","targeted-alpha-therapy"],"targets":["fap"],"drugs":["fap-2286"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"FAP-targeted alpha or beta radioligands produce disease control in FAPI-PET-avid pancreatic, gastric, and sarcoma patients irrespective of tumour-cell genotype, and sensitise to immunotherapy by depleting immunosuppressive fibroblasts.","rationale":"Stroma is genetically stable (no resistance mutations); crossfire range of 177Lu (2 mm) covers adjacent tumour cells; CAF depletion relieves T-cell exclusion.","test":"Phase 2 FAP-2286 cohorts with FAPI PET selection and paired biopsies for CAF depletion and T-cell infiltration; combination with PD-1 in pancreatic cancer.","maturity":"early-clinical"},{"id":"idea-fap-theranostics-sarcoma","kind":"idea","name":"FAP-targeted radioligand therapy for sarcoma","aka":[],"tldr":"Sarcomas, a group of rare and hard-to-treat cancers, often carry a marker called FAP not just on the supporting tissue around the tumour but on the cancer cells themselves. A radioactive drug built to find FAP is being tried as a treatment, but the small studies done so far disagree about whether it actually shrinks tumours.","summary":"Fibroblast activation protein (FAP) is usually found on the stromal cells surrounding a tumour rather than on cancer cells directly, which limits how selective a FAP-targeted therapy can be, but sarcomas are one of the few cancer types where the tumour cells themselves can express FAP. 68Ga-FAPI PET has shown superior lesion detection compared with 18F-FDG PET across multiple sarcoma subtypes in prospective imaging cohorts, making FAP an attractive target for a therapeutic radioligand in a disease with essentially no PSMA or somatostatin-receptor expression to exploit.\n\nThe handful of early-phase therapeutic studies published so far give a mixed signal. A 5-patient pilot study of 177Lu-FAPI-2286 in metastatic sarcoma reported partial response in 4 of 5 patients by RECIST, with a 52% mean reduction in primary tumour volume. A separate, later 6-patient exploratory study of the same drug in metastatic sarcoma found no RECIST partial or complete responses at all, only stable disease in some patients (with mixed results by other volumetric metrics), a median overall survival of just 4 months, and 3 of 6 patients dying during follow-up. A first-in-human dose-escalation trial of a related FAP ligand, 177Lu-FAPI-XT (NCT06211647/NCT06197139, 14 patients across several tumour types including fibroblastic sarcoma subtypes), found an overall disease control rate of 35.7%, rising to 50% in the sarcoma subtypes specifically, but no complete or partial responses in the whole cohort, alongside a favourable safety profile with no dose-limiting toxicity up to 11.1 GBq. Separately, the Novartis-sponsored LuMIERE trial (NCT04939610) is testing 177Lu-FAP-2286 in pancreatic, non-small-cell lung and breast cancer, not specifically in sarcoma.\n\nThese are all small, uncontrolled, single-arm case series (5-14 patients each) with conflicting response rates, so whether FAP-targeted radioligand therapy has genuine, reproducible activity in sarcoma, and if so in which histological subtypes, remains unresolved.","asOf":"2026-09-22","links":[{"label":"Feasibility and therapeutic potential of [177Lu]Lu-FAPI-2286 in patients with advanced metastatic sarcoma (EJNMMI, 2024)","url":"https://pubmed.ncbi.nlm.nih.gov/39060377/"},{"label":"Safety and efficacy of 177Lu-FAPI-XT radioligand therapy in advanced sarcoma and other cancer entities: first-in-human, dose-escalation study (EJNMMI, 2026)","url":"https://pubmed.ncbi.nlm.nih.gov/41087606/"},{"label":"Theranostics in Sarcoma: A Critical Review of Current Evidence and Future Directions (2026 review)","url":"https://link.springer.com/content/pdf/10.1007/s11864-026-01386-0.pdf"},{"label":"A Study of 177Lu-FAP-2286 in Advanced Solid Tumors (LuMIERE) (ClinicalTrials.gov, NCT04939610)","url":"https://clinicaltrials.gov/study/NCT04939610"}],"tags":["FAP","sarcoma","theranostics"],"related":["fap","fap-2286","fapi-pet","idea-fap-theranostics-pancancer","f-18","ga-68","lu-177"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Because sarcoma tumour cells, unlike most other cancers, can themselves express fibroblast activation protein, targeting FAP with a therapeutic radioligand will produce meaningful and reproducible disease control in advanced sarcoma, a cancer type with almost no PSMA or somatostatin-receptor expression to exploit with existing radioligand therapies.","rationale":"68Ga-FAPI PET reliably detects more sarcoma lesions than 18F-FDG PET, establishing that FAP is a genuine, targetable marker in this disease. However, the three published or presented therapeutic case series (5, 6 and 14 patients respectively) give conflicting results: one reported 4/5 partial responses, another reported zero objective responses with a 4-month median overall survival in a similar 6-patient cohort, and a third reported disease control (mostly stable disease) in half of its sarcoma subtype patients but no objective responses at all. This inconsistency across small, uncontrolled series means the true response rate and the subtypes most likely to benefit (solitary fibrous tumour and myofibroblastic sarcoma showed the most disease control in the dose-escalation study) are not yet established.","test":"A larger, prospective phase 2 basket trial of a FAP-targeted radioligand (such as 177Lu-FAPI-2286 or 177Lu-FAPI-XT) restricted to FAP-PET-selected sarcoma patients, ideally enriched for the subtypes (solitary fibrous tumour, myofibroblastic sarcoma) that showed the most disease control in the dose-escalation series, roughly 40-60 patients, with RECIST objective response rate and progression-free survival as endpoints, to resolve the conflicting signal from the existing small case series.","maturity":"early-clinical","actor":"research","cost":"medium","horizonYears":7},{"id":"idea-mced-plus-fapi","kind":"idea","name":"FAPI PET as the workup for MCED positives","aka":[],"tldr":"When a blood test says 'cancer signal, origin unclear', a FAPI PET scan may find it where FDG cannot.","summary":"When a blood test reports a cancer signal of unclear origin, this idea sends the patient for FAPI PET/CT rather than FDG PET as the first-line work-up. Many MCED-positive patients have no cancer found on standard imaging, which creates anxiety and cost, whereas FAPI PET is more sensitive than FDG in pancreatic, gastric, low-grade and peritoneal disease, exactly the cancers MCED promises to catch, and has low background in liver, brain and bowel. The test is a prospective diagnostic study nested in a Galleri deployment such as the NHS or a PATHFINDER-like cohort, randomising FDG versus FAPI PET. Speculative in maturity, it addresses the bottleneck The hardest cancers are found late and is linked from the ideas on a 28-day MCED-positive resolution pathway and whole-population interception.","asOf":"2026-09-04","links":[{"label":"PATHFINDER: the first prospective test of a multi-cancer blood test in people without symptoms (The Lancet 2023)","url":"https://doi.org/10.1016/S0140-6736(23)01700-2"}],"tags":[],"related":[],"indications":[],"sections":[],"technologies":["fapi-pet","fdg-pet"],"targets":["fap"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"FAPI PET/CT increases the cancer detection rate and reduces time to diagnosis in MCED-positive, FDG-negative or tissue-of-origin-uncertain patients.","rationale":"Complementary biology (stroma vs glucose); FAPI has low background in liver, brain, and bowel.","test":"Prospective diagnostic study nested in a Galleri deployment (e.g., NHS or PATHFINDER-like) randomising FDG vs FAPI PET as first-line workup.","maturity":"speculative"},{"id":"idea-reg-alpha-emitter-portfolio","kind":"idea","name":"Fund alpha emitters beyond actinium-225: lead-212, terbium-149 and astatine-211","aka":[],"tldr":"Almost every alpha cancer therapy in development relies on one scarce isotope. Developing several alternatives at once would stop the whole field waiting on a single supply chain.","summary":"Actinium-225 dominates targeted alpha therapy pipelines, but lead-212 (from thorium-228/radium-224 generators, used by Orano Med and Perspective Therapeutics), astatine-211 (cyclotron-produced, short half-life, suited to regional supply) and terbium-149 have complementary properties and independent supply routes. The proposal is a public-private programme that funds isotope-agnostic chelator and linker chemistry, comparative dosimetry and small head-to-head clinical studies so that a given targeting ligand can be paired with whichever alpha emitter is available, and that de-risks generator and cyclotron capacity for each.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Manufacturing cost and time for living and radioactive medicines): Hernandez, Prasad & Gellad, Total costs of chimeric antigen receptor T-cell immunotherapy (JAMA Oncology 2018)","url":"https://doi.org/10.1001/jamaoncol.2018.0977"}],"tags":[],"related":["ac-225","pb-212","at-211","ra-224"],"indications":[],"sections":[],"technologies":["targeted-alpha-therapy"],"targets":[],"drugs":[],"companies":["orano-med","perspective-therapeutics"],"institutions":[],"pathways":[],"terms":["alpha-vs-beta"],"trials":[],"people":[],"bottlenecks":["b-manufacturing-cell-therapy"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Within five years at least two alpha emitters other than actinium-225 reach late-stage trials with GMP supply exceeding clinical demand, and the proportion of alpha therapy trials delayed by isotope supply falls below 10%.","rationale":"Diversifying supply has repeatedly been cheaper than expanding a single constrained route; lead-212 generators are already in clinical use and astatine-211 chemistry has matured at several centres.","test":"Award funding to three ligand programmes to produce matched actinium-225, lead-212 and astatine-211 versions and compare biodistribution, dosimetry and manufacturability in first-in-human studies.","maturity":"preclinical-evidence","actor":"philanthropy","cost":"large","horizonYears":5},{"id":"idea-regional-radiopharmacy-network","kind":"idea","name":"In-house hospital radiopharmacy compounding to cut dose waste","aka":[],"tldr":"Radioactive treatments lose strength every day as they travel from a central factory to the hospital, so by the time a dose arrives some of its power has decayed away. Installing compact, automated dose-preparation equipment inside individual hospitals, so they compound the treatment themselves from bulk material, could cut that wasted radioactivity and get treatment to more places.","summary":"Lutetium-177 decays with a roughly 6.6-day half-life, so every day a finished dose spends in transit from a centralised commercial manufacturer to a treating hospital is activity permanently lost, and the further a treatment centre is from that manufacturer, the more waste and scheduling risk it faces. An alternative model is for individual hospitals to compound doses themselves from bulk shipments of the raw isotope, using compact automated synthesis units designed to fit inside an existing hospital radiopharmacy hood. A 2025 paper describes one such unit, 'MiniLu', a cassette-based, self-contained radiosynthesis platform that achieved greater than 99% radiochemical purity and about 95% final dose yield for two PSMA-targeting therapeutic ligands, explicitly designed for hospital-resident compounding rather than centralised manufacturing.\n\nThis decentralisation is already happening at small scale in some markets: a 2026 market analysis reports that hospital radiopharmacy units in Mexico City, Monterrey and Guadalajara have grown from an estimated 3-5 to 8-12 sites capable of onsite GMP labelling since 2022, explicitly to reduce logistical waste from short-half-life lutetium-177, with domestically compounded lutetium-177 dotatate capturing an estimated 20-30% of treatment volume in that market. The joint EANM/SNMMI/IAEA guide to setting up a theranostics centre documents the radioactive-material licensing and radiation-safety steps a hospital needs to run in-house compounding.\n\nThis is a narrower, single-institution version of the regional cyclotron-hub policy idea already in this graph (a national or multi-country network of shared hubs); this idea is specifically about individual hospitals building their own point-of-care compounding capability, which trades a larger upfront capital and licensing cost per site for less dependence on shipping schedules and less decay-related waste. No controlled study quantifying the waste or access benefit of this decentralised model over centralised commercial dose manufacturing was found.","asOf":"2026-09-22","links":[{"label":"Optimization of the radiosynthesis of PSMA-targeting drugs using a cassette-based platform (MiniLu) (PMC, 2025)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12623512/"},{"label":"Peptide Receptor Radionuclide Therapy (PRRT) Market in Mexico (IndexBox market report, 2026)","url":"https://www.indexbox.io/store/mexico-peptide-receptor-radionuclide-therapy-prrt-market-analysis-forecast-size-trends-and-insights/"},{"label":"Joint EANM, SNMMI, and IAEA Enabling Guide: How to Set up a Theranostics Center (Journal of Nuclear Medicine)","url":"https://jnm.snmjournals.org/content/63/12/1836"},{"label":"The growth of radiotherapeutics: Addressing supply chain complexity (pharmaphorum, 2026)","url":"https://pharmaphorum.com/rd/growth-radiotherapeutics-addressing-supply-chain-complexity"}],"tags":["radiopharmacy","supply chain","access"],"related":["idea-reg-regional-radiopharmacy-hubs","radiopharmacy-network","radiopharmaceutical-gmp-release","therapy-isotope-supply-chain","lu-177"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Installing automated, hospital-resident radiopharmacy compounding units that prepare short-half-life doses (lutetium-177 or actinium-225 ligands) on demand from bulk isotope shipments will reduce dose waste from radioactive decay in transit and improve treatment access outside major metropolitan centres, compared with relying solely on centralised commercial dose manufacturing and next-day shipping.","rationale":"A described automated cassette-based synthesis unit ('MiniLu') demonstrates that hospital-hood-compatible, hospital-resident compounding of lutetium-177 PSMA ligands can achieve greater than 99% purity and about 95% yield, comparable to centralised manufacturing. Market data from Mexico show hospital radiopharmacy sites capable of onsite GMP labelling roughly doubling since 2022, explicitly to reduce Lu-177 decay waste, and now handling an estimated 20-30% of treatment volume in that market — real-world evidence the model is being adopted, though no controlled comparative study of waste reduction or access improvement was found.","test":"A controlled before/after study across a multi-site hospital system, comparing dose waste (activity discarded to decay or scheduling failures), turnaround time and patient access (drive time to nearest treatment site) before and after installing in-house automated compounding units at 3-5 hospitals, against a comparable set of hospitals continuing to rely on centralised commercial dose supply.","maturity":"early-clinical","actor":"industry","cost":"large","horizonYears":7},{"id":"idea-dosimetry-guided-dosing-standard","kind":"idea","name":"Kidney-dosimetry-guided dosing as the default for PSMA radioligand therapy","aka":[],"tldr":"Right now, most patients get the same number of treatment cycles at the same radioactive dose regardless of their own biology. Measuring how much radiation actually reaches each patient's kidneys after the first dose could let doctors safely give some patients more cycles and stop earlier in others, rather than using one fixed schedule for everyone.","summary":"The label dosing for lutetium-177 vipivotide tetraxetan (Pluvicto) is a fixed 7.4 GBq every six weeks for up to six cycles, as tested in the VISION trial, regardless of how much radiation an individual patient's kidneys, salivary glands or tumours actually receive. Dosimetry studies show this fixed approach leaves dose headroom in many patients: a single-institution series at the University of Wisconsin found that among 19 patients with post-cycle-one voxel-level SPECT/CT dosimetry, kidney and salivary gland absorbed doses tracked the VISION phase 3 benchmarks, and 15 of 19 patients could have safely received a seventh cycle and 18 of 19 an additional cycle based on a 24 Gy kidney and 20 Gy salivary gland threshold, while a smaller number needed early discontinuation or dose delay. In neuroendocrine tumour PRRT, the LUMEN and LUTADOSE studies found that tumour-absorbed dose measured after the first cycle predicts progression-free survival, reinforcing that a fixed four- or six-cycle schedule is a population average rather than a patient-specific optimum.\n\nSeveral trials are now testing personalised dosing directly rather than relying on retrospective series. FLEX-MRT (NCT06216249, UCLA, randomised phase 2, about 90 patients) compares a flexible, SPECT/CT-response-guided schedule of up to 12 cycles with treatment holidays against the standard fixed six-cycle regimen, with 2-year survival as the primary endpoint. PRODIGY-2 (NCT06943495, CHU de Québec) is testing whether renal-dosimetry-guided activity escalation is feasible and safe compared with the fixed-activity regimen. In neuroendocrine tumours, DOBATOC (NCT04917484) is a randomised phase 2 testing kidney-dose-governed individualised dosing (targeting a 24 Gy cumulative kidney dose) against fixed dosing, with progression-free survival as the primary outcome.\n\nThis proposal is deliberately broader than the existing dosimetry-personalised-PRRT idea already in this graph, which is specific to neuroendocrine tumours: the claim here is that dosimetry-guided dosing should become the default approach across radioligand therapies generally, including PSMA-targeted treatment, not just PRRT.","asOf":"2026-09-22","links":[{"label":"FLEX-MRT: Phase 2 Randomized Trial of Flexible Dosing Schedule of 177Lu-PSMA-617 (ClinicalTrials.gov, NCT06216249)","url":"https://clinicaltrials.gov/study/NCT06216249"},{"label":"PRODIGY-2: Personalized vs. Fixed-Activity 177Lu-PSMA-617 (ClinicalTrials.gov, NCT06943495)","url":"https://clinicaltrials.gov/study/NCT06943495"},{"label":"Personalized Dosimetry Guides 177Lu-PSMA-617 Therapy (conference coverage, University of Wisconsin series)","url":"https://www.hmpgloballearningnetwork.com/site/rpei/conference-coverage/personalized-dosimetry-guides-177lu-psma-617-therapy-prostate-cancer"},{"label":"Radioligand therapy and tumor dosimetry: where are we and where are we going? (2026 review)","url":"https://link.springer.com/article/10.1007/s40336-026-00769-5"},{"label":"VISION: 177Lu-PSMA-617 (ClinicalTrials.gov, NCT03511664)","url":"https://clinicaltrials.gov/study/NCT03511664"}],"tags":["dosimetry","personalised dosing","prostate"],"related":["idea-net-dosimetry-prrt","radioligand-dosimetry","pluvicto","vision","lu-177"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Replacing lutetium-177-PSMA-617's fixed six-cycle, fixed-activity regimen with a kidney-dosimetry-guided number of cycles and activity will let more patients safely receive additional beneficial cycles, and will identify others who should stop earlier, without exceeding organ-radiation-dose limits.","rationale":"A retrospective series of 19 patients found organ doses consistent with VISION trial benchmarks and identified that the great majority could have safely received extra cycles based on kidney and salivary gland dose thresholds. In neuroendocrine PRRT, the LUMEN and LUTADOSE studies independently found that cycle-one tumour-absorbed dose predicts progression-free survival, supporting the general principle that a fixed schedule under- or over-treats many patients. Multiple randomised trials (FLEX-MRT, PRODIGY-2, DOBATOC) are now directly testing personalised, dosimetry-guided dosing against fixed dosing; none has yet reported a mature result.","test":"FLEX-MRT (NCT06216249), an already-enrolling randomised phase 2 trial (approximately 90 patients) comparing a SPECT/CT-response-guided flexible dosing schedule of up to 12 cycles, including treatment holidays, against the standard fixed six-cycle regimen of 177Lu-PSMA-617, with 2-year survival as the primary endpoint; DOBATOC (NCT04917484) provides the analogous randomised test in neuroendocrine PRRT.","maturity":"being-tested-at-scale","actor":"research","cost":"medium","horizonYears":5},{"id":"idea-neoadjuvant-psma-therapy","kind":"idea","name":"Neoadjuvant PSMA radioligand therapy before prostatectomy","aka":[],"tldr":"For men with high-risk prostate cancer that hasn't spread yet, giving a dose or two of PSMA-targeted radioactive treatment before surgery, rather than only using it after the cancer has spread, might kill hidden cancer cells surgery alone would miss. It is still experimental and hasn't yet been shown to help patients live longer or avoid the cancer coming back.","summary":"Lutetium-177-PSMA-617 is approved for metastatic castration-resistant prostate cancer, but its combination of tumour-targeted radiation and imageable gamma emission has prompted interest in moving it earlier, to localised high-risk disease, on the theory that it could eliminate occult micrometastases before they become detectable. The LuTectomy trial (NCT04430192, Peter MacCallum Cancer Centre) tested this in 20 men with high-risk localised prostate cancer and high PSMA expression on PSMA PET, giving one cycle (10 patients) or two cycles (10 patients) of approximately 5 GBq 177Lu-PSMA-617 six weeks before robotic radical prostatectomy. The trial delivered a median tumour absorbed dose of 35.5 Gy across all lesions (19.6 Gy to the prostate), was well tolerated with no grade 3/4 toxicity, and did not compromise surgical safety; 45% of patients achieved a 50% or greater PSA decline, and 80% showed a partial histological response (stromal fibrosis, reduced tumour cell density), but no patient achieved a pathological complete response with a single or double cycle.\n\nBecause monotherapy did not achieve pathological complete responses, follow-on trials are testing combinations and longer regimens. The German NEPI trial (randomised, EudraCT 2021-004894-30, 46 patients) is comparing androgen deprivation therapy plus two cycles of 177Lu-PSMA-617 with or without the checkpoint inhibitor ipilimumab, with pathological complete response as a co-primary endpoint. In the United States, the PRELUDE trial (NCT06798558, Hackensack University Medical Center and others) is a phase 2 study giving two cycles of 177Lu-PSMA-617 before prostatectomy and following patients for two years for biochemical recurrence.\n\nNo trial has yet reported a survival, metastasis-free survival, or biochemical-recurrence benefit from this strategy, and neoadjuvant radioligand therapy is not recommended by any current guideline; a 2025 review explicitly states the approach 'does not yet have data to support any benefit' in these harder outcomes and remains investigational.","asOf":"2026-09-22","links":[{"label":"Administering [177Lu]Lu-PSMA-617 Prior to Radical Prostatectomy (LuTectomy): phase 1/2 study (European Urology, PubMed 2024)","url":"https://pubmed.ncbi.nlm.nih.gov/37891072/"},{"label":"Neoadjuvant 177Lutetium-PSMA-617 Radioligand Therapy for High-Risk Prostate Cancer (review, PMC 2025)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12563130/"},{"label":"Lu-177-PSMA-617 before Radical Prostatectomy (PRELUDE) (NCI trial listing, NCT06798558)","url":"https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2025-04728"}],"tags":["neoadjuvant","prostate","surgery"],"related":["pluvicto","prostate-high-risk","prostatectomy","idea-psma-pet-guided-mdt","lu-177"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Giving one or two cycles of lutetium-177-PSMA-617 before radical prostatectomy in men with high-risk localised prostate cancer will reduce micrometastatic disease burden and improve long-term biochemical-recurrence-free survival compared with prostatectomy alone, without making surgery less safe.","rationale":"The LuTectomy trial demonstrated that neoadjuvant 177Lu-PSMA-617 delivers substantial targeted radiation dose (median 35.5 Gy to lesions) with minimal toxicity and no impairment of surgical safety, and produced partial histological responses in 80% of patients, but achieved zero pathological complete responses with up to two cycles, showing monotherapy alone is probably insufficient. Whether the observed PSA declines and histological changes translate into fewer biochemical recurrences or better long-term survival is unverified; a 2025 review states this explicitly.","test":"The randomised NEPI trial (EudraCT 2021-004894-30, 46 patients), testing androgen deprivation plus 177Lu-PSMA-617 with or without ipilimumab with pathological complete response as a co-primary endpoint, and the US phase 2 PRELUDE trial (NCT06798558) following patients for two-year biochemical recurrence, are the next steps toward establishing whether this strategy has a genuine oncological benefit; a phase 3 trial with metastasis-free or overall survival as the primary endpoint would be required to change practice.","maturity":"early-clinical","actor":"research","cost":"medium","horizonYears":8},{"id":"idea-pretargeted-alpha-therapy","kind":"idea","name":"Pretargeted alpha radioimmunotherapy","aka":[],"tldr":"Instead of injecting a radioactive antibody that circulates in the blood for days, doctors first give a plain antibody that finds the tumour, wait for it to clear, then inject a small, fast-moving radioactive alpha payload that only attaches where the antibody is already waiting. This two-step trick could let radioactive antibodies treat solid tumours without poisoning the bone marrow.","summary":"Directly labelled antibodies carrying alpha emitters are attractive because alpha particles are extremely damaging over a very short range, but full-length antibodies circulate for days, so a directly labelled alpha antibody keeps irradiating blood and marrow long after most of it has left the tumour. Pretargeting separates the two steps: a bispecific antibody (one arm binds the tumour antigen, the other binds a small hapten) is given first and allowed to clear from circulation over hours to days, then a small radiolabelled hapten is injected and rapidly binds the antibody already sitting on the tumour, or clears from the body within hours if unbound.\n\nThe approach has a long clinical history with beta and gamma emitters going back over thirty years, including phase I/II trials of iodine-131 and lutetium-177 pretargeting in medullary thyroid cancer, small-cell lung cancer and CEA-positive colorectal cancer, but it has never reached market approval; a 2017 review notes that pretargeted lutetium-177/CEA trials in colorectal cancer were disappointing because tumour retention was too fast relative to lutetium-177's multi-day half-life. That mismatch is exactly why alpha emitters, most of which have half-lives of minutes to hours (bismuth-213, astatine-211), are now seen as a better fit for pretargeting's fast hapten kinetics. Preclinical proof of concept for alpha-pretargeting exists: a 2025 study from Memorial Sloan Kettering used a three-step regimen (anti-HER2/anti-DOTA bispecific antibody, a clearing agent, then actinium-225-labelled DOTA) to achieve complete responses in 20/20 HER2-positive breast cancer xenografts with tumour-to-kidney dose ratios of roughly 60:1 and no chronic nephrotoxicity at curative doses.\n\nNo alpha-emitter pretargeting regimen has yet been tested in patients; all current human experience with actinium-225 or bismuth-213 antibody therapy uses direct labelling (for example anti-CD33 225Ac antibodies in acute myeloid leukaemia).","asOf":"2026-09-22","links":[{"label":"225Ac alpha-pretargeted radioimmunotherapy of HER2-expressing breast cancer (J Nucl Med, 2025)","url":"https://jnm.snmjournals.org/content/early/2025/06/05/jnumed.125.269601"},{"label":"Pretargeting: A Path Forward for Radioimmunotherapy (PMC review)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12079710/"},{"label":"Pretargeting for imaging and therapy in oncological nuclear medicine (PMC, 2017)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC5824696/"}],"tags":["alpha therapy","antibody","pretargeting"],"related":["targeted-alpha-therapy","radioimmunotherapy","her2","ceacam5","lu-177","ac-225","i-131","bi-213","at-211"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"A three-step pretargeting regimen (bispecific antibody, clearing agent, then an alpha-emitting hapten) will achieve a substantially higher tumour-to-normal-tissue radiation dose ratio than directly labelled alpha-emitting antibodies, enabling curative-intent alpha radioimmunotherapy of solid tumours without dose-limiting marrow or kidney toxicity.","rationale":"Mechanistically, pretargeting decouples the antibody's slow blood clearance from the radioactive payload's fast clearance, which matters most for alpha emitters whose half-lives (minutes to hours) are far shorter than an antibody's circulation time. Preclinical 225Ac-pretargeted radioimmunotherapy against HER2-positive breast cancer achieved 100% complete response and roughly 60:1 tumour:kidney dose ratios in two xenograft models without chronic nephrotoxicity at curative doses (Cheal, Santich et al., J Nucl Med 2025). Decades of clinical pretargeting experience exist with beta and gamma emitters (iodine-131, lutetium-177), establishing the two-step logistics and bispecific-antibody dosing are feasible in patients, but those beta-emitter trials had disappointing tumour retention. No alpha-emitter pretargeting regimen has been tested clinically.","test":"A first-in-human phase 1 dose-escalation trial of a pretargeted alpha regimen (bispecific antibody plus clearing agent, then an actinium-225- or bismuth-213-labelled hapten) in patients with a refractory HER2-positive or CEA-positive solid tumour, roughly 20-30 patients, with safety/maximum tolerated dose as the primary endpoint and surrogate imaging-based tumour dosimetry as a key secondary endpoint.","maturity":"preclinical-evidence","actor":"research","cost":"large","horizonYears":10},{"id":"idea-psma-pet-guided-mdt","kind":"idea","name":"PSMA-PET-guided metastasis-directed therapy as a curative strategy in oligorecurrent prostate cancer","aka":[],"tldr":"When PSMA PET finds only a few spots after surgery, zap each spot with focused radiation and delay or avoid lifelong hormone therapy.","summary":"The idea is to use PSMA PET after prostate surgery to find the few sites of recurrence and treat each with stereotactic radiotherapy plus short-course androgen deprivation. The oligometastatic state is real in prostate cancer, the radiotherapy is ablative and cheap, and PSMA PET removes the staging blind spot that undermined older trials such as ORIOLE and STOMP. The hypothesis is better metastasis-free and ADT-free survival than systemic therapy alone, though whether it changes survival or merely postpones hormone therapy is unproven. The test is a randomised phase 3 with PSMA PET at baseline and progression and ctDNA as a stratifier; PEACE V/STORM and NRG GU011 are under way, so it is being tested at scale.","asOf":"2026-09-06","links":[{"label":"ORIOLE: observation versus stereotactic ablative radiation for oligometastatic prostate cancer (JAMA Oncology 2020)","url":"https://doi.org/10.1001/jamaoncol.2020.0147"}],"tags":[],"related":[],"indications":["prostate"],"sections":[],"technologies":["psma-pet"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["oligometastatic","biochemical-recurrence"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"PSMA-PET-directed SBRT to ≤5 metastases, with short-course ADT, improves metastasis-free and ADT-free survival versus systemic therapy alone in oligorecurrent disease.","rationale":"Oligometastatic state is real in prostate cancer; SBRT is ablative and cheap; PSMA PET removes the staging blind spot that undermined older trials.","test":"Randomised phase 3 with PSMA PET at baseline and progression, ADT-free survival and MFS endpoints, ctDNA and PSMA-PET total-volume as stratifiers.","maturity":"being-tested-at-scale"},{"id":"idea-tr2-psma-volume-qualification","kind":"idea","name":"Qualify PSMA PET tumour volume as a validated imaging biomarker","aka":[],"tldr":"PSMA scans could measure prostate cancer burden and response far better than PSA, but no one has done the standardisation work to make the measurement trustworthy across scanners.","summary":"Total PSMA-positive tumour volume and SUV metrics predict outcome in metastatic prostate cancer and response to radioligand therapy, but acquisition, reconstruction and segmentation vary between centres. A QIBA-style profile (phantom calibration, harmonised reconstruction, validated segmentation software) followed by biomarker qualification for defined contexts of use (prognosis, response assessment) would let PSMA volume be used as an endpoint and selection tool in trials.","asOf":"2026-09-08","links":[{"label":"RSNA QIBA","url":"https://www.rsna.org/research/quantitative-imaging-biomarkers-alliance"}],"tags":[],"related":["psma-pet-to-rlt","idea-total-body-pet-dosimetry"],"indications":["prostate"],"sections":[],"technologies":["psma-pet","pet-ct"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Harmonised PSMA volumetric measurements will achieve test-retest and inter-site coefficient of variation under 15% and will predict overall survival on radioligand therapy better than PSA response.","rationale":"FDG PET response criteria (PERCIST, Deauville) needed the same standardisation before adoption; PSMA PET is now widespread enough to justify it.","test":"A multi-centre phantom and test-retest study followed by retrospective validation on trial imaging from VISION and PSMAfore, then a qualification submission.","maturity":"early-clinical","actor":"research","cost":"medium","horizonYears":4},{"id":"idea-reg-legacy-radium-recovery-ac225","kind":"idea","name":"Recover legacy radium-226 sources worldwide as the feedstock for actinium-225","aka":[],"tldr":"Thousands of old radium sources sit in hospital and industrial storage. They are exactly the raw material needed to make actinium-225, the scarcest cancer isotope.","summary":"Actinium-225 supply from thorium-229 generators (the legacy US and Russian stockpiles) is limited to tens of curies a year, far short of projected demand for alpha radioligand therapy. Accelerator routes (radium-226 irradiated in cyclotrons, linacs or via spallation at TRIUMF) scale with radium feedstock. Radium-226 exists in large quantities in disused brachytherapy sources, industrial gauges and uranium mill tailings, currently classed as waste and expensive to store. The proposal is a coordinated recovery, purification and target-fabrication programme run with the IAEA and national nuclear agencies, offering source holders free disposal in exchange for the material.","asOf":"2026-09-08","links":[{"label":"IAEA on actinium-225 supply","url":"https://www.iaea.org/newscenter/news/actinium-225-production-and-supply"}],"tags":[],"related":["ac-225"],"indications":[],"sections":[],"technologies":["targeted-alpha-therapy","radioligand-therapy"],"targets":[],"drugs":["ac225-psma","ryz101"],"companies":["terrapower-isotopes","orano-med"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-manufacturing-cell-therapy"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Recovered radium-226 sufficient to supply multiple accelerator producers can be secured within five years at a cost per curie of actinium-225 below the thorium-generator route, lifting global actinium-225 output by an order of magnitude.","rationale":"Radium disposal is already a cost that source holders would pay to avoid, and purification chemistry is established. The binding constraint on the accelerator route is licensed feedstock, not physics.","test":"Inventory recoverable radium-226 in ten countries, run a pilot recovery of 50 grams with one accelerator producer, and price the resulting actinium-225 against current generator supply.","maturity":"early-clinical","actor":"policy","cost":"medium","horizonYears":4},{"id":"idea-reg-ac225-accelerator-pharmacopoeia","kind":"idea","name":"Regional cyclotron hubs for actinium-225 with an agreed actinium-227 impurity limit","aka":[],"tldr":"Actinium-225 can be made in particle accelerators, but the product contains a trace of a long-lived impurity that regulators have not agreed how to handle. Settle the limit and build the hubs.","summary":"Proton irradiation of radium-226 yields actinium-225 with a small admixture of actinium-227 (half-life 21.8 years), while electron linac photonuclear and high-energy spallation routes differ in impurity profile. Without a harmonised monograph, each producer negotiates specifications with each regulator, slowing investment. The proposal is a joint European, US and Japanese pharmacopoeia monograph setting actinium-227 and other radionuclidic impurity limits based on dosimetry and waste handling, paired with public co-investment in three to five regional cyclotron or linac hubs sized for clinical supply.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Manufacturing cost and time for living and radioactive medicines): Hernandez, Prasad & Gellad, Total costs of chimeric antigen receptor T-cell immunotherapy (JAMA Oncology 2018)","url":"https://doi.org/10.1001/jamaoncol.2018.0977"}],"tags":[],"related":["ac-225"],"indications":[],"sections":[],"technologies":["targeted-alpha-therapy"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["alpha-vs-beta","dosimetry"],"trials":[],"people":[],"bottlenecks":["b-manufacturing-cell-therapy"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"A harmonised monograph published within two years is followed by at least three accelerator producers reaching GMP supply, and clinical trial sponsors report isotope supply as the limiting factor in fewer than 10% of alpha therapy trials, down from the majority today.","rationale":"Molybdenum-99 supply diversified only when regulators agreed specifications for non-HEU and accelerator-produced material. Investment follows regulatory certainty.","test":"Commission the dosimetric analysis of actinium-227 contamination at candidate limits, convene the pharmacopoeial groups, and track producer investment decisions and trial supply reports before and after publication.","maturity":"early-clinical","actor":"regulator","cost":"medium","horizonYears":3},{"id":"idea-reg-regional-radiopharmacy-hubs","kind":"idea","name":"Regional radiopharmacy hubs and harmonised transport rules for short-lived isotopes","aka":[],"tldr":"Radioactive cancer drugs decay while they travel and get stuck at borders. Regional production and simpler transport rules would get more doses to patients on time.","summary":"Radioligand therapies are often labelled centrally and shipped internationally, losing activity to decay and to customs delays; dangerous goods rules differ by country and carrier. The proposal is a network of regional GMP radiopharmacies (one per few million population) receiving bulk isotope and cold kits, labelling on demand, and delivering same-day, combined with an IAEA-brokered harmonisation of Class 7 transport paperwork and pre-clearance for medical isotopes at major airports.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Manufacturing cost and time for living and radioactive medicines): Hernandez, Prasad & Gellad, Total costs of chimeric antigen receptor T-cell immunotherapy (JAMA Oncology 2018)","url":"https://doi.org/10.1001/jamaoncol.2018.0977"}],"tags":[],"related":[],"indications":[],"sections":[],"technologies":["radioligand-therapy"],"targets":[],"drugs":["pluvicto","lutathera"],"companies":[],"institutions":[],"pathways":[],"terms":["theranostics"],"trials":[],"people":[],"bottlenecks":["b-manufacturing-cell-therapy"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Regional labelling and pre-clearance reduce the share of radioligand doses cancelled or postponed for supply reasons from roughly 5-10% to below 1% and reduce shipped activity per delivered dose by at least a quarter.","rationale":"Nuclear medicine already runs this way for diagnostic isotopes (technetium generators, fluorine-18 cyclotron networks). Therapeutic isotopes have longer half-lives but far higher per-dose value, so the economics of regional hubs are favourable.","test":"Pilot two regional hubs in a large country and measure dose cancellation rates, shipped activity per dose and cost per dose against central supply over one year.","maturity":"early-clinical","actor":"industry","cost":"medium","horizonYears":3},{"id":"idea-accelerator-ac225-at-scale","kind":"idea","name":"Scaling actinium-225 supply with proton accelerators instead of the thorium-229 cow","aka":[],"tldr":"Most of the world's actinium-225, a rare radioactive metal used in some newer cancer treatments, comes from slowly extracting it from an old stockpile of another radioactive element. A different method — firing high-energy protons at ordinary thorium metal in an accelerator — can make much bigger batches, needed if actinium-225 treatments are ever to reach more than a small number of patients.","summary":"Historically, essentially all of the world's actinium-225 has come from 'milking' a legacy stockpile of thorium-229 (itself derived from uranium-233), a process that yields only about 1-1.2 curies a year worldwide, enough for roughly 1,000-1,200 patients and far too little to run more than the most preliminary clinical trials. The US Department of Energy's Isotope Program established the Ac-225 Tri-Lab Effort in 2014-2015 across Brookhaven, Los Alamos and Oak Ridge National Laboratories to develop an alternative: firing high-energy (greater than 70 MeV) proton beams at thorium-232 targets to produce actinium-225 by spallation, a reaction that does not depend on the finite thorium-229/uranium-233 stockpile.\n\nIn June 2021, Brookhaven demonstrated that this accelerator route could generate about 60% of the entire annual thorium-229-derived supply in a single 12-day irradiation and processing campaign. The FDA accepted a Type II Drug Master File for accelerator-produced actinium-225 nitrate from Oak Ridge National Laboratory in January 2020, and the Tri-Lab effort has since distributed more than 1,100 millicuries of accelerator-produced actinium-225 to evaluators, with batch sizes targeted to grow from the historical 50-100 mCi range toward 100-1,000 mCi per batch. Brookhaven completed an $8.5 million refurbishment of its All-Purpose Hot Cell facility in March 2023 specifically to expand actinium-225 processing capacity, and separately NorthStar Medical Radioisotopes has pursued a different accelerator route (electron-beam photonuclear transmutation of radium-226) intended to produce up to 200 curies a year per accelerator.\n\nA known trade-off of the proton-spallation route is co-production of actinium-227, a long-lived (22-year) alpha emitter; the DOE Isotope Program states this is kept to 2% or less of total activity at product release, and held a joint roundtable with the US Nuclear Regulatory Commission in March 2023 to work through the regulatory implications of that impurity for hospitals and clinics using the material.","asOf":"2026-09-22","links":[{"label":"Production Methods for Ac-225 (DOE Isotope Program)","url":"https://www.isotopes.gov/information/actinium-225"},{"label":"Tri-Lab effort makes strides toward increasing supply of Ac-225 (ORNL news, 2021)","url":"https://www.ornl.gov/news/tri-lab-effort-makes-strides-toward-increasing-supply-ac-225-0"},{"label":"Streamlined Actinium-225 Processing through new All-Purpose Hot Cells (DOE Isotope Program, 2023)","url":"https://isotopes.gov/BNL-AP-Hot-Cells"},{"label":"Accelerating Production of Non-Carrier Added Actinium-225 (NorthStar technical report)","url":"https://www.northstarnm.com/wp-content/uploads/2023/11/Accelerating-Production-of-Non-Carrier-Added-Actinium-225-n.c.a.-Ac-225.pdf"},{"label":"DOE Isotope Program virtual roundtable with NRC on accelerator-produced Ac-225","url":"https://isotopes.gov/NRC-roundtable"}],"tags":["isotope supply","actinium-225","manufacturing"],"related":["actinium-225-supply","northstar-medical-radioisotopes","idea-reg-ac225-accelerator-pharmacopoeia","ac-225"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Producing actinium-225 by proton-beam spallation of thorium-232 in linear accelerators, rather than extracting it from the legacy thorium-229 stockpile, can scale world supply from roughly 1-1.2 curies a year to the hundreds-of-curies scale needed for large randomized trials and eventual commercial radioligand therapy.","rationale":"The DOE Tri-Lab effort demonstrated in 2021 that a single 12-day accelerator campaign could produce about 60% of the entire annual thorium-229-derived supply, and the FDA has already accepted a Drug Master File for the accelerator-produced material, showing the regulatory pathway is viable. The main open questions are whether batch sizes can be sustained at the 100-1,000 mCi scale needed for a registrational trial, and how regulators and clinics will handle the co-produced, long-lived actinium-227 impurity.","test":"The 2021 Brookhaven demonstration campaign already showed technical feasibility at scale; the next milestone is whether the renovated Brookhaven All-Purpose Hot Cell facility and expanded Los Alamos target capacity sustain routine batches in the hundreds of millicuries, and whether an actinium-225 radioligand therapy programme can complete a registrational trial supplied entirely from accelerator-produced material under an agreed actinium-227 impurity limit.","maturity":"being-tested-at-scale","actor":"engineering","cost":"large","horizonYears":5},{"id":"idea-net-antagonist-ligands","kind":"idea","name":"SSTR antagonist radioligands to increase tumour dose","aka":[],"tldr":"Radioligand therapy for neuroendocrine tumours built on somatostatin receptor antagonists rather than the agonists used today: antagonists bind the receptor in every state and are not internalised, so they occupy several times more sites per cell and deliver more radiation per dose. The test is a randomised phase 2 against agonist lutetium therapy.","summary":"The idea is to build peptide receptor radionuclide therapy for neuroendocrine tumours on somatostatin receptor 2 antagonists rather than the agonists used today. Antagonists bind receptors in every conformational state and are not internalised, so they occupy several times more binding sites on each cell and deliver more radiation per dose. First-in-human studies of the antagonist 177Lu-satoreotide tetraxetan showed higher tumour uptake and dose than agonists, and early trials report responses in patients refractory to agonist PRRT. The hypothesis is higher response rates at an equivalent renal dose, including in tumours with low SSTR2 expression; the test is a randomised phase 2 of antagonist versus agonist 177Lu-PRRT in grade 1 to 2 gastroenteropancreatic NETs.","asOf":"2026-09-07","links":[{"label":"Reidy-Lagunes et al., Phase 1 trial of the SSTR antagonist radioligand 177Lu-satoreotide tetraxetan in neuroendocrine tumours (Clinical Cancer Research 2019)","url":"https://doi.org/10.1158/1078-0432.CCR-19-1026"}],"tags":[],"related":["lu-177"],"indications":["neuroendocrine"],"sections":[],"technologies":["prrt"],"targets":["sstr2"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Antagonist PRRT achieves higher response rates than agonist PRRT at equivalent renal dose, including in low-SSTR-expressing tumours.","rationale":"Antagonists bind receptors in all conformational states and are not internalised, increasing binding sites several-fold.","test":"Randomised phase 2 antagonist vs agonist 177Lu-PRRT in grade 1-2 GEP-NETs.","maturity":"early-clinical"},{"id":"idea-tb161-instead-of-lu177","kind":"idea","name":"Terbium-161 instead of lutetium-177 in the same ligands","aka":[],"tldr":"Terbium-161 is a close chemical cousin of lutetium-177 that, as well as giving off the same kind of radiation, also releases a shower of extremely short-range electrons. In theory that extra radiation could finish off single cancer cells and tiny clusters that a lutetium-177 treatment might miss, using the same targeting molecules already in use.","summary":"Terbium-161 decays with a half-life of about 6.95 days and emits beta particles similar in energy to lutetium-177's, plus roughly ten times more conversion and Auger electrons per decay. These electrons travel only nanometres to micrometres, so preclinical dosimetry modelling (Champion et al.; Müller et al.) predicts 2-3-fold higher absorbed dose to single cells and micrometastases than lutetium-177 at the same injected activity, while producing only modestly higher organ doses to kidney and salivary gland. Because terbium-161 is chemically a lanthanide like lutetium-177, the same DOTA-based chelators and labelling protocols can be reused for PSMA and somatostatin-receptor ligands.\n\nClinical translation is under way but not yet comparative. The first-in-human VIOLET trial at Peter MacCallum Cancer Centre (NCT05521412, 30 patients with metastatic castration-resistant prostate cancer) established that 161Tb-PSMA-I&T is feasible and safe up to 7.4 GBq, with organ doses similar to historical 177Lu-PSMA-617 data, and the study has since opened a 9.5 GBq expansion cohort. A German programme (REALITY, NCT04833517) is running an intra-individual head-to-head dosimetry comparison of 161Tb-PSMA-617 against 177Lu-PSMA-617 in the same patients. Neither trial has yet reported a comparative efficacy result, and global terbium-161 supply remains a research-scale bottleneck: the reactor-based no-carrier-added production route needed to avoid stable terbium contamination is far less mature than lutetium-177 supply chains.\n\nThe open question is whether the extra subcellular dose actually translates into better tumour control at a clinically tolerable normal-organ dose, rather than just a favourable dosimetry ratio in phantoms and mice.","asOf":"2026-09-22","links":[{"label":"Peter Mac / UCSF-UCLA PSMA Conference 2025: Michael Hofman on terbium-161 (VIOLET)","url":"https://www.urotoday.com/video-lectures/2025-ucsf-ucla-psma-conference/video/4752-beyond-lutetium-psma-exploring-terbium-161-for-treatment-resistant-prostate-cancer-presentation-michael-hofman.html"},{"label":"Terbium-161 in nuclear medicine: preclinical and clinical status (PubMed, 2025)","url":"https://pubmed.ncbi.nlm.nih.gov/39978166/"},{"label":"Opportunities and potential challenges of using terbium-161 for targeted radionuclide therapy in clinics (EJNMMI, 2023)","url":"https://link.springer.com/article/10.1007/s00259-023-06316-y"},{"label":"From lutetium to terbium: a new era in PSMA-targeted radioligand therapy (PMC, 2025)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12629902/"}],"tags":["prostate","isotope alternative","auger electrons"],"related":["lu177-radioligand-therapy","prrt","radioligand-dosimetry","psma-pet","lu-177","tb-161"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Substituting terbium-161 for lutetium-177 in the same PSMA or somatostatin-receptor ligand will produce a higher objective response rate at an equivalent kidney and salivary-gland radiation dose, because terbium-161's additional Auger and conversion electrons deposit extra lethal energy in micrometastases that lutetium-177's longer-range beta particles largely miss.","rationale":"Preclinical dosimetry work (Müller et al., Grünberg et al., Champion et al.) consistently found terbium-161 delivers several-fold higher absorbed dose than lutetium-177 to single cells and small tumour clusters, and dual-isotope SPECT imaging confirmed the two radiolanthanides are pharmacokinetically interchangeable when attached to the same peptide. The first-in-human VIOLET trial (30 patients) showed 161Tb-PSMA-I&T is safe with organ doses comparable to 177Lu-PSMA-617, but was single-arm and not powered to detect an efficacy difference. No completed trial has yet reported a head-to-head efficacy comparison.","test":"A randomised phase 2 trial in metastatic castration-resistant prostate cancer comparing 161Tb-PSMA-I&T against 177Lu-PSMA-617 at kidney-dose-matched activities, powered on PSA50 response rate or PSMA-PET-defined progression-free survival, roughly 150-200 patients; the ongoing REALITY intra-individual dosimetry comparison (NCT04833517) is a smaller precursor step.","maturity":"early-clinical","actor":"research","cost":"medium","horizonYears":6},{"id":"idea-total-body-pet-dosimetry","kind":"idea","name":"Total-body PET for personalised radioligand dosing","aka":[],"tldr":"Ultra-sensitive whole-body scanners can measure exactly where a radioactive drug goes at tiny tracer doses, allowing each patient's therapeutic dose to be tailored.","summary":"Radioligand therapy is given at fixed activity despite wide variation in tumour and kidney dose, so this idea uses ultra-sensitive total-body PET with 44Sc- or 89Zr-labelled analogues to measure each patient's pharmacokinetics before treatment and tailor the therapeutic dose. Dosimetry-guided prescription of 177Lu-PSMA is expected to raise tumour absorbed dose and response without exceeding kidney and marrow limits. Personalised dosimetry is established in radioiodine and SIRT, and total-body scanners from United Imaging and Siemens Healthineers remove the imaging-time and dose barriers. The test is a randomised trial of dosimetry-guided versus fixed-dose Pluvicto in prostate cancer with PSA50 and rPFS endpoints. At early-clinical maturity it addresses the bottleneck Wrong doses.","asOf":"2026-09-04","links":[{"label":"VISION: lutetium-177 PSMA-617 radioligand therapy extends survival in advanced prostate cancer (New England Journal of Medicine 2021)","url":"https://doi.org/10.1056/NEJMoa2107322"}],"tags":[],"related":["zr-89","sc-44","lu-177"],"indications":["prostate"],"sections":[],"technologies":["pet-ct","radioligand-therapy","spect"],"targets":[],"drugs":["pluvicto"],"companies":["united-imaging","siemens-healthineers"],"institutions":[],"pathways":[],"terms":["dosimetry"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Dosimetry-guided activity prescription for 177Lu-PSMA increases tumour absorbed dose and response without exceeding kidney and marrow limits, compared with fixed 7.4 GBq.","rationale":"Established in radioiodine and SIRT; total-body PET removes the imaging-time and dose barriers to pre-therapy dosimetry.","test":"Randomised dosimetry-guided vs fixed-dose Pluvicto trial with PSA50 and rPFS endpoints.","maturity":"early-clinical"},{"id":"idea-trop2-pet-selection","kind":"idea","name":"TROP2 PET to choose and sequence TROP2 ADCs","aka":[],"tldr":"Use a whole-body TROP2 scan instead of a single tissue stain to decide which patients get a TROP2 ADC, which one, and when to switch.","summary":"The proposal is to use a whole-body TROP2 PET scan, rather than a single tissue stain, to decide which patients receive a TROP2 ADC, which agent they get and when to switch. Baseline uptake and heterogeneity would predict benefit, and a fall in uptake at progression would signal antigen loss that should prompt a move to a non-TROP2 ADC rather than a second TROP2 agent. IHC on archival tissue failed to predict sacituzumab govitecan benefit, whereas PSMA PET already plays this role for Pluvicto and 89Zr-antibody and 68Ga-nanobody tracers image human tumours. The test is an imaging sub-study inside a first-line TNBC ADC trial, then a randomised PET-guided versus standard sequencing trial. At early-clinical maturity, it bears on the bottleneck Biomarkers are not validated or standardised.","asOf":"2026-09-04","links":[{"label":"ASCENT: sacituzumab govitecan doubles survival in heavily pretreated metastatic triple-negative breast cancer (New England Journal of Medicine 2021)","url":"https://doi.org/10.1056/NEJMoa2028485"}],"tags":[],"related":["psma-pet-to-rlt","ga-68","zr-89"],"indications":[],"sections":[],"technologies":["trop2-pet","immuno-pet"],"targets":["trop2"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Baseline TROP2 PET uptake (SUV, heterogeneity index) predicts PFS on TROP2 ADCs better than IHC, and a fall in uptake at progression indicates antigen-loss resistance that should prompt a switch to a non-TROP2 ADC rather than a second TROP2 agent.","rationale":"PSMA PET does exactly this for Pluvicto. TROP2 is internalising and abundant; 89Zr-antibody and 68Ga-nanobody tracers already image human tumours.","test":"Prospective imaging sub-study in a first-line TNBC ADC trial (e.g., a TROPION-Breast05 or sac-TMT cohort) correlating baseline and on-treatment TROP2 PET with response and PFS; then a randomised PET-guided vs standard sequencing trial.","maturity":"early-clinical"},{"id":"idea-total-body-pet-lower-dose-tracers","kind":"idea","name":"Using total-body PET's sensitivity to cut diagnostic tracer dose, not just scan time","aka":[],"tldr":"New whole-body scanners are so much more sensitive than standard PET machines that they can produce a clear picture using a small fraction of the usual radioactive tracer dose. Most of that extra sensitivity has been used to make scans faster; using it instead to lower the radiation dose given to patients and staff is a separate, less-explored option.","summary":"Total-body PET scanners such as the uEXPLORER and PennPET Explorer cover roughly 194 cm of the body in one bed position, versus 15-35 cm for conventional PET, giving them a reported 40-fold gain in overall sensitivity. That extra sensitivity is most often spent on shortening scan time or improving image quality at a standard tracer dose, but it can equally be spent on reducing the injected activity while keeping scan time and image quality constant, which lowers radiation dose to the patient and to staff handling the syringe.\n\nEvidence for the dose-reduction use case exists but is still limited in scale. Phantom studies on the uEXPLORER found contrast recovery for FDG images was preserved down to about 30% of standard injected activity, and healthy volunteers have been imaged with diagnostic-quality results at doses as low as 14.8-25 MBq (roughly 0.4-0.7 mCi), around 5% of a typical 10-20 mCi clinical FDG dose. A retrospective single-centre study of 88 patients with hepatic malignancies found that a tenfold reduction in injected FDG activity (about 0.37 MBq/kg versus the standard 3.7 MBq/kg) produced comparable kinetic and static image quality in both dynamic and static imaging. Total-body PET has also been used to image 68Ga-DOTATATE at roughly one-fifth of the standard clinical dose in at least one reported case, which is relevant given ongoing global gallium-68 generator supply constraints.\n\nThis is a distinct proposal from the existing total-body-PET-for-dosimetry idea in this graph, which uses total-body PET's whole-body coverage to personalise therapeutic radioligand dosing; this idea is specifically about lowering the injected activity of diagnostic tracers such as FDG, PSMA or somatostatin-receptor agents while keeping diagnostic accuracy unchanged. No large, prospective, blinded, multi-reader diagnostic-accuracy trial comparing standard-dose against substantially dose-reduced total-body PET has been reported.","asOf":"2026-09-22","links":[{"label":"Total Body PET: Why, How, What for? (PMC review)","url":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595297/"},{"label":"One-tenth-activity total-body PET versus full-activity imaging in hepatic malignancies (QIMS, 2023)","url":"https://qims.amegroups.org/article/view/118297/html"},{"label":"Total-body PET/CT — first clinical experiences and future perspectives (eScholarship, UCSF/UC Davis)","url":"https://escholarship.org/content/qt1wx8761n/qt1wx8761n_noSplash_6eb388d1960fed7f031a438777911ba9.pdf"}],"tags":["total-body PET","dose reduction","imaging"],"related":["idea-total-body-pet-dosimetry","total-body-pet-screening","nuclear-medicine-hardware","fdg-pet","ga-68"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Total-body PET's roughly 40-fold sensitivity gain over conventional PET can be used to cut injected diagnostic tracer activity by 90% or more while preserving diagnostic image quality and lesion detection, reducing radiation dose to patients and staff, rather than being used only to shorten scan duration.","rationale":"Phantom and retrospective clinical studies on the uEXPLORER total-body PET scanner show preserved contrast recovery and comparable kinetic/static image quality at 70-90% reductions in injected FDG activity, and diagnostic-quality images have been produced in healthy volunteers at roughly 5% of a standard clinical FDG dose. These findings are from phantom evaluations and single-centre retrospective series rather than prospective, blinded, multi-reader diagnostic-accuracy comparisons, so the clinical reliability of very-low-dose protocols for lesion detection in a general oncology population is not yet established.","test":"A prospective, multi-reader, blinded diagnostic-accuracy study in which the same patients undergo total-body PET/CT at both standard and substantially reduced (for example 90% lower) injected activity, scored independently for lesion detection and reader confidence against a reference standard, in roughly 50-100 patients undergoing routine FDG oncology staging.","maturity":"preclinical-evidence","actor":"research","cost":"large","horizonYears":5}]