Teaching pack: Radiopharmaceuticals & Theranostics

Radiopharmaceuticals and theranostics pair a molecule that homes to the tumour with a radioactive atom, using one isotope to see the tumour and another to treat it. The section covers theranostic pairs such as 68Ga or 18F for PET imaging, 177Lu for beta therapy and 225Ac or 212Pb for alpha therapy, directed at PSMA, SSTR, FAP and other targets. Pluvicto and Lutathera are approved, alpha emitters and new targets are in late-stage trials, and isotope supply is the bottleneck. Linked technologies include PSMA PET, somatostatin receptor PET, radioligand therapy with beta emitters, targeted alpha therapy, PRRT, radioiodine therapy, MIBG theranostics and radioembolisation, and the companies Curium, Blue Earth Diagnostics, Sirtex Medical and Y-mAbs Therapeutics point here.

• Actinium-225 supply: thorium stocks, accelerators and radium targets: Actinium-225 is the alpha-emitting atom behind the most promising next wave of radioligand therapies, and there is not enough of it. Almost all of it used to come from one decaying stock of thorium in a US national laboratory. New routes use accelerators and old radium.
• Alpha-emitter nanogenerators and daughter trapping: Actinium-225 releases four alpha particles as it decays, but the daughters escape and irradiate the kidneys and salivary glands. Nanocarriers try to hold them in place.
• Astatine-211 alpha therapy: A rare alpha-emitting halogen that can be attached to antibodies and small molecules like iodine, tested in leukaemia conditioning and brain and ovarian cancer.
• Auger-electron therapy: Auger-electron therapy uses radioactive atoms such as iodine-125 or terbium-161 that release cascades of low-energy electrons travelling only nanometres to micrometres, so they kill a cell only if the atom sits on or inside its DNA and spare the neighbours. Terbium-161 can replace lutetium-177 in existing PSMA ligands; true nuclear delivery remains preclinical.
• Cyclotron isotope production (F-18, Ga-68, Cu-64, Zr-89, At-211): Proton-rich isotopes for PET scans and some therapies are made by hitting a target with a beam from a cyclotron. Fluorine-18 is made every morning within driving distance of the scanner; gallium-68 comes from either a generator or a cyclotron; copper-64 and zirconium-89 last long enough to ship across a country.
• Gamma probes, handheld gamma cameras and dose calibrators: The small radiation detectors that make nuclear medicine and sentinel node surgery work: a pen-sized probe that clicks when the surgeon nears the radioactive lymph node, and the well counter in the hot lab that checks every dose before it is injected.
• Lutetium-177 radioligand therapy: Cancer-seeking molecules carrying the radioactive metal lutetium-177, which delivers short-range radiation to tumours it binds; approved for neuroendocrine tumours and prostate cancer.
• Medical cyclotrons, hot cells, and synthesis modules: The particle accelerators and shielded robotic chemistry boxes that make PET tracers in hospital basements and commercial pharmacies.
• MIBG imaging and 131I-MIBG therapy: A noradrenaline look-alike that neuroblastoma cells swallow: labelled with a small amount of radioactivity it shows the tumour on a scan; with a large amount it treats it.
• Peptide receptor radionuclide therapy (PRRT): A radioactive version of the hormone mimic used for the scan; it homes to neuroendocrine tumour cells and irradiates them from inside.

• Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch · A cancer is shown to depend on a hormone, and systemic cancer therapy begins (historic)
• Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch · A blood test arrives, and an epidemic of diagnoses follows it (historic)
• Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch · Does treating localised disease help? Three trials, three answers, one rule (historic)
• Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch · The screening trials disagree, and the policy swings twice (historic)
• Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch · Chemotherapy works, a little, and then the receptor drugs arrive (historic)
• Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch · The genome: a quiet sequence, a rearranged structure, and one actionable fifth (historic)
• Radiopharmaceutical roadmap: iodine → lutetium → actinium · Radioiodine and early radioimmunotherapy (historic)
• Radiopharmaceutical roadmap: iodine → lutetium → actinium · Radium-223 and Lutathera (historic)
• Radiopharmaceutical roadmap: iodine → lutetium → actinium · PSMA theranostics (current)
• Radiopharmaceutical roadmap: iodine → lutetium → actinium · Earlier lines, consolidation, and an M&A wave (current)
• Radiopharmaceutical roadmap: iodine → lutetium → actinium · Alpha emitters and new targets (emerging)
• Radiopharmaceutical roadmap: iodine → lutetium → actinium · Speculative: radioligands as a standard modality (speculative)

• VISION (phase 3, n=861): Overall survival: 15.3 months vs 11.3 months, HR 0.62
• PSMAddition (phase 3, n=1,144): Radiographic progression-free survival: Updated HR 0.67; OS HR 0.80, immature
• PSMAfore (phase 3, n=469): Radiographic progression-free survival: 12 months vs 5.6 months, HR 0.41
• PEACE-3 (EORTC 1333) (phase 3, n=446): Radiological progression-free survival: pending
• ALSYMPCA (phase 3, n=921): Overall survival: 14.9 months vs 11.3 months, HR 0.7
• PSMA-PreRP (phase 3, n=764): Sensitivity for pelvic nodal metastasis (per patient, nodal-region correlation, versus histopathology): 40%

1. What is theranostics and what is the best-known example?
   Answer

   Using the same targeting molecule for a diagnostic scan and a treatment: PSMA PET shows where prostate cancer is, and 177Lu-PSMA-617 (Pluvicto) delivers radiation to the same target.
2. What did the VISION trial show?
   Answer

   177Lu-PSMA-617 plus standard care improved overall survival (15.3 vs 11.3 months, HR 0.62) in PSMA-positive metastatic castration-resistant prostate cancer after ARPI and taxane.
3. Why might an alpha-emitting PSMA drug work after lutetium PSMA has stopped working?
   Answer

   Alpha particles (actinium-225) deposit far more energy over 50-100 µm, causing clustered double-strand breaks independent of oxygen and cell cycle, so beta-resistant, hypoxic, or small-volume disease can still be killed; retrospective series show PSA responses in about half after 177Lu failure. Supply of Ac-225 and salivary toxicity are the limits.
4. What is the difference between lutetium-177 and actinium-225 as therapeutic isotopes?
   Answer

   177Lu emits beta particles (range 1-10 mm, crossfire helps bulky heterogeneous tumours, marrow toxicity, 6.7-day half-life); 225Ac emits alpha particles (range 50-100 µm, very high energy, oxygen-independent clustered DNA damage, good for micrometastases, daughter redistribution and supply constraints).
5. Why is actinium-225 supply a problem?
   Answer

   It is made in tiny quantities from a legacy thorium-229 stockpile or accelerators; commercial-scale expansion is a 3-5 year effort (TerraPower's Philadelphia plant aims for a 20-fold increase), so phase 3 alpha trials and future launches are gated by production.

• NCI: Dictionary of Cancer Terms: radiopharmaceutical: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/radiopharmaceutical