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An Accelerated Platform using Lead-212 Targeted α-particle Therapy to Radically Improve Cancer Lethality of Prostate Cancer Theranostics using Novel Targets and Better Understanding of Resistance: the Cancer Lethality Lead Collaboration


Michael Hofman, MBBS

Principal Investigators: Michael Hofman, MBBS (Peter MacCallum Cancer Centre), Mohammad Haskali, PhD (Peter MacCallum Cancer Centre), Luc Furic, PhD (Peter MacCallum Cancer Centre), Johannes Czernin, MD (University of California, Los Angeles), Christine Mona, PhD (University of California, Los Angeles), Caius Radu, MD (University of California, Los Angeles), Tom Hope, MD (University of California, San Francisco), Felix Feng, MD (University of California, San Francisco), Ken Herrmann, MD (Uniklinik Essen), Katharina Lückerath, PhD (Uniklinik Essen), Heidi Fettke, PhD (Peter MacCallum Cancer Centre), Elie Besserer, PhD (University of California, Los Angeles), Martin Sjoestroem, MD, PhD (University of California, San Francisco), Valeska von Kiedrowski, PhD (Uniklinik Essen)

Co-Investigators: Shahneen Sandhu, MBBS (Peter MacCallum Cancer Centre), Anna Trigos, PhD (Peter MacCallum Cancer Centre), Arun Azad, MD, PhD (Peter MacCallum Cancer Centre), Declan Murphy, FRACS (Peter MacCallum Cancer Centre), Giuseppe Carlucci, PhD (University of California, Los Angeles), Thuc Le, PhD (University of California, Los Angeles), Jonathan Tranel, PhD (University of California, San Francisco), Wolfgang Fendler, MD (Uniklinik Essen), Anna Pacelli, PhD (Uniklinik Essen)

Young Investigators: Marwa Rahimi, PhD (Peter MacCallum Cancer Centre), Magdalena Staniszewska, PhD (Uniklinik Essen)

Description:

  • Radioligand therapy (RLT) using Lutetium-177 PSMA, a small molecule with radioactive payload, is the latest FDA-approved treatment for men with lethal prostate cancer and improves survival and quality-of-life. While striking responses can occur, one-third of patients exhibit primary resistance and the patients who do respond will eventually recur. Thus, while RLT is highly promising, further optimization is needed.
  • An alternative approach is the use of alpha-emitting radioactive payloads, which have better tumor cell killing potential than the beta emitter Lutetium-177.
  • Michael Hofman and team are developing novel RLTs for prostate cancer that combine novel chemistry approaches to target prostate cells with the alpha emitter Lead-212.  Lead-212 has advantages over other radioemitters including ease of production using a novel desktop generator rather than nuclear reactor or cyclotron.
  • A cutting-edge chemistry approach will be used to develop and optimize high affinity cyclic peptides that can target prostate cancer proteins ROR1, DLL3 and others. These will be labeled with Lead-212 and compared with existing ligands targeting PSMA and FAP for RLT in preclinical prostate cancer imaging and treatment models. In-human biodistribution will be evaluated in pilot clinical trials.
  • The team will also use samples from advanced and lethal prostate cancer cases to characterize novel targets and biomarkers, and identify resistance mechanisms to RLT treatment.
  • If successful, this team will develop next-generation RLTs to radically improve outcomes for men with metastatic prostate cancer. The team aims to translate these theranostic agents for commercialization, regulatory approval and global adoption within 7-10 years. Not only would this improve lives for patients with prostate cancer but it would also have direct applicability in a broader range of cancers.

What this means to patients:  The team will develop a new treatment called targeted alpha therapy using the radioactive substance Lead-212. This emits highly energic particles that can eradicate cancer whilst travelling less than the width of a human hair limiting side effects. This will be combined with a mRNA-based technology to discover new small molecules that lock onto cancer cells enabling targeted delivery of the radioactive payload. Additionally, we will characterize mechanisms of treatment resistance and develop biomarkers for better personalizing these treatments. We hope these discoveries will transform treatment for men with highly aggressive and lethal prostate cancers currently lacking effective diagnostics/therapies. The targets are also expressed in other cancers and may have equal or greater impact beyond prostate cancer.

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