LAST WEEK TODAY!

A summary of what was published on ProstateWarriors.com during the past week

Hi fellow warriors! We’re approaching the end of a very interesting year, full of clinical trials and progress. Even today, here are some clinical and preclinical studies with strong potential. Stay strong and fight on!

As usual, we also have a podcast if you prefer to listen to the newsletter, you can find it HERE.​

Clinical Research

• Phase 1/2 Trial for TD001, a PSMA-Targeted ADC
  TD001, an investigational antibody-drug conjugate (ADC), is preparing to recruit patients for its Phase 1/2 clinical trial aimed at treating men with metastatic castration-resistant prostate cancer (mCRPC) whose tumors express prostate-specific membrane antigen (PSMA). Mechanistically, TD001 combines a monoclonal antibody against PSMA with exatecan, a topoisomerase I inhibitor payload, using a cleavable linker designed for stability in circulation and efficient release inside the tumor cell. Preclinical work suggests TD001 achieves sustained tumor growth inhibition and leverages a bystander effect from the membrane-permeable exatecan, which may allow killing of adjacent tumor cells even those with lower PSMA expression, a key feature attractive in heterogeneous advanced disease. This approach positions TD001 as a potential alternative to radioligand therapies, which are limited by dose constraints, and bispecific T cell engagers, which are constrained by immune-mediated toxicities.​
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• Phase 2 REVELUTION Trial, Leuprolide vs Relugolix​
  The REVELUTION trial, a prospective Phase 2 study, investigated the cardiovascular impact of two different types of androgen deprivation therapy (ADT) in 94 ADT-naïve men with prostate cancer receiving pelvic radiotherapy. The primary endpoint measured the change in total coronary plaque volume (TPV) over 12 months, comparing cohorts receiving radiotherapy alone, radiotherapy plus the GnRH agonist leuprolide, and radiotherapy plus the GnRH antagonist relugolix. Results showed that leuprolide significantly increased the median TPV by 52.0 mm³, compared to only 25.0 mm³ with relugolix, suggesting that GnRH agonists may accelerate atherosclerosis more rapidly than antagonists, despite both achieving equivalent testosterone suppression. Additionally, over a median 2.2-year follow-up, major adverse cardiovascular events (MACE) occurred in 9.7% of patients on leuprolide, but none in the relugolix group.​
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• Phase 1 Trial for ITC-6146RO, a B7-H3 Targeting ADC
  ITC-6146RO, an experimental antibody-drug conjugate (ADC), has received IND approval to commence a first-in-human Phase 1 trial for patients with advanced or metastatic solid tumors who have stopped responding to standard therapies, including metastatic castration-resistant prostate cancer. This drug is designed to selectively attack tumors that display the surface protein B7-H3, which is found at high levels in several aggressive cancers. The ADC features an antibody targeting B7-H3, a chemical OHPAS linker, and a potent duocarmycin-based payload that damages DNA. The OHPAS linker and payload modification technologies incorporate platform innovations aimed at maximizing stability in the blood and ensuring selective activation only under specific acidic and enzymatic conditions inside the tumor cell, thereby aiming to widen the therapeutic window.​
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• PROSTest: Blood-Based mRNA Assay for 177Lu-PSMA Success​
  PROSTest is a novel, minimally invasive blood-based mRNA assay that uses a 27-gene qPCR signature, processed via machine learning, to predict treatment outcomes for 177Lu-PSMA radioligand therapy in metastatic castration-resistant prostate cancer (mCRPC). A multi-center retrospective study of 268 mCRPC patients demonstrated that changes in the PROSTest score after just one treatment cycle correlated strongly with progression-free survival (PFS) and overall survival (OS).A decline in the score post-first-cycle indicated superior outcomes, with 90% of objective responders showing score reductions, compared to 75% of progressors showing increases. This predictive ability, which yields molecular insights after minimal drug exposure, positions PROSTest as a sensitive biomarker that captures circulating tumor RNA dynamics, potentially allowing physicians to identify early non-responders and make personalized treatment decisions before toxicity accumulates.
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Preclinical Research & Reviews

• Phase 1 Trial Results Validating CBLB Inhibition With ISM3830, an AI Designed Drug​
  Clinical validation for targeting the Casitas B-lineage lymphoma-b (CBLB) pathway, the mechanism on which the AI-developed drug ISM3830 is based,comes from early findings in the Phase 1 trial of NX-1607, another CBLB inhibitor. In this study, 6 of 13 prostate cancer patients experienced PSA reductions of 50% or more at optimized dosing; notably, some heavily pretreated patients achieved near-complete PSA collapses of up to 90% and clearance of circulating tumor cells and superior concentration of tumor-infiltrating lymphocytes in metastatic castration-resistant prostate cancer (mCRPC). Unlike traditional small-molecule discovery pipelines, ISM3830 was prioritized based on AI-predicted potency, selectivity, metabolic stability, and T-cell–restorative activity and is now being positioned for first-in-human trials within 18–24 months, leveraging the growing clinical evidence that CBLB inhibition can effectively counter tumor-induced immunosuppression.​
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• Triaptosis: A New Cell Death Pathway via Endosomal Collapse Triaptosis is a newly characterized form of programmed cell death that focuses on destroying the internal “trafficking system” of cancer cells, specifically the endomembrane transport network. The process is initiated by menadione, a controlled pro-oxidant, which oxidizes and inactivates the key enzyme PIK3C3 (VPS34). Triaptosis is notable because it operates independently of classic death pathways that cancers often disable, such as apoptosis. Preclinical work in mouse models of aggressive metastatic prostate cancer showed that oral administration of menadione was able to slow or control tumor growth more effectively and for longer periods than standard androgen-deprivation approaches, suggesting it targets an “Achilles’ heel” inherent to rapidly growing malignant cells.​
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And…that’s all folks! For today at least!
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Have a great weekend!

Max