LAST WEEK TODAY!

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

Hi fellow warriors! This week we had several updates in both clinical trials and preclinical research. I had to keep an eye on the newsletter’s length! 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.
​For more details on everything I talk about here, you can always visit ProstateWarriors.com.​

Clinical Research

• Phase 1/2: DS-3939a – Novel ADC for TA-MUC1-Positive Cancers​
  DS-3939a is a novel antibody-drug conjugate (ADC) in a Phase 1/2 trial that began dosing in Asia, North America, and Europe in September 2023. It targets TA-MUC1, a glycoprotein overexpressed in ~90% of advanced prostate cancers with lymph node metastases, contributing to tumor progression and immune evasion. Using DXd technology, DS-3939a delivers a potent cytotoxic payload via a humanized antibody that binds selectively to tumor-specific glycoforms of TA-MUC1—minimally expressed in healthy tissues. Preclinical models showed significant tumor regression in TA-MUC1-positive prostate cancer, with no effect on TA-MUC1-negative cells.​
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• Phase 1: BL-M14D1 – ADC for TROP2-Positive Neuroendocrine Tumors
  ​BL-M14D1 is an ADC in Phase 1 trials, recruiting in China with planned global expansion. It targets TROP2, a glycoprotein overexpressed in various epithelial and neuroendocrine cancers, including NEPC. BL-M14D1 uses an anti-TROP2 antibody linked to a presumed topoisomerase I inhibitor, with an innovative linker that releases the toxic payload only within cancer cells. This approach maximizes tumor targeting while minimizing harm to normal tissue, offering promise for aggressive cancers with few current options.
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• Phase 1b: LumOnate Trial – Triple Combo for mCRPC
  ​This Phase 1b trial investigates 177Lu-PSMA-I&T (radioligand), olaparib(PARP inhibitor), and pembrolizumab (PD-1 inhibitor) for metastatic castration-resistant prostate cancer (mCRPC). The goal: attack cancer via DNA damage, block repair, and boost immune response. Prior studies support this strategy—ECLIPSE showed PFS benefits with 177Lu-PSMA-I&T, PRINCE showed 56% response with 177Lu-PSMA-617 + pembrolizumab, and LuPARP showed 66% PSA decline with 177Lu-PSMA-617 + olaparib.
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• Phase 1: SYN608 – Targeting PARG in HRR-Deficient Tumors
  ​SYN608 is in Phase 1 trials for HRR-deficient cancers, including prostate cancers with mutations like BRCA , ATM and others. It inhibits PARG, an enzyme vital to DNA repair. By blocking PARG, SYN608 causes DNA damage accumulation, selectively killing cancer cells. It showed strong activity in preclinical models, even in tumors resistant to similar agents, and appears to have a favorable cardiac safety profile.
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• Phase 1: RV-01 – Radiopharmaceutical Targeting B7H3
  ​RV-01 (Betabart) is a monoclonal antibody linked to Lutetium-177, targeting the immune checkpoint B7H3, overexpressed in aggressive prostate cancers and low in normal tissues. IND clearance was granted by the FDA, with trials to begin in late 2025. Its liver-based clearance could reduce kidney toxicity, a common issue with radiopharmaceuticals. Preclinical models showed tumor shrinkage and survival benefits.
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Preclinical Research

• AI Minibinder Platform Accelerating Immunotherapy​
  Developed by researchers at DTU and the Scripps Research Institute, this platform uses artificial intelligence to rapidly design “minibinders”,small proteins that guide T cells to attack cancer by targeting specific pMHC molecules. What once took years can now be achieved in 4 to 6 weeks.These binders include an integrated virtual safety screen to avoid off-target effects. The envisioned workflow resembles CAR-T therapy: isolate immune cells, genetically enhance them with minibinders, then reinfuse. This could reduce time to clinical translation to under five years, while increasing precision and safety.
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• LYA914: Oral PROTAC Targeting AR and AR-V7
  ​LYA914 is an orally available PROTAC designed to degrade both full-length androgen receptors and their resistant splice variant AR-V7, which drives resistance in castration-resistant prostate cancer. It binds to the AR’s DNA-binding domain and triggers proteasomal degradation. This irreversible targeting overcomes the limitations of drugs like enzalutamide. In preclinical models, LYA914 significantly inhibited tumor growth, including in tumors resistant to enzalutamide, demonstrating greater potency than existing AR-targeting therapies.
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• MYCi975 + Metformin Combo for MYC-Driven Cancers
  ​A study from Northwestern Medicine showed that combining the MYC inhibitor MYCi975 with metformindisrupts metabolic pathways essential to cancer cell survival. MYCi975 pushes cancer cells to rely on mitochondrial complex I genes, and metformin blocks this adaptation, leading to metabolic collapse. In prostate cancer cell models, this combination proved highly effective, especially when mitochondrial gene expression was low. This could serve as both a targeted strategy and a biomarker-guided therapy for MYC-driven cancers, pending further clinical validation.
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• CDK4/6 and PARP Inhibitor Sequencing
  ​Researchers at the Vall d’Hebron Institute of Oncology discovered that prostate cancer cells enter a dormancy-like state after CDK4/6 inhibition, enabling resistance. However, withdrawing CDK4/6 inhibitors creates a brief window where cells accumulate DNA damage, making them highly vulnerable to PARP inhibitors. This timed sequence, rather than concurrent administration, greatly enhanced tumor control in preclinical models. Combining CDK4/6 with senolytics could further eliminate dormant cells, offering a two-pronged strategy to prevent relapse.
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• ATNM-400, Non-PSMA Actinium-225 Radioconjugate
  ​ATNM-400 targets a protein associated with prostate cancer progression and resistance to androgen receptor pathway inhibitors. Using Actinium-225, it delivers potent radiation with high precision. In preclinical studies, ATNM-400 showed higher efficacy than both 177Lu-PSMA-617 and 225Ac-PSMA-617, achieving 40% complete cures when combined with enzalutamide.It required lower doses, maintained tumor retention for over 9 days, and cleared quickly from normal tissues, potentially reducing side effects. These features suggest strong promise for patients with treatment-resistant prostate cancer, pending clinical trials.
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And…that’s all folks! For today at least!
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Have a great weekend!

Max