LAST WEEK TODAY!

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

Hi fellow warriors! I want to wish you all a Merry Christmas! We’ve almost reached Newsletter number 52, and new trials and research keep coming in. 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.
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Clinical Research

• Phase 3 Trial: Inavolisib and the InavoPC Study for mCRPC
  ​The InavoPC trial is a randomized, open-label study evaluating Inavolisib, a highly selective PI3Kα inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC). This treatment strategy addresses a major resistance mechanism where 40–60% of patients exhibit PTEN gene inactivation, which triggers the PI3K-AKT-mTOR survival pathway and allows the cancer to bypass standard hormonal therapies. By combining Inavolisib with enzalutamide, the therapy aims to simultaneously block both the androgen receptor and PI3K pathways, effectively cutting off the tumor’s primary escape routes. Inavolisib is particularly notable for its 300-fold selectivity for the PI3Kα isoform, which helps minimize the toxic off-target effects often associated with broader inhibitors while specifically triggering the degradation of mutant p110α proteins in cancer cells.​
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• Phase 1/2 Trial: GVV858 Targeting CDK2 in Resistance
  GVV858 is a novel CDK2 inhibitor currently being evaluated in a Phase 1/2 clinical trial for patients with mCRPC who have developed resistance to androgen deprivation therapy (ADT). The drug is designed to target a specific subset of patients with CCNE1 amplification, a genetic trait that allows cancer cells to progress through the cell cycle independently of testosterone signals. In these aggressive tumors, the cancer essentially finds a “backdoor” to continue dividing even when hormones are suppressed; GVV858 acts on the molecular brakes of the cell cycle to stop this division. Preclinical data suggest that these CCNE1-amplified cells become uniquely dependent on CDK2, making them highly vulnerable to this targeted approach.​
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• Phase 1/2 Trial: AB-3028 Programmable CAR-T Therapy
  ​Advancing into human evaluation, AB-3028 is a highly engineered CAR-T cell therapy that utilizes a “programmable circuit” to overcome the typical failures of immunotherapy in solid tumors. To prevent damage to healthy tissues, the therapy uses an “AND-gate” design, meaning the T cells only activate when they recognize both PSMA and a second priming antigen on the tumor surface. Furthermore, the cells are equipped with specialized modules to resist the immunosuppressive environment of the tumor and a synthetic JAK/STAT activator to prevent T-cell exhaustion. This Phase 1/2 trial will specifically test the safety and preliminary efficacy of a single infusion in heavily pretreated patients with PSMA-positive mCRPC.​
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• Phase 1 Trial: AO-252 as a Brain-Penetrating TACC3 Inhibitor
  AO-252 is a first-in-class, oral TACC3 inhibitor currently in Phase 1 trials for aggressive, metastatic prostate cancer. TACC3 is a protein frequently overexpressed in advanced cases, where it drives genomic chaos, tumor invasion, and resistance to standard treatments by ramping up signaling pathways like Wnt/β-catenin. One of the most promising features of AO-252 is its ability to penetrate the blood-brain barrier, having shown the capacity to cause full regressions in brain metastases during preclinical modeling. By disrupting TACC3’s partnerships with other proteins, the drug triggers “mitotic disasters” that halt tumor growth, with early clinical data showing tumor shrinkage even at low doses.​
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Preclinical Research & Reviews

• Reprogramming Allergy Cells for Tumor Targeting
  ​Researchers have developed a method to convert mast cells—the immune cells responsible for allergies—into a targeted weapon against cancer. By “sensitizing” these cells with tumor-specific IgE antibodies (such as those targeting HER2), the mast cells are programmed to treat the tumor as if it were a massive allergen. Once they home in on the cancer, they release a burst of inflammatory signals that transform “cold” tumors into “hot” ones, making them visible and attractive to cancer-killing T cells. Beyond stimulation, these mast cells can act as living delivery vehicles, shielding oncolytic viruses from the immune system during circulation and releasing them directly inside the tumor to destroy cancer cells from within. This platform offers significant potential for personalization, as mast cells could theoretically be loaded with various therapeutic cargos tailored to a patient’s specific tumor markers.​
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• Identifying the CYP51A1 Bypass Pathway in Hormone Resistance
  ​New research has identified a specific mechanism that explains why some prostate cancers survive despite maximal androgen blockade: an alternative steroidogenic pathway mediated by the enzyme CYP51A1. While modern therapies typically target the CYP17A1 enzyme to stop testosterone production, cancer cells can use CYP51A1 to synthesize DHEA directly from cholesterol-derived oxysterols, completely bypassing the blocked route. Preclinical experiments demonstrated that knocking out CYP51A1 abolished the tumor’s ability to produce testosterone and significantly slowed growth in castrated models. This discovery suggests that truly effective hormonal therapy may require co-targeting both the classical CYP17A1 axis and this newly defined CYP51A1 route to prevent the cancer from shunting cholesterol through this hidden bypass.​
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And…that’s all folks! For today at least!
Please let me know if there is anything I can improve in my newsletters, and let me know if you have enjoyed the podcast.

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Have a great weekend!

Max