LAST WEEK TODAY!

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

Hi fellow warriors! This week the focus is on preclinical research. The fact that the AACR Annual Meeting 2026 is starting in less than a month means there are a lot of interesting new developments in the preclinical field. I’ll try to focus mainly on research that is about to enter Phase 1 clinical trials, otherwise there would simply be too many updates! 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 Trial: Enolen Implant for Localized Prostate Cancer
  ​In a National Cancer Institute–led phase 1 study, researchers evaluated Enolen, an investigational anti-androgen implant designed to deliver enzalutamide directly into the prostate. The study involved 18 evaluable patients with localized prostate adenocarcinoma who received the sustained-release reservoirs prior to scheduled surgery. Results showed a mean 84% reduction in measurable tumor volume on MRI over approximately five weeks. Notably, the treatment maintained high concentrations of the drug within the prostate while systemic levels remained low, avoiding typical systemic hormonal toxicities like sexual dysfunction.
  ​
• Real-World Outcomes for Darolutamide in nmCRPC
  ​The DEAR-EXT study, published on Nature, analyzed real-world data from over 1,300 men with nonmetastatic castration-resistant prostate cancer (nmCRPC) to compare the effectiveness of darolutamide, enzalutamide, and apalutamide. This observational analysis found that darolutamide was associated with a significantly lower risk of treatment discontinuation,roughly a 25% reduction, compared to the other agents, primarily due to better tolerability regarding side effects like fatigue. Patients treated with darolutamide also experienced a lower risk of disease progression to metastatic CRPC and demonstrated deeper biochemical responses in PSA levels.
  ​
• Phase 1 Trial (Soon!): FX-111 a Selective ARon Degrader
  FX-111 is an experimental degrader that selectively targets ARon, the hormone-bound and transcriptionally active form of the androgen receptor found in the nucleus. Unlike classical antagonists, FX-111 remains effective even in high-androgen environments and can degrade clinically relevant AR mutants that cause resistance to other therapies. Preclinical evidence suggests it completely silences androgen-driven programs, potentially allowing for treatment without the need for full systemic androgen deprivation therapy (ADT).
  ​

Preclinical Research & Reviews

• Dual AR-V7/AR Molecular Glue Degrader
  ​Scientists have identified a first-in-class molecular glue degrader that simultaneously targets both the full-length androgen receptor (AR) and its AR-V7 splice variant, which is a primary driver of drug resistance. In animal models resistant to enzalutamide, these compounds strongly suppressed tumor growth and showed over ten-fold higher potency compared to existing degraders like ARV-110. By binding to the N-terminal domain (NTD) of the receptor, this drug bypasses mutations in the ligand-binding domain that often render current therapies ineffective.
  ​
• CAR-T Strategy for Bone Cancer and Metastatic Disease
  ​A novel CAR-T cell therapy engineered to recognize the Oncostatin M (OSM) receptor has shown robust activity against osteosarcoma in preclinical mouse models, including the successful attack of metastatic lesions. This strategy is conceptually relevant to metastatic prostate cancer, where higher OSMR levels are linked to more advanced disease and higher Gleason scores. Because OSMR signaling drives proliferation and invasiveness in prostate cancer, this CAR-T approach could eventually be adapted to target both primary lesions and bone-metastatic deposits.
  ​
• AI CellVoyager Agent for Hypothesis Generation
  CellVoyager is an AI agent that automates the analysis of single-cell RNA-seq data by planning additional steps and proposing biological hypotheses. It acts as a digital research assistant, identifying new cell-state contrasts or pathway associations that human experts have rated as plausible and interesting. This architecture allows researchers to continuously re-mine legacy datasets for overlooked biology and can be applied to other domains, such as multi-omics integration or secondary analyses of clinical trials.
  ​
• AUTOTAC Degraders ATB‑238 and ATB‑239
  Autophagy-Targeting Chimeras (AUTOTACs), such as the second-generation compounds ATB-238 and ATB-239, are designed to force cancer cells to destroy the androgen receptor and its splice variants like AR-v7. These molecules proved effective in several prostate cancer models, including a bone-in-culture system mimicking the complex microenvironment of lethal metastases. Furthermore, ATB-238 demonstrated synergistic killing when combined with docetaxel, suggesting a potential for these degraders to be integrated into existing treatment strategies.
  ​
• Ferroptosis-Nanoparticles for Immune Activation
  ​Researchers have developed nanoparticles that carry docetaxel and a light-activated dye, designed to open specifically within the high-hydrogen-peroxide environment of tumors. When exposed to near-infrared light, these particles trigger a “triple hit” of heat, oxidative damage, and chemotherapy, driving cancer cells into ferroptosis. This process spills danger signals that turn “cold” tumors “hot” by attracting killer T cells, resulting in 100% survival in mouse models when combined with anti-PD-1 immunotherapy.
  ​
• HLX3902 Trispecific T-Cell Engager
  HLX3902 is a trispecific T-cell engager that simultaneously targets STEAP1 on prostate tumor cells and both CD3 and CD28 on T cells. By integrating a costimulatory signal (Signal 2), the drug helps T cells resist exhaustion and maintain functional stamina over multiple rounds of antigen exposure. In preclinical models, HLX3902 achieved deep and sustained tumor control after a single low dose, and an IND submission to begin clinical trials is expected in early 2026.
  ​
• JMKX007129: Next-Generation AR-NTD Inhibitor
  JMKX007129 is a small-molecule drug that targets the N-terminal domain (NTD) of the androgen receptor to overcome resistance seen with current ligand-binding domain inhibitors. It is significantly more potent and selective than previous drugs in its class, showing 20-fold higher activity in AR-positive cells than in AR-negative ones. The compound, which is currently in IND-enabling studies, has also shown synergy when combined with existing AR inhibitors or degraders, leading to a stronger anti-growth effect.
  ​
• JZY3032 and Domain-ALTeration Chimeras
  Domain-ALTeration Chimeras (DALTACs) represent a new therapeutic class that “miswires” protein complexes by enforcing non-productive interactions rather than degrading the proteins. The first-in-class molecule JZY3032 targets the androgen receptor–p300 complex, jamming its architecture to block oncogenic transcription while leaving the proteins themselves intact. This lineage-selective approach potently inhibits the growth of prostate cancer models dependent on the AR–p300 axis while sparing cells that do not share this dependency.
  ​
• ²²⁵Ac-RAX104: Next-Generation PSMA Alpha Radioligand
  RAX104 is a PSMA-targeting ligand that, when labeled with actinium-225, demonstrates a 22-fold higher affinity for PSMA than the ligand used in Pluvicto. It dissociates more slowly from the receptor, leading to superior tumor retention and three times higher absorbed activity in tumors without increasing systemic exposure. In preclinical tests, it produced stronger growth inhibition and longer survival at a fivefold lower dose than existing radioligands, supporting the proposal for upcoming human safety trials.
  ​
• SonoPIN: Ultrasound-Guided Precise Drug Delivery
  ​Researchers have developed SonoPIN, a method using ultrasound and microbubbles to deliver large anticancer molecules, like PROTACs, directly into tumor cells. The technique uses focused ultrasound to oscillate microbubbles that puncture cell membranes, allowing bulky drugs to flow into the targeted cells with high precision. In early lab experiments, this method achieved a 70% reduction in target protein levels and killed roughly half of the targeted cancer cells while leaving over 99% of non-targeted cells alive.
  ​
• TBI-001: Target for Neuroendocrine Prostate Cancer
  TBI-001 is an experimental drug designed to target the TRIB2 protein, which acts as a central hub for resistance and the development of treatment-emergent neuroendocrine prostate cancer (t-NEPC). The molecule binds TRIB2 and induces its degradation, which in turn disrupts survival pathways like AKT and BCL2 and suppresses aggressive neuroendocrine gene programs. In animal models, TBI-001 produced significant tumor regression and reduced markers associated with metastasis and immune evasion.
  ​

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.

If this newsletter was delivered to your SPAM folder, make sure to let your email system know that it is not spam.
​
​
Have a great weekend!

Max