Triple AKR1C3/COX2/sEH Inhibition for the Treatment of Lethal Prostate Cancer
Abstract
Clinical Significance: Prostate cancer will claim lives of over 30,000 American men in 2022 alone. The disease evolves from primary tumors to castration-resistant prostate cancer (CRPC), which only takes around 2-3 years. Metastasis is the primary cause of mortality in prostate cancer patients. Bone metastases occur in more than 90% of patients with advanced prostate cancer and are associated with poor survival. CRPC is still driven by androgens, such as testosterone, which is why androgen receptor signaling inhibitors (ARSI) are widely used to treat the disease. These drugs included enzalutamide (XTANDI), abiraterone acetate (ZYTIGA), apalutamide (ERLEADA™) and darolutamide (Nubeqa). Although these drugs are highly effective initially, patients often quickly develop resistance to these drugs. Therefore, there is an urgent need to identify strategies to control the emergence of ARSI-resistant prostate cancer. Our research team has shown that genes such as AKR1C3, which promotes the production of androgens, are upregulated in prostate cancer cells and xenograft tumors that have stopped responding to enzalutamide and abiraterone treatment. Clinical data from the literature confirm that inflammation promotes the development of prostate cancer and is accompanied by high-grade cancer. PTUPB, previously identified as an anti-inflammatory small molecule, has shown great potential to inhibit AKR1C3 enzymatic activity and synergize with enzalutamide treatment in ARSI-resistant prostate cancer. The overarching goal of this translational application is to further develop PTUPB and build a strong rationale for translating the drug to a clinical trial for the treatment of lethal CRPC. Notably, our assembled team has a great deal of experience in the design and implementation of clinical trials for the treatment of men with CRPC. Research strategies and major expected outcomes: We have developed a novel small-molecule, PTUPB, which is more effective than our previous reports on indomethacin in AKR1C3 enzymatic activity inhibition, as well as in suppression of prostate cancer growth. Preliminary data also demonstrated that PTUPB inhibited tumor inflammatory response and had a superior pharmacokinetic profile. In this project, we will evaluate the properties of PTUPB and test its efficacy in novel patient tumor-derived models of CRPC for future clinical trial initiation. We will determine whether PTUPB alone and in combination with enzalutamide suppresses prostate cancer progression using novel prostate cancer metastasis models. We will study PTUPB for its inhibition of steroidogenesis and the inflammatory network and discover novel targets for prostate cancer treatment. Translational Implications: Our team has extensive expertise in translating therapeutics into the clinical setting underscoring the feasibility of our proposal. After the completion of the project, we expect to initiate a pre Investigational New Drug (IND) consultation with the FDA and perform the studies in the following year. We expect to conduct a single-center, open-label, single-arm phase I dose escalation study using PTUPB in CRPC patients subsequent to the IND report within 5 years. We will also consult with our prostate cancer patient’s advocate to ensure that patients’ voices or concerns are considered. PTUPB is based on the FDA approved celecoxib structure. Therefore, we do not anticipate the potential adverse effects of PTUPB but will validate its safety and tolerability. Importantly, our previous findings indicate that PTUPB may reduce cardiovascular risks compared with celecoxib. The outcomes of the proposed studies will provide a strong rationale for translating PTUPB into the clinical setting and addressing the major unmet need to overcome ARSI resistance in CRPC patients. We believe that PTUPB will ultimately increase the overall survival and improve the quality of life of men diagnosed with CRPC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310325
Entities
People
- Chengfei Liu
Organizations
- United States Army
- University of California, Davis