BKI-1553: Transformational Therapy for Castrate-Resistant Prostate Cancer
Abstract
Rationale: Multiple studies have now shown that targeting the androgen receptor in prostate cancers resistant to standard androgen deprivation therapies, such as gonadotropin-releasing hormone agonists, e.g., ZoladexTM, respond to newer androgen receptor-targeted therapies, e.g., abiraterone, enzalutamide, or apalutamide. Additionally, patients presenting with metastases who have not been treated respond to these androgen receptor-targeting drugs as first-line therapies and have their lives significantly extended. Unfortunately, resistance eventually develops in almost all of these patients and resistant tumors continue to be driven by some form of the androgen receptor, e.g., androgen receptor structural variants (splice variants that are no longer responsive to the therapies) or intratumoral androgen synthesis. These data suggest that additional drugs that target the androgen receptor through novel mechanisms not used by the current therapies could provide life-extending treatment for men who now have lethal prostate cancer. Our group has developed a new drug, 1553, that targets the androgen receptor activity by a novel pathway. We have shown that 1553 can be given orally in multiple animal species and once a day or every other day administration achieves blood levels that exert the desired biological effect on the androgen receptor. Furthermore, in preclinical toxicity studies, we have shown 1553 has an excellent safety profile. The objectives and aims of this proposal are to further determine the effects and actions (pharmacodynamics) of 1553 and the best strategies for administration. We will also perform the preclinical studies necessary to lead to the good laboratory practice studies (GLP) that are required for filing an investigational new drug application (IND) with the Food and Drug Administration (FDA) so that we can begin clinical trials in men with lethal prostate cancer. Applicability: This proposal is directly applicable to the 2019 PCRP Overarching Challenges to develop a treatment to improve the outcome of men with lethal prostate cancer and reduce deaths in African Americans, Veterans, and other high-risk groups, as well as all men suffering from lethal prostate cancer. The applicability comes from the fact that our lead compound is already in hand and basic drug development has been completed. This proposal will determine how best to administer the drug and we will perform the preclinical safety and toxicity testing necessary to make an IND application that leads to therapeutic trials in the target population. Targeted Patient Populations: Men with prostate cancer resistant to standard androgen deprivation in combination with second-generation androgen receptor-targeting drugs and men presenting with castration-sensitive primary metastatic disease. Potential Clinical Applications: In combination with current drugs, e.g., abiraterone, enzalutamide, or apalutamide, treatment of men resistant to standard androgen deprivation therapy and men presenting with primary metastatic disease. The potential benefits are improved response rate with prolongation of life without the side effects of chemotherapeutic agents such as docetaxel or PARP inhibitors. Potential risks are toxicities not discovered in preclinical toxicity testing and lack of efficacy in human trials, especially if there is associated toxicity-limiting dose escalation. Projected Time to Clinical Trial and Patient-Related Outcome: Completion of current proposal and GLP testing should take 3-4 years. IND application is a 6-month process. We anticipate beginning clinical trials in 5 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010146
Entities
People
- Stephen R Plymate
Organizations
- United States Army
- University of Washington