Developing Mediator Kinase Inhibitor for Castration-Refractory Prostate Cancer
Abstract
Rationale, Objective, and Aims of the Application: Prostate cancer (PCa) is the most common, and the second most lethal, cancer among men in the U.S. Aggressive PCa is treated through androgen deprivation (chemical castration) but that treatment eventually fails and the disease progresses to castration-resistant prostate cancer (CRPC) that inevitably becomes resistant to all the approved treatments and is presently incurable. There is an urgent need for new types of drugs that would be effective against advanced CRPC. A protein called Mediator kinase acts in cancer cells to enable cancers to metastasize and to adapt to therapeutic drugs thereby becoming resistant to treatment. We have discovered that Mediator kinase plays an important role in the development and worsening of CRPC. We have also discovered molecules that selectively inhibit the Mediator kinase. These inhibitors suppress the growth of treatment resistant CRPC tumors in animal models, without apparent toxicity to the organism. Our current drug candidate is orally available, highly potent, and selective for its target (Mediator kinase) and shows excellent in vivo efficacy. We are planning to test this drug candidate in clinical trials. Prior to human testing, we are required to demonstrate the lack of toxicity of the drug candidate in two animal models, one of which should be a rodent and the other a larger animal. This grant application requests funding to carry out the requisite Good Laboratory Practice (GLP) toxicity testing in a rodent model (mice) and a pilot study in large animals (monkeys). Our initial non-GLP studies already give us confidence of the likely success of this testing. The proposed studies will be followed by a full-scale GLP toxicity testing in monkeys. Once the animal safety studies are complete, we plan to submit an Investigational New Drug application to the Food and Drug Administration and to start clinical trials in CRPC patients. Ultimate Applicability of the Research: This proposal directly addresses an overarching challenge in PCa: develop treatments that improve outcomes for men with lethal prostate cancer. Mediator kinase inhibitors are uniquely promising for this goal, since animal studies suggest that they become especially effective once CRPC tumors become resistant to anti-androgen therapies. The success of the clinical trials that we are planning after the proposed animal safety studies could lead to the approval of our novel, potentially breakthrough drug for currently incurable CRPC patients in 5-6 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210205
Entities
People
- George Wilding
Organizations
- Senex Biotechnology (United States)
- United States Army