Therapeutic Targeting of Recurrent Castrate-Resistant Prostate Cancer by ACK1 Tyrosine Kinase Inhibitor (R)-9b
Abstract
Prostate cancer is one of the most common cancer among men, with more than 1 million men diagnosed with this disease every year around the world. Almost one third of the patients with localized high-risk prostate cancer are treated with surgery, chemotherapy, radiation, or androgen deprivation therapy (ADT); however, even though these treatments provide sufficient benefits, patients soon stop responding and develop a stage commonly referred to as castration-resistant prostate cancer (CRPC). In recent years, CRPCs have frequently been treated with two distinct therapeutics, Enzalutamide and Abiraterone, which although they provides relatively benefits, once again led to recurrence in about a year. Large efforts are currently drawn towards developing therapies that could help CRPC patients with the recurrence. We have developed a new class of small molecule inhibitor (R)-9b that not only suppresses a critical regulator of CRPCs, an Androgen Receptor (AR), but also its splice variant, AR-V7, which is known to be specifically upregulated upon Enzalutamide and and Abiraterone treatment and considered to be the major reason for the drug-resistance. Significantly, (R)-9b suppressed Enzalutamide-resistant CRPC tumor growth in animal models. Enthused with this observation, we undertook extensive pre-Investigational New Drug studies that revealed excellent drug-like properties of (R)-9b, indicating it could potentially emerge to be the “third generation” of antagonist. This proposal is primarily explores various strategies that would allow us to test efficacy of (R)-9b as a new therapeutic option for Enzalutamide (or Abiraterone)-resistant prostate cancer. Briefly, it will assess toxicity of this compound in non-rodent model and later in various patient derived organoids (PDOs) and patient derived xenografts (PDXs). Overall, a successful completion of this study could lead to the development of a new class of AR pathway antagonist that could provide significant palliative benefits to recurrent CRPC patients. The objective of this proposal is to perform preclinical studies to take (R)-9b compound into clinical trials.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110202
Entities
People
- Nupam P. Mahajan
Organizations
- United States Army
- Washington University in St. Louis