A Novel Class of Galectin-1 Inhibitors for Prostate Cancer Therapy
Abstract
Recently, most physicians have adopted abiraterone (ABI) with prednisone or Enzalutamide (ENZ) as a first-line therapy for castration-resistant prostate cancer (CRPC) patients, since the survival rate is significantly higher. However, about half of prostate cancer patients develop drug resistance. Therefore, there is an urgent and unmet clinical need to develop therapeutic drugs that overcome drug resistance. Docetaxel remains the most effective first subsequent therapy among patients who progressed on ABI, with a median effective period of 4.2 months. Hence, our goal is to find ways to prolong the efficacy of docetaxel in post-ABI patients. Multiple studies indicate a role for Galectin-1 (Gal-1) in tumor formation and aggressiveness in docetaxel resistance. The goal of this proposal is to study the anti-cancer mechanism of our novel Gal-1 inhibitor, S-LLS30, and further develop it into a successful drug candidate for clinical trial. In Aim 1 of this proposed research, we will investigate the mechanism of Gal-1 involvement in docetaxel resistance and a potential role for novel Gal-1 inhibitor S-LLS30 in overcoming such resistance. In Aim 2, we will test the role of nuclear and cytoplasmic Gal-1 in mediating the effects of the S-LLS30 on the response of ABI-resistant CRPC to docetaxel. In addition, we will evaluate the effects of S-LLS30 in a patient-derived xenograft mouse model derived from biopsy material of patients with post-ABI CRPC expressing nuclear vs. cytosolic Gal-1. The proposed studies will not only enhance our understanding of Gal-1’s involvement in docetaxel resistance in CRPC and the expression of alternatively spliced androgen receptor variants, but also provide strong scientific evidence that S-LLS30 is an excellent drug candidate for further translational development. S-LLS30 represents a novel class of anti-cancer drug, and its successful development will have great impact on future therapies against CRPC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910727
Entities
People
- Ruiwu Liu
Organizations
- United States Army
- University of California, Davis