Targeting Metabolic Pathways in Overcoming Drug Resistance in Metastatic Castrate-Resistant Prostate Cancer
Abstract
Castration-resistant prostate cancer (CRPC) emerges as tumor and undergoes adaptation to low levels of androgens by either synthesizing its own androgens (intratumoral androgens) or altering the androgen receptor. Treatment with new-generation androgen signaling inhibitors (ASI) (abiraterone acetate and enzalutamide) offers an initial response, followed by drug resistance, and the patient clinically progresses on these agents. Given the promise of targeting HMG-CoAR, the rate-limiting enzyme for cholesterol synthesis with statins and AMPK, master regulator of metabolic pathways activation with biguanides using a combination of simvastatin (SIM) and metformin (MET) as a safe, efficacious, and cost-effective agent to treat ASI-resistant CRPC, it is imperative to understand the molecular mechanism(s) and signaling pathways by which the synergistic combination of SIM plus MET inhibits tumor progression. This proposal will provide mechanistic understanding and represents an innovative effort that aims to significantly reduce cancer mortality and improve survivorship and the quality of life of CRPC patients fighting this lethal form of prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810618
Entities
People
- Sanjay Gupta
Organizations
- Case Western Reserve University
- United States Army