Sulindac-derived compounds for breast cancer therapy
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Resistance of breast cancer to available therapies and lack of treatment for triple-negative breast cancer (TNBC) represent critical unmet medical needs in the treatment of breast cancer. The PI3K/AKT signaling pathway is abnormally activated in more than 70% of breast tumors and is believed to play a key role in TNBC and drug resistance. Thus, the pathway has been targeted for developing therapeutics against TNBC and for overcoming drug resistance. However, current strategies that rely on direct inhibition of PI3K/AKT activities have resulted in profound toxicities because they affect normal cells and cell pathways. Identification of better therapeutic targets that are responsible for the aberrant activation of the PI3K/AKT pathway will offer new strategies for developing novel and effective TNBC drugs. We recently discovered that retinoid X receptor-alpha (RXR-alpha) is abnormally processed into a shortened, truncated, form of the protein called tRXR-alpha as cells become cancers and that breast tumors have particularly high levels of this tRXR-alpha protein. In addition, we found that tRXR-alpha protein promotes breast cancer cell growth by binding to PI3K and activating the PI3K/AKT pathway. Therefore, tRXR-alpha represents a potential therapeutic target for TNBC and drug resistance. Moreover, we discovered that nonsteroidal anti-inflammatory drug (NSAID) Sulindac and Sulindac-derived compounds (analogs) could bind to tRXR-alpha, block it from activating the PI3K/AKT pathway, and inhibit the growth of breast cancer cells. Thus, in this IDEA grant application, we propose to develop new Sulindac analogs with improved efficacy and selectivity for breast cancer therapy and for overcoming drug resistance. 
 
 
 
 
 
 
 
 The question(s) or central hypotheses of the research: 
 
 The central hypotheses of our research are: (i) tRXR-alpha is a tumor protein and plays a critical role in the development of breast cancer, the survival of TNBC cells and drug resistance, (ii) tRXR-alpha is a novel therapeutic target involved in the abnormal activation of the PI3K/AKT pathway and (iii) Sulindac analogs targeting tRXR-alpha represent a new class of therapeutics for treating breast cancer including TNBC and for disabling drug resistance. 
 
 
 
 
 
 
 
 
 
 The general methodology: 
 
 We will design, synthesize and evaluate a few new Sulindac analogs with a goal of identifying a drug candidate. We will first design new Sulindac analogs using computer-aided drug design approaches and will evaluate the inhibitory effects of the new analogs on the activity of the PI3K/AKT pathway. We will then use a panel of TNBC and non-TNBC breast cancer cell lines to evaluate and determine the effects of the new analogs on breast cancer cell growth and apoptosis. Furthermore, we will use breast tumor animal models to determine the anti-tumor effects of the analogs 
 
 
 
 
 
 
 
 
 
 Innovative elements of the project:
 
 There are several innovative and exploratory aspects of the project: (i) our concept that tRXR-alpha is a key molecule involved in the aberrant activation of PI3K/AKT pathway in breast cancer cells is novel and significant. This provides a new target and strategy to modify the PI3K/AKT pathway for breast cancer therapy, (ii) our discovery that Sulindac and analogs could target tRXR-alpha to kill cancer cells including TNBC cells offers a great starting point to develop small molecule therapeutics for breast cancer treatment and drug resistance and (iii) since our proposed Sulindac analogs are derived from an existing drug with proven drug safety in human, they hold great promise on a "critical path" to advance the topic under investigation to clinic.