Cytoskeletal Modulation Results in Drug Resistance of Gastric Cancer Through Inhibition of p53-Mediated Apoptosis
Abstract
Scientific Objective and Rationale: Despite recent advances in therapy for gastric cancer such as the incorporation of trastuzumab for HER-2 positive disease, drug resistance, recurrent disease, and systemic metastases have limited our ability to eradicate advanced gastric cancer. Many mechanisms have been described to account for why the disease ultimately relapses, including secondary mutations in key driver genes, activation of bypass signaling pathways, survival signals secreted by the surrounding tumor environment, and the presence of a dormant tumor population with stem cell-like properties that is more resistant to drug therapy. In this proposal, we have identified a new mechanism that contributes to drug resistance of both targeted and chemotherapeutic agents. Inhibition of the Rho-ROCK-myosin pathway results in decreased p53-mediated apoptosis. Based on this observation, we hypothesize that therapeutic strategies that increase the level of wild-type p53 may promote drug sensitivity and increase tumor killing. Career Goal in Cancer Research: Dr. Wang is a medical oncologist and physician-scientist at the University of California, San Francisco. Her career aspiration is to understand how cancer cells evade cytotoxic drug treatment by using a variety of high-throughput functional genomic tools. This award will help expand her training to include biostatistics and cancer genomics, both important skills for performing future translational studies in oncology, as well as offering protected research time to generate a large body of work to successfully compete for National Institutes of Health funding. Applicability: Currently there are several MDM2 inhibitors in clinical trials, such as idasanutlin, which reactivates p53 activity. Based on our model, addition of these compounds to standard therapy may enhance tumor killing and achieve a deeper and more durable remission for all patients (including Veterans) with gastric cancer. Since many of these MDM2 inhibitors already have a proven safety profile in human Phase I trials, testing them in other settings should be relatively straightforward. Therefore, meaningful clinical readout may be achieved within 3 years. This strategy of combining a p53 activator with standard therapy may be applied to the neoadjuvant, adjuvant, or metastatic setting for treatment of gastric cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710365
Entities
People
- Victoria Wang
Organizations
- United States Army
- University of California, San Francisco