Combining Immunotherapy and MYC Synthetic Lethality for Metastatic Breast Cancer
Abstract
Metastasis, the spread of cancer throughout the body, remains the single greatest challenge that breast cancer patients face, because therapeutics directed against metastatic breast cancer often result in only partial and transient responses. One of the major challenges for improving such therapies is our inability to identify ways to selectively kill metastatic tumor cells. Immunotherapies that reactivate the patient s immune cells to attack breast cancer cells have the potential to eliminate even large metastatic tumors, offering hope for long-term clinical benefit for patients. Unfortunately, typically less than 20% of patients with metastatic breast cancer will respond to current immunotherapies, and recently approved combinations of chemotherapy and immune therapies only modestly extend patient survival. Our partnering labs have discovered that the MYC cancer gene is frequently overexpressed or activated in aggressive breast cancer subtypes, such as receptor triple-negative breast cancer (TNBC), ER+ luminal B tumors, or in early stages of metastatic disease. Unfortunately, selective MYC-directed small molecule inhibitors have yet to be developed for clinical use. Nevertheless, the partnering investigators have discovered a variety of pathways, which when inhibited can preferentially kill MYC high cells, while sparing non-tumor cells – an approach known as synthetic lethality (SL). The Partnering PIs labs have also generated compelling preliminary data demonstrating that new combinations of SL drugs and immunotherapy can durably eradicate between 50%-75% of aggressive TNBC tumors, and mice in which the tumors completely regress are resistant to subsequent tumor formation. Such SL and immunotherapy combining approaches have been translated by the partnering investigators to two early-phase clinical studies; one of these studies is nearing completion and has already demonstrated promising early results for patients with metastatic TNBC [ASCO 2020]. Using experimental models of breast cancer, we and others have also discovered that tumors driven by the MYC oncogene tend to be devoid of infiltrating immune cells, suggesting that these cancers will be especially resistant to immunotherapies and therefore, the immunotherapy agent needs to be carefully chosen. Selectively killing MYC-high breast tumor cells would be predicted to both diminish the aggressiveness of breast cancers and render them more sensitive to reactivation of the patient s immune responses. In this proposal, we seek to discover the role of MYC using data and samples from four ongoing clinical trials seeking to determine optimized MYC biomarkers and if MYC activity predicts response to various immunotherapy combinations. Using advanced preclinical models, we next seek to identify better SL plus immunotherapy combinations, which can be translated to next-generation clinical trial concepts. Finally, we are cognizant that many promising treatment approaches, even immunotherapies, may generate tumor resistance and recurrence. We propose an innovative approach to help identify mechanisms through which tumor cells may escape, even our best combinations of therapeutics. Better understanding of tumor resistance mechanisms would allow for the development of even better future therapies. Finally, by substituting conventional chemotherapy combinations, our proposal seeks to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. The proposed studies bring together two dedicated teams of researchers, clinicians and advocates – exploring and cross-validating between multiple clinical trials, preclinical model systems, and shared expertise. Our transdisciplinary research culture will build stronger bidirectional support for the intersection of research, oncology, art, and advocacy exchange as a creative tool for transformation. For example, during the project advocates will give insights how to tailor ou
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110774
Entities
People
- Andrei Goga
Organizations
- United States Army
- University of California, San Francisco