Mismatch Repair Loss, the Immune Environment, and the Breast Cancer Secretome
Abstract
Overarching Challenge: The proposed work will address the overarching challenge of revolutionizing treatment regimens to those that are less toxic and more effective. It will do so by implementing a precision medicine approach to match assayable biomarkers to U.S. Food and Drug Administration (FDA)-approved therapies in breast cancer patients who are resistant to current standard of care. Rationale and Objectives: Most breast cancer diagnoses (>70% of patients) are estrogen receptor positive and HER2 negative (ER+/HER2-). While ER+/HER2- breast cancer patients initially respond to standard endocrine therapies, 1 in 5 patients is intrinsically resistant to treatment, and 1 in 4 patients will eventually develop resistance. There are few options available to this patient population once their cancer becomes resistant to endocrine therapies. None of the pharmacological interventions approved by the FDA improves objective survival rates and many negatively impact quality of life. By understanding the biology of endocrine therapy-resistant breast cancer, we can use molecular diagnostics to identify specific patient cohorts and match them to the treatment strategy that is likely to be effective in increasing survival with minimal toxicity. We recently identified that loss of a DNA damage repair gene, MLH1, in ER+/HER2- breast cancer cells, induces instant resistance to endocrine therapy. This resistance occurs because MLH1 loss changes the proteins that ER+/HER2- breast cancer cells secrete into their environment. On studying the types of proteins that MLH1- ER+/HER2- breast cancer cells secrete we made two discoveries with therapeutic consequences: 1) MLH1 loss causes cells to secrete factors that bind to, and activate, a group of growth-promoting proteins found at the cell membrane. There are many available inhibitors for these growth-promoting proteins that are FDA-approved for advanced ER+/HER2- breast cancer but have not shown significant impact in all-comers clinical trials. 2) MLH1 loss also causes ER+/HER2- breast cancer cells to secrete a set of proteins that change the immune cells surrounding the tumor to promote metastasis. This change in the immune environment suggests that these patients would benefit from a specific immunotherapeutic combination. Using our knowledge of the unique biology of MLH1 loss in ER+/HER2- breast cancer cells, we propose to identify the optimal combinatorial therapies that target the growth-promoting proteins in MLH1- cells (Aim 1) and the immune environment (Aim 2) in a series of preclinical experiments. The objective of this proposed study is to provide proof of concept for clinical trials rationally designed to test an optimized treatment regimen, with the overall goal of transforming how advanced ER+/HER2- breast cancer patients are treated. Impact and Relevance: Who this project will help: This study will primarily help the 15% of primary and 30% of metastatic ER+/HER2- breast cancer patients whose tumors are MLH1-defective and resistant to endocrine therapy. Potential Clinical Applications: This work is critical for providing preclinical proof of concept that the proposed FDA-approved therapeutic strategies will be effective in MLH1- ER+/HER2- breast cancer patients. The relevance of this work lies in identifying a diagnostic strategy that is already in routine clinical use to predict response to FDA-approved therapies that currently lack stratifiers. Time to Patient-Related Outcomes: Implementation of a clinical trial stemming from this work will likely occur within 5 years of completion of proposed work since all therapies being tested are FDA-approved, as is the diagnostic assay to identify MLH1 loss. Moreover, we have already established collaborations with clinicians at multiple institutions to implement the clinical trial (including Drs. Bora Lim, Stephen Shiao, and Matthew Ellis). Impact on Ending Breast Cancer: At a conservative estimate, we expect at l
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210573
Entities
People
- Svasti Haricharan
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army