Exploiting Molecular Origins and Therapeutic Implications of DNA Damage-Triggered Innate Immune Responses in Breast Cancer
Abstract
Although immunotherapy drugs called PD-1 inhibitors, which prime the body’s immune system to attack cancer, are efficacious in various cancers, less than 8% of breast cancer patients benefit from such treatment. The goal of our application is to address the overarching challenge in breast cancer immunotherapies: not only to develop ways to identify which breast cancer patients can most likely benefit from such immunotherapy drugs, but also to increase the drugs’ effectiveness in patients for whom they currently do not work. By testing hundreds of different genes, our lab has determined that abnormalities in how cancers respond to DNA damage (called DNA damage response) may predict which breast cancers will respond to PD-1 inhibitors. Specifically, we found that abnormalities in the DNA damage response occurring during the S-phase (synthesis phase) of the cell cycle may activate antitumor innate immunity and indicate responsiveness to immunotherapy. Importantly, as a proof-of-concept study, our preliminary data demonstrated we can identify an abnormality in a gene from our genetic screen, called NPRL2, in patients with defective S-phase DNA damage response. Crucially, our lab studies have shown that the loss of S-phase DNA damage response increases responsiveness to immunotherapy in breast cancer. Based on results from our clinical and laboratory studies, we now wish to study the following: 1. Determine how abnormalities in S-phase DNA damage response enhance responsiveness to immunotherapy in breast tumors by studying NPRL2 in proof-of-concept experiments. 2. Determine if a gene signature derived from S-phase DNA damage response or the loss of NPRL2 can predict immunotherapy-responsive breast cancers by using breast cancer animal models and also breast tumor samples collected from patients. 3. Evaluate if we can use cancer drugs known to lead to defective S-phase DNA damage response to directly enhance the responses to immunotherapy drugs in animal models with both primary tumors and metastatic breast tumors by activating antitumor innate immunity, thus turning immune cold tumors to immune hot tumors. Completion of this project will provide essential preclinical data to develop clinical trials that personalize immunotherapy: (1) by developing a new test for S-phase DNA damage response to identify which breast cancer patients are most likely to respond to PD-1/L1i-based combinations; and (2) by identifying more effective, less toxic drugs that are suitable for immunotherapy-based combination regimens. S-phase DNA damage response is a fundamental biological pathway in all breast cancer subtypes and at all development and progression stages. Thus, we expect our new S-phase DNA damage response pathway-based biomarker and personalized PD-1/L1i-based combination regimens will benefit breast cancer patients of all major molecular subtypes (ER+, HER+, basal-like) and at all disease stages, including both primary and metastatic tumors.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210502
Entities
People
- Timothy A Yap
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army