Defining and Therapeutically Targeting the Immunological Landscape of SF3B1-Mutant Breast Cancer
Abstract
New diagnostics and therapeutics have dramatically improved the detection and treatment of early-stage breast cancer over the past two decades, but therapeutic options for treating advanced or metastatic breast cancer have not advanced at the same rate. As a consequence, once breast cancer spreads or metastasizes to distant places in the body, it is considered incurable. Current therapies for metastatic breast cancer can reduce the rate at which the cancer spreads, but do not actually eradicate the cancer. Furthermore, although existing treatments may initially be effective, metastatic breast cancer inevitably becomes treatment-resistant and spreads. As metastasis is the cause of almost all breast cancer-related death, there is a pressing need to develop new ways to treat metastatic breast cancer. Immunotherapy, or harnessing a patient’s immune system to fight cancer, has revolutionized the treatment of many types of advanced cancer. Immunotherapy is effective against many cancers that were previously considered untreatable, enabling patients to live decades after being diagnosed with aggressive, late-stage cancer. However, immunotherapy is not effective for most breast cancer patients. In this proposal, we seek to realize the promise of immunotherapy for treating advanced breast cancer by (1) identifying a subset of breast cancer patients whose cancers can be treated with existing immunotherapeutic drugs and (2) developing new classes of immunotherapeutics for treating advanced breast cancer. A subset of breast cancers contain genetic changes or mutations affecting the SF3B1 gene. This gene is critical for “RNA splicing,” a molecular process in which genetic information is read from DNA in order to make proteins. Mutations in SF3B1 cause RNA splicing to go awry, helping breast cancers to grow. Although mutations in SF3B1 cause cancer, we hypothesize that they also make breast cancers vulnerable to treatment with immunotherapy. Specifically, we discovered that breast cancers with SF3B1 mutations produce many abnormal proteins that may be recognized by the immune system as foreign. This is important because immunotherapy only works when cancer cells produce such foreign proteins, which is not the case for most breast cancers. Therefore, we hypothesize that we can destroy breast cancers with SF3B1 mutations by increasing the immune system’s ability to recognize and destroy cancer cells that are producing abnormal proteins. We will test this hypothesis by identifying abnormal proteins that are produced by breast cancers with SF3B1 mutations, identifying cancer-destroying immune cells that recognize these abnormal proteins, and determining the efficacy of immunotherapy in combination with other treatments for triggering destruction of breast cancers with SF3B1 mutations. The proposed research has the potential to rapidly improve treatment options for advanced breast cancer in two ways. First, if our hypothesis that breast cancers with SF3B1 mutations are vulnerable to combinations of existing drugs (“immune checkpoint inhibitors” and “CDK4/6 inhibitors”) is correct, then this research could change how advanced breast cancer is treated within 3 years. Second, if we are able to identify immune cells that specifically recognize abnormal proteins produced by breast cancers with SF3B1 mutations, then this research could stimulate the development of an entirely new type of immunotherapeutic (“adoptive cell transfer”) for treating advanced breast cancer. Therefore, the proposed research addresses two overarching challenges: • “Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival” • “Eliminate the mortality associated with metastatic breast cancer” Overall, we expect the proposed research to identify a novel, genetically defined subtype of breast cancer that is uniquely response to immunotherapy. These studies will help to realize the promise
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010597
Entities
People
- Evan W Newell
Organizations
- Fred Hutchinson Cancer Center
- United States Army