Novel Synthetic Lethal Therapies for Triple-Negative Breast Cancer
Abstract
Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous disease. Despite therapy, many patients eventually develop recurrence and metastasis, which result in poor prognosis. Conventional chemotherapy used to treat TNBC suffers from the issues of drug resistance and toxicities. Thus, innovative approaches, such as combinations of novel targeted therapies, are urgently needed for TNBC treatment. This proposal aims to address this important issue by investigating several novel combination targeted therapies against TNBC. Our proposal will address the challenges of revolutionize treatment regiments by replacing them with ones that are more effective, less toxic, and impact survival and eliminate the mortality associated with metastatic breast cancer. We have identified small molecule inhibitors against a TNBC therapeutic target that is involved in DNA replication and transcriptional control. We also performed genome-wide CRISPR-Cas9 screening using these inhibitors and identified new therapeutic targets that have synthetic lethal interactions with TopBP1 in TNBC. Some inhibitors of these new synergistic therapeutic targets have either been U.S. Food and Drug Administration (FDA) approved or used in prior clinical trials. The synergy between our inhibitors and these FDA-approved or previously used drugs has been validated in our preliminary study. In this proposal, we will investigate the mechanisms leading to the synergy of these new drug combinations in a panel of breast cancer cell lines. We will also perform transcriptome profiling and genome-wide CRISPR-Cas9 screen to elucidate the mechanisms of synergistic drug combinations. Subsequently, the efficacy of the combination therapy will be tested in two patient-derived xenograft models of breast cancer. If confirmed, we will develop new combination targeted therapies for breast cancer patients, especially for the patients with TNBC, and for those patients with advanced diseases or metastatic diseases who do not have effective therapies. Therefore, we anticipate that the proposed studies will have a major impact on breast cancer therapy. Since we already identified potent compounds and combination therapies, we anticipate a reasonable time frame to achieve the goal of this project and to develop these new combinations for future clinical trials to achieve a patient-related outcome. After successful completion of this work, we hope to advance the combination therapy to early phase trials in a timely fashion, potentially with added resources of another funding partner.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210226
Entities
People
- Weei-Chin Lin
Organizations
- Baylor College of Medicine
- United States Army