Exploiting a New Achilles Heel of Mutant p53 in Breast Cancer
Abstract
Mutations and loss of TP53 are the most common genetic abnormalities found in nearly half of all human cancers and more than 80% of triple-negative breast cancer. Mutated TP53 is strongly associated with high tumor grade, poor prognosis, and resistance to chemotherapy. Unfortunately, we don’t have any specific therapy targeting mutant p53. The main goal of this project is to identify the vulnerability of mutant p53 and develop new therapies targeting its Achilles’ heel. Our group has been studying how mutant p53 can contribute to the aggressiveness of cancer cells. Normal cellular growth requires replication checkpoint response. Our recent study uncovers new mechanisms of replication perturbation caused by mutant p53. These findings open new opportunities to develop therapies against mutant p53. Based on our understanding of the molecular defects, we performed a large-scale compound screening and identified novel compounds targeting this new mechanism of checkpoint defect. In addition, the common structural feature of these initial lead compounds provides us very valuable information in drug design. Our proposed research will address two overarching challenges: (1) identify what drives breast cancer growth, and determine how to stop it and (2) revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. The types of breast cancer patients that our research will help are those harbor mutations of tumor suppressor p53 (TP53), especially in triple-negative breast cancer. In this proposal, we will investigate new therapeutic strategies to treat cancers that contain mutant p53. We will also utilize the structural information to design more potent compounds. This project will combine multiple approaches in molecular biology, cell biology, molecular docking, pharmacokinetics, and medicinal chemistry to develop new targeted therapies. The efficacy of these new drugs will be tested in patient-derived xenograft models of breast cancer. Success of this project will provide the first-of-its-kind therapy for mutant p53-harboring breast cancer. Therefore, it is expected to have a very significant impact. Since our preliminary studies already have identified several potent compounds, we anticipate a reasonable time frame to achieve the goal of this project and to develop these new compounds for future clinical trials to achieve patient-related outcome. On successful completion of this work, we hope to advance a few drug-like compounds 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
- Oct 29, 2018
- Source ID
- W81XWH1810329
Entities
People
- Weei-Chin Lin
Organizations
- Baylor College of Medicine
- United States Army