Therapeutic Targeting of Genomic Instability in Triple-Negative Breast Cancer
Abstract
This proposal addresses two fiscal year 2022 (FY22) Breast Cancer Research Program (BCRP) Overarching Challenges: (1) Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival; and (2) Eliminate the mortality associated with metastatic triple-negative breast cancer (TNBC). TNBC is an aggressive form of the disease, which is associated with a high risk of relapse and short survival in the metastatic setting. Currently, it has fewer treatment options than other forms of breast cancer. Our objective is to lower mortality and improve treatment for patients affected by TNBC by developing biological and computational methods that will identify treatment strategies to overcome the cancer evolution that is responsible for the development of drug resistance and the failure of existing treatments. Cancers are adaptable systems constantly changing in response to evolutionary pressure. These processes occur differently across the individual cells of a single tumor. Genome sequencing methods to evaluate patient tumors typically assess the tumor as a single blended genome, obscuring information about important processes occurring in single cells. This proposal builds on work from our groups and our collaborators over several years, which has laid a strong foundation of sophisticated single-cell genome sequencing and computational analysis, along with laboratory models of breast cancer which mimic the behavior of clinical disease one to 15. Altogether, these tools enable the study of cancer as a mosaic of distinct genomes: sequencing of these single-cell genomes can reveal information about a cancer s response to drug treatments. In recent work, we have shown that these single-cell processes can lead to resistance to platinum salts, a standard chemotherapy treatment used today for people with TNBC. This proposal seeks to use novel single-cell genome sequencing methods in TNBC tumors transplanted from patients and grown in the lab within specialized strains of mice or as cells in a laboratory culture under customized growth conditions. We will not only study the behavior of these patient-derived cancers as they evolve over time, but we will also study these TNBC genomes as they respond to drug treatment, drug withdrawal, and under direct genetic editing of cancer cells. We aim to inform treatment decisions and improve treatment options by identifying combinations of existing therapeutics and those positioned to be tested in patients in the near future. We expect several outcomes that will lead to near-term clinical benefits for patients with early and metastatic TNBC. This proposal will: (1) identify new strategies that can be tested in clinical trials, together with predictive markers, to select drugs for patients based on associations between their tumor s genetic markers and the relative effectiveness of each drug in that context; and (2) identify combinations of existing and emerging drugs that, when informed by genetic testing of patients, can overcome single-drug resistance. Our work will also create a better understanding of cancer evolution and a general framework for the investigation of new drugs for breast cancer, which will advance and accelerate ongoing progress towards durable breast cancer treatment and cures.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310820
Entities
People
- Samuel Aparicio
Organizations
- Provincial Health Services Authority
- United States Army