BLRD Research Career Scientist Award Application

Rlr Va Medical Center, Indianapolis IN

Investigators

Linked publications & trials

Abstract

Project summary: My current research is focused on understanding mechanisms by which breast cancer initiates and progresses. While many studies on breast cancer progression are focused on cancer cell biology, we are evaluating breast cancer as a systemic disease that influences the function of multiple organs. Breast cancer- associated deaths are not simply due to metastasis of cancer cells to distant organs or resistance to treatment but also due to its effects on bone and skeletal muscle. Our VA funded study focused on dissecting cancer- associated skeletal muscle changes, developing biomarkers of skeletal muscle changes for early detection of cancer-induced systemic effects and therapeutic modalities to limit the effects of cancer on skeletal muscle. Outcome of these studies have been published in eight manuscripts. Human skeletal muscle cell lines generated as part of this study have been distributed to other investigators. Focusing on the VA’s efforts on translational research, our new merit award application is on developing efficient drug screening strategies and to understand mechanisms of drug resistance using physiologically/pathologically relevant experimental conditions. Ultimate goal is to reduce the current clinical trial failure rate of 90%, enhance reproducibility in biomedical research, and to develop new combination therapies. In our recent publication in iScience, we demonstrated that new combination therapies can be identified only when cancer cells are evaluated for drug sensitivity under physiologic oxygen levels of 3-5% but not at current practice of ambient air, which contains 21% oxygen. Additional studies in the laboratory are on 1) mechanisms associated with breast cancer metastasis and therapeutic resistance; 2) genetic ancestry-dependent variability in the normal breast biology, which has resulted in initiation of a Phase II clinical trial; 3) defining cell-of-origin of breast cancer using single cell genomics; 4) biologic understanding of inflammatory breast cancer, which, unlike other breast cancer types, does not have a cell-of-origin but appears to involve aberrant interactions between breast epithelial cells and endothelial cells; 5) mechanisms associated with mutant PIK3CA-driven breast cancer initiation; 6) improving biospecimen collection and storage methods to enhance reproducibility of disease-specific biomarkers; and 7) developing chemoprevention strategies by understanding earliest events in breast cancer initiation. In the last study, we are focusing on a gene called TONSL, which is amplified in 20% of breast cancers and has immortalizing function. These studies are funded by independent agencies. Goals of these ongoing efforts are to comprehensively understand breast cancer development and progression and further contribute to individualizing breast cancer characterization and treatment. We aim to develop methods to classify breast cancer based on cell-of-origin and develop therapeutic modalities based on genomic aberrations. The laboratory has been very productive over the years with 70 publications since 2014. Our publications have received more than 21,000 citations with H-factor of 74. Our recently developed normal breast atlas, published in Nature Medicine, is now part of the Human Cell Atlas, a global effort to map every cell type of the body and available to researchers across the globe through CellXGene. The institutional infrastructure, both at IU and VA, and collaborations within and outside the institution and continuous extramural funding for the past 28 years enabled us to achieve these goals.