Investigating the biology and therapeutic vulnerabilities of ER+ metastatic breast cancer with activating HER2 mutations

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Project Summary/Abstract The candidate, Ms. Utthara Nayar, PhD, is a translational cancer biologist, and currently a Research Fellow in Medicine at Dana-Farber Cancer Institute, Harvard Medical School, and the Broad Institute of MIT and Harvard. She employs genomic technology to investigate mechanisms of resistance in estrogen receptor- expressing (ER+) metastatic breast cancer (MBC). Prior to this, she trained in viral oncology laboratories at Cornell University and Brigham and Women's Hospital. She expects to pursue an academic career at the intersection of basic and translational research in breast cancer that will involve molecular and genomic approaches, in collaboration with physician-scientists and computational biologists working to end the disease. This proposal lays out a structured 3-year plan of research and coursework, including the acquisition of data science, grant-writing, and translational skills, which will uniquely situate the investigator as an experienced experimental biologist and bioinformatician. The research project proposed, in combination with the team of collaborators and institutional environment, is designed to position her on a road to independence within the field of therapeutic response and resistance in breast cancer. The primary reason for breast cancer mortality is the development of resistance, through largely unknown mechanisms, to targeted anti-estrogen therapies in ER+ MBC. Dr. Nayar recently identified acquired activating mutations in human epidermal growth factor receptor 2 (HER2), which activates the MAPK pathway, in patients with resistance, and demonstrated that these directly conferred resistance to anti-ER agents. Since this is an emerging class of resistance, a deeper understanding of the biology and therapeutic vulnerabilities of tumors bearing such mutations or related genetic alterations in the MAPK pathway is required. The scientific objective of this proposal is to study the effect of MAPK signaling from HER2 mutations in ER+ MBC in terms of two major biological consequences that Dr. Nayar identified through global transcriptomic analysis in ER+ HER2- mutant tumors: altered ER pathway, and enhanced interferon and inflammatory signaling. This application proposes to investigate these questions in two distinct aims. In specific Aim 1, the effect of HER2 mutations on the ER-associated and global transcriptional network will be examined using genome-scale in vitro approaches (ChIP-seq/ATAC-seq). Aim 2 determines the implication of enhanced inflammatory signaling in ER+ HER2- mutant tumors, by ascertaining the autocrine and paracrine effects on signaling and immunogenicity in cell line and mouse model systems, as well as by examining tumor immune microenvironment in patient tumor samples. At the end of the project, we can expect to gain a deeper understanding of HER2-mutant and related breast tumors in terms of the effect of MAPK activation on ER signaling and immunogenicity, as well as their potential for targetability by epigenetic (Aim 1) or immunotherapeutic (Aim 2) approaches.