Titles and Affiliations

Professor, Biological Chemistry & Molecular Pharmacology
Harvard Medical School
Professor, Cancer Biology, Dana-Farber Cancer Institute
Co-leader, Breast Cancer Program, Dana-Farber/Harvard Cancer Center
Boston, Massachusetts

Research area

Developing safe and effective therapeutic strategies for treating BRCA1-deficient triple-negative breast cancer.

Impact

Triple-negative breast cancer (TNBC) is an aggressive form of the disease with poor prognoses and limited treatment options. PARP inhibitors have emerged as an efffective treatment for TNBC that are deficient in their ability to repair DNA damage (due to defective BRCA1). However, the impact of PARP inhibitors in patients with advanced BRCA-associated TNBC is relatively modest. The relationship between tumor cells and the tumor microenvironment markedly affects tumor development and therapeutic response. Dr. Zhao and her colleagues will investigate how the establishment of an immune suppressive tumor microenvironment promotes resistance to PARP-inhibitors and evaluate strategies to overcome this resistance. Her research will inform the development of more effective therapies for patients with this aggressive form of breast cancer.   

Progress Thus Far

Dr. Zhao and her team have developed and characterized several laboratory models of invasive TNBC that is driven in part by the loss of the BRCA1 gene. Using these models, they discovered an important mechanism of drug resistance that is mediated by macrophages – a type of immune cell – present in BRCA-deficient breast tumors. Moreover, they have identified an effective therapy to reprogram these macrophages to regain anti-tumor and pro-inflammatory functions, which can dramatically enhance the response to PARP inhibitor treatment

What's next

In the coming year, the team will build upon their findings to understand the molecular mechanisms underlying macrophage-mediated drug resistance including the reprogramming of macrophages to enhance PARP inhibitor treatment. They hope to gain insights to improve the design of more effective treatment options. 

 “If not for BCRF, we would not have been able to discover novel molecular and cellular mechanisms underlying the tumor and tumor immune microenvironment, which are the key to developing safer and more effective treatments for breast cancer.” – Dr. Zhao

Biography

Jean Zhao is Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School and Dana-Farber Cancer Institute (DFCI). Dr. Zhao’s research centers on understanding kinase signaling pathways in cancer. She has pioneered a new front in understanding signal transduction by integrating genetics and pharmacological approaches, thus changing the way we think about important problems in the targeted therapy of cancer. Specifically, she has conducted seminal work to determine distinct roles of isoforms of PI3K in the normal physiological functions and in the pathogenesis of cancer. Her work laid a foundation for the new field of targeting isoforms of PI3K in cancer and guided the design of current clinical trials of PI3K inhibitors for cancer patients. Dr. Zhao is a leader in the systems and functional approaches to targeting kinases in cancer, and has identified a number of novel oncogenic kinases and lead compounds, providing the groundwork for innovative therapeutic interventions. More recently, she is leading a major effort to establish patient-derived models of metastatic breast cancer. This work is designed to investigate the molecular and genetic basis for this disease and the mechanisms of drug resistance in order to translate fundamental preclinical findings into novel and improved therapeutic strategies for patients. Dr. Zhao’s honors and awards include Career Development Awards from NIH/NCI, V Scholar Award and Starr Foundation Award. She is a member of Committee for Women Faculty and Executive Committee for Research at DFCI, and serves as Co-Leader of the Breast Cancer Program at Dana-Farber/Harvard Cancer Center.

BCRF Investigator Since

2015