Biomarkers and Therapeutic Strategy for ER+, Endocrine-Sensitive Breast Cancer

Project Overview

• Approximately 80% of breast cancers are estrogen receptor-positive (ER+) and endocrine therapy is used as a standard treatment. However, over 40% of advanced ER+ breast cancer patients do not respond to endocrine therapies due to primary resistance, and those who initially respond to the therapy may develop secondary acquired resistance.
• The reasons pertaining to endocrine therapy failure or resistance are currently unknown. One study demonstrated that elevated levels of activated C-Src tyrosine kinase (CSK) in an ER+, endocrine-sensitive breast cancer cell line leads to Tamoxifen resistance.
• Dana-Farber scientists have developed a new therapeutic approach to treat ER+ breast cancer patients that have CSK loss. 
• Dana-Farber Cancer Institute is seeking the right partner with an interest in licensing these assets for further development into new oncology therapeutics (Co-Exclusive License or Non-Exclusive License).

Technology

A research team from Dana-Farber Cancer Institute has uncovered a new mechanism for breast cancer endocrine resistance and a potential way to stratify ER+ breast cancer patients according to their predicted sensitivity to endocrine therapy.

Using genome-wide CRISPR screening experiments, the researchers showed that deletion of C-Src tyrosine kinase (CSK) stimulates cell growth without hormone in two ER+ breast cancer cell lines. Additionally, activation of P21 Protein-Activated Kinase 2 (PAK2), which relies on SRC-family kinase (SFK) activation, also promotes cancer cell growth.

Patients with CSK deletion and PAK2 activation have worse clinical outcomes. It was further demonstrated as a proof-of-concept that PAK2 and SFK inhibitors can effectively suppress the growth of CSK-null cells, but not CSK wild-type cells. These findings support a novel therapeutic solution to treat ER+ breast cancer patients that have CSK loss. 

Further Details:

Brown and Xiao et al. Estrogen-regulated Feedback Loop Limits the Efficacy of Estrogen Receptor-Targeted Breast Cancer Therapy, Proc. Natl. Acad. Sci. USA 2018, (115)31, 7869-7878

Team Members: Myles Brown, MD, Xiaole Shirley Liu, PhD, Tengfei Xiao, PhD, Wei Li, PhD

Applications

• Re-purposing PAK2 and CSK inhibitors to treat breast cancer patients with CSK loss.
• ER+ breast cancer patient stratification plans using predictive markers for endocrine therapy sensitivity.

Opportunities

Dana-Farber Cancer Institute is seeking the right partner with an interest in licensing these assets for further development into new oncology therapeutics (Co-Exclusive License or Non-Exclusive License).