Targeting Metabolic Reprogramming in ER+ Breast Cancer

Project Summary: Adjuvant endocrine therapies are effective in treating estrogen receptor-positive (ER+) breast cancer, but drug-tolerant persister cancer cells (DTPs) contribute to cancer recurrence in approximately 1/3 of patients. Thus, targeting DTPs is an attractive therapeutic approach, but it has been hampered by a lack

of understanding of DTP biology. Our long-term goal is to discover vulnerabilities of DTPs that can be thera- peutically targeted. The overall objective of this project is to determine the consequences of, and vulnerabilities created by, metabolic reprogramming in ER+ breast cancer cells that enable tolerance of estrogen deprivation.

Our central hypothesis is that estrogen deprivation induces reprogramming of energy metabolism that creates therapeutic vulnerabilities in ER+ breast cancer DTPs. The rationale for this project is that identification of the vulnerabilities of DTPs in ER+ breast cancer will enable the rational development of therapeutic strategies to

target DTPs and prevent cancer recurrence. The central hypothesis will be tested by pursing two specific aims: 1) Determine the effects of estrogen deprivation on energy metabolism in ER+ breast cancer; and 2) Deter- mine the metabolic vulnerabilities conferred by ER+ breast cancer cell persistence during estrogen deprivation.

The first aim will utilize ER+ breast cancer cells to measure the effects of estrogen deprivation on bioenerget- ics and underlying mechanisms. In the second aim, we will measure the effects of inhibition of mitochondrial oxidative phosphorylation on the source and amount of ATP production, and on cell fate in endocrine-sensitive

and endocrine-persistent ER+ breast cancer cell lines and tumors. Results from these studies will provide a fundamental understanding of how metabolic reprogramming creates vulnerabilities in bioenergetic depend- ence, and provide data to guide clinical testing of metabolic disruptors to induce energetic catastrophe in ER+

breast cancer. The acquisition of such knowledge is essential to the development of improved therapeutic strategies to target endocrine-persistent breast cancer cells. The proposed research is innovative because it will test the therapeutic potential of suppressing OXPHOS to elicit energetic catastrophe as well as elucidate

the mechanism underlying bioenergetic shifts in breast cancer cells that survive endocrine therapy. The pro- posed research is significant because it will implicate OXPHOS reliance as a therapeutic vulnerability in DTPs and provide justification for clinical testing of metabolic disruptors. The environment at Dartmouth College and

Dartmouth Cancer Center is ideal for the proposed translational research with a long-standing history of clini- cian-scientist collaborations and cancer research support. The cadre of assembled Sponsoring Team mem- bers will provide support in both research and clinical mentorship with expertise, materials, and dedicated pre-

ceptorship time. Together with the outlined training plan, the proposed work will support the Applicant’s career plan to become an independent, highly productive physician-scientist focused on oncology.