Page 22 - Hormel Report 2023

Robert Clarke, PhD
“Our research establishes mechanisms
of drug resistance and identifies new
therapeutic targets for breast cancer.”
Robert Clarke
22 | THE HORMEL INSTITUTE Cancer Systems Biology
EXECUTIVE DIRECTOR, THE HORMEL INSTITUTE / PROFESSOR
// UNIVERSITY OF MINNESOTA
More than 280,000 women are estimated to have been newly diagnosed with breast cancer in 2022. Seventy percent
of these will express estrogen receptor alpha and can be treated with endocrine therapies – such as tamoxifen, aromatase inhibitors alone –
or in combination with CDK4/6 inhibitors. Unfortunately, more than 50% of these patients will develop resistance to endocrine therapies and do not have any targeted therapeutic option.
Our laboratory uses novel approaches to investigate and understand the mechanisms responsible for endocrine therapy resistance in estrogen receptor positive breast cancer patients. We use multi-omics platforms and mathematical and computational modeling to determine altered pathways responsible for endocrine therapy resistance. We further lever- age that knowledge to discover novel targeted therapies and investigate its efficacy in in vitro and in vivo models.
Cell Communications in Antiestrogen Resistance
This research project investigates how endocrine therapy resistant cells communicate with the endocrine therapy sensitive and confer resistant phenotype to the sensitive cells in a heterogenous population. This project studies how these dynam- ical changes are affected by gap junctions and mi- crovesicle secretions. Other aims include building mathematical models of cell population dynam- ical changes and learning the basic principles of how resistant cells affect responses in a mixed population. Also, we will analyze data sets from patients to find key features of molecular signaling
associated with ER+ breast cancer recurrence.
Metabolic Adaptations Leading to Endocrine Therapy Resistance
In this project we investigate the metabolic adap- tations that are responsible for acquired/ de novo endocrine therapy resistance. We have identified high amino acid uptake, high glucose uptake
and glycolytic pathways that can be blocked by inhibiting the PFKFB3 enzyme and determined that impaired TCA cycle in endocrine therapy re- sistant cells accumulates high levels of succinate that may control the stability of hypoxia-inducible factor-1 alpha. We further aim to study how the altered function of electron transport chain in
the mitochondria may influence the response to endocrine therapies.
Role of Sirtuins in Endocrine Therapy Resistance
The primary objective of this project is to determine the roles of sirtuins (SIRTs) as key