Strategies to Target Metabolic Addictions in Brain Metastatic Breast Cancer
Abstract
In 2020, approximately 170,000 women are projected to be living with metastatic (stage IV) breast cancer in the United States. Although metastatic breast cancer is generally considered to be incurable, it is often treatable and can be stably managed for prolonged periods as a chronic disease. However, the onset of brain metastases (BMs) is still considered an end-stage event, and median survival after diagnosis is measured only in months. Moreover, as more patients survive the typical latency of 2-3 years, the incidence of BMs is increasing. Treatment options for patients with brain-metastatic breast cancer are usually restricted to surgery or radiation, which along with the BMs themselves can have neurocognitive effects that negatively impact quality of life. Consequently, there is an overarching challenge to develop new therapeutic strategies that eliminate the mortality associated with brain-metastatic breast cancer. In order to fuel their continuous proliferation, cancer cells must be able to make use of the metabolic supplies that are available in their immediate environment. Because metabolite levels vary between organs in the body, metastatic cancer cells must have the flexibility to survive passage in the blood and then adapt to different nutrient availability at the metastatic site. The brain presents a particularly hostile environment in this respect, as many nutrients are maintained at much lower levels than in blood plasma or in other organs such as the liver. Consequently, breast cancer BMs adopt a unique metabolic profile, characterized by the expression of highly efficient pathways to harness energy from nutrients. In addition, we have found that breast cancer BMs exhibit elevated levels of autophagy, a process that allows for the recycling of cellular components. Because some of these adaptations seem to be selectively essential for metastatic growth of breast cancer cells in the brain, targeting them with drugs has the potential to block the growth of breast cancer BMs while minimizing adverse side effects in the patient. In this research plan, I propose experiments to develop and evaluate drug combination strategies that will induce a metabolic crisis in brain-metastatic breast cancer cells and thereby inhibit their growth. Since autophagy allows cancer cells to survive metabolic stress, I plan to use one drug that will create intense metabolic stress in BMs, and simultaneously use a second drug to block the adaptive autophagy response to this stress. Importantly, I will focus on novel combinations of drugs that are already used for other indications in order to streamline possible clinical application of these approaches. I also propose experiments to examine how brain-metastatic breast cancer cells co-opt neurons and glial cells in the brain and use them as an additional source of nutrients. Again, I will evaluate drug combination strategies designed to disrupt these processes and cut off the fuel supply to BMs without disrupting normal brain function. Finally, I propose a screen using CRISPR/Cas9 technology, which will identify additional essential metabolic enzymes – and potential new drug targets – in breast cancer BMs. The overall goal of this study is to develop urgently needed new therapy options for breast cancer patients with BMs, focusing on rational combinations of drugs that are already approved for other indications. This approach is intended to eliminate the mortality associated with brain-metastatic breast cancer, and to limit the need for more invasive treatments that adversely impact quality of life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110071
Entities
People
- Michael J Lukey
Organizations
- Cold Spring Harbor Laboratory
- United States Army