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Strategies to Target Metabolic Addictions in Brain Metastatic Breast Cancer

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[Technical Report, Annual Report]

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The overarching goal of this project is to determine whether the unique metabolic phenotype of brain metastases arising from breast cancer presents new opportunities for therapeutic intervention. Specifically, we are addressing whether the nutrient environment of the brain increases the dependence of metastatic breast cancer cells on lysosomal function and autophagy, thereby sensitizing brain metastases to lysosomotropic agents that disrupt autophagy. We are also testing the hypothesis that drug combination strategies can be developed in which treatment with a metabolic inhibitor further increases the dependence of brain-metastatic breast cancer cells on lysosome functionautophagy, such that concomitant treatment with a lysosome inhibitor yields a synergistic response. During the present reporting period, we found that brain-metastatic triple-negative breast cancer TNBC cells are markedly sensitized to lysosome inhibitors in a physiological culture medium that models the nutrient composition of the brain interstitial fluid ISF. Unexpectedly, the sensitivity of HER2 brain-metastatic breast cancer models to lysosome inhibitors is unaffected by the nutrient environment, potentially reflecting a poor ability to activate autophagy when the HER2-mTORC1 axis is constitutively active. We have also found that lysosome inhibitors selectively synergize with OXPHOS inhibitors against brain-metastatic TNBC cells in physiological, but not standard, culture medium.

Subject Categories:

  • Medicine and Medical Research
  • Anatomy and Physiology
  • Pharmacology

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[A, Approved For Public Release]