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Metabolic vulnerabilities in TSC and LAM
Investigating the molecular mechanisms of TSC and LAM pathogenesis
We recently made the surprising discovery that macropinocytosis in TSC is mediated via a lipid kinase, DGKA; Targeting DGKA using a repurposed drug strongly inhibited macropinocytosis and TSC2-deficient cell growth.
Kovalenko et al. Cancer Research. 2021.
Goal
The main goal of our research is to understand how mTORC1-hyperactive cells acquire and process nutrients, and how these processes go awry in Tuberous Sclerosis and Lymphangioleiomyomatosis. We are focused on elucidating the molecular mechanisms that drive nutrient uptake via macropinocytosis, which is elevated in mTORC1-hyperactive cells, and discovering therapeutic modalities that target multiple nutrient uptake pathways.
Approach
Our laboratory employs biochemistry, live cell imaging, metabolomic, and transcriptomic methodologies to identify cellular pathways and drugs that will lead to the elimination of tumors in individuals with TSC. Our models include cultured cell lines, in vivo imaging, and xenograft mouse models.
Impact
Our research has shown that simultaneous targeting of nutrient uptake pathways can selectively suppress the growth of TSC2-deficient cells, but not TSC2-expressing cells. This may lead to completely novel therapeutic strategies for TSC, with the potential to induce a cytotoxic, rather than cytostatic, effect on TSC-associated tumors.
Research at University of New England,
College of Osteopathic Medicine
Learn more about our research at the Department of Biomedical Sciences here