Posted June 26, 2014
Elizabeth Henske, M.D., Brigham and Women's Hospital

Elizabeth Henske, M.D. Tuberous Sclerosis Complex (TSC) is a rare multi-system disorder that causes the growth of benign tumors in vital organs such as the brain, kidneys, heart, eyes, and lungs. TSC is a genetic disease caused by a mutation in the TSC1 or TSC2 gene, which leads to the activation of mammalian target of rapamycin complex 1 (mTORC1). mTORC1 is a protein complex that controls the synthesis of other proteins that, in turn, cause tumor growth. Recent research has also shown that mTORC1 functions as a master regulator of cellular metabolism and autophagy, a process through which cells undergo "self-eating" to maintain metabolic homeostasis. mTORC1 inhibitors have had remarkable success in the treatment of TSC. However, they can cause serious toxicities, do not induce complete tumor responses, and do not induce responses that are sustained when the treatment is discontinued; thus, development of improved targeted therapies for TSC is necessary.

Dr. Elizabeth Henske of Brigham and Women's Hospital hopes to identify novel therapeutic options for the treatment of TSC by targeting cellular metabolism pathways. She has recently discovered that TSC2-deficient cells have low autophagy levels and are highly dependent on autophagy for survival in vitro and in vivo. Furthermore, recently published work, she elucidated that inhibition of autophagy in TSC2-deficient cells leads to altered metabolites in the pentose phosphate pathway (PPP) and in glutamate biosynthesis pathways. Through additional experimentation, she found that these pathways can be targeted without the use of mTORC1 inhibitors, although details of how these pathways alter metabolic reprogramming and contribute to the growth and survival of TSC2-deficient cells are still largely unknown.

With support from a TSCRP FY12 Idea Development Award, Dr. Henske will further define the mechanism of metabolic reprogramming in TSC. Additionally, she will determine the impact of metabolic reprogramming on the proliferation and survival of these cells. Using patient-derived cells, she will perform a screen of FDA-approved compounds to identify agents that affect metabolic reprogramming and cause cell death in TSC. Furthermore, Dr. Henske has developed a novel mouse model using the TSC2-deficient cells and will utilize it to test candidate compounds identified in the drug screen. Ultimately, Dr. Henske hopes to increase the understanding of how metabolic reprogramming contributes to cell growth and survival in TSC2-deficient cells. Augmenting the current body of knowledge with the results of Dr. Henske's research may provide the edge needed to successfully develop highly effective, metabolically targeted therapeutic strategies for children and adults with TSC.


Public and Technical Abstracts: Dysregulation of Cellular Metabolism: Novel Therapeutic Opportunities for TSC

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