Program Director/Principal Investigator (Last, First, Middle):Kwiatkowski, David J. et al., Project 2: Cantley and Shaw Abstract Over the past five years it has become clear that many tumors rewire their metabolism to support rapid growth, but that the molecular details of how each tumor rewires its metabolism depends on the unique oncogenes and tumor suppressors that dominantly control metabolism, which include all of the hamartoma syndrome genes, as the PI3K/ mTOR/ LKB1 pathways play a major role in metabolic control in normal and cancer cells. The focus of this project is to better understand metabolic vulnerabilities and provide preclinical data that would support the development of biomarker driven clinical trials to evaluate such drugs in patients with germline or the many tumors containing sporadic mutations in hamartoma syndrome genes (PTEN, LKB1, TSC1, TSC2).
Kwiatkowski, David J. et al., Project 2: Cantley and Shaw Narrative The hypothesis guiding this proposal is that mutations in hamartoma syndrome genes (PTEN, LKB1, TSC1, TSC2) dominantly rewire metabolism exposing unique vulnerabilities. The focus of this project is to better understand the molecular and biochemical basis for the metabolic vulnerabilities and provide preclinical data that would support the development of biomarker driven clinical trials to evaluate such drugs in patients with germline or the many tumors containing sporadic mutations in hamartoma syndrome genes. We have characterized and developed three novel cancer metabolism based oncology therapeutic modalities over the past 5 years and now we are poised to decode the selectivity, mechanisms for resistance, and optimize combination therapies. The specific aims are: 1) Examining efficacy of biguanides to target tumor oxidative phosphorylation in different genetic cancer subsets and in combination with different modalities; 2) Exploit the vulnerability of tumors with defects in hamartoma genes to agents that enhance reactive oxygen stress (ROS) and impair ATP synthesis; and, 3) To define the genetic vulnerabilities of tumors with defects in hamartoma genes to agents that suppress fatty acid synthesis.
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