MTORC2 metabolic reprogramming in t cell… (F31CA301702) – Project Grant to Rutgers The State University…

Abstract: Leukemia is the 10TH most common cancer in the united states, and IT is prevalent worldwide. Studies over the last decade has identified the multiple heterogenous entities that cause leukemias and one of the branches includes t cell acute lymphoblastic leukemia (t-all) which has an increased prevalences among children and young adults. Although mortality rate has decreased due to improved treatments, there remains a need to devise more effective strategies to combat the considerable toxicity with current treatment regimen that generates long-term undesirable consequences such as damage to other tissues. Most treatment are non- specific and utilizes highly toxic compounds to stop proliferating cells. These include the desired targeted cancer cells but will also include the undesired bystander proliferating cells in the body. However, emerging studies including from our lab reveal that understanding how cancer cells reprogram their nutrient consumption and metabolism could unravel more specific and effective therapeutic opportunities. All cancer cells are dependent on abundant supply of nutrients, such as glucose and amino acid glutamine, to fuel their rapid growth and proliferation. Interestingly, recent studies reveal that depending on the genetic mutations, cell type and microenvironment of cancer cells, these cells have specific nutrient dependencies and metabolic idiosyncrasies. Using a mouse model of t lymphoma, we found that this type of cancer that is triggered by a mutation in a tumor suppressor gene, pten, is dependent on the presence of mtor, as part of the mtor complex 2 (MTORC2). Mtor is a signaling molecule that orchestrates metabolic process. Mutations in pten are common in cancer because they upregulate PI3K/MTORC2 signaling, which enhances nutrient consumption and anabolic metabolism. There are ongoing clinical trials to inhibit the PI3K/mtor pathway in cancer, but early results revealed limited efficacy due to dose-limiting toxicities. So far, the clinical efficacy of mtor inhibition is limited to cancers with hyperactive mtor signaling. Mtor inhibitors downregulate overall metabolism while upregulating salvage mechanisms. Hence, these inhibitors have mostly cytostatic but not cytotoxic effects. Here, we propose to further analyze MTORC2 signaling by identifying activation amplification during t-lymphoma development and how MTORC2 reprogram metabolism during lymphomagenesis. Our studies should provide insights on better therapeutic strategies to target mtor and metabolism to prevent lymphoma.

MTORC2 metabolic reprogramming in t cell lymphoma

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