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Crosslinking of antigen receptors on T and B lymphocytes causes activation of PI3K (phosphoinositide 3-kinase) and increases production of 3-phosphorylated phosphoinositides. Various other cell surface receptors on lymphocytes contribute to PI3K activation. Downstream of PI3K, the protein kinase mTOR (mammalian target of rapamycin) coordinates various aspects of lymphocyte proliferation and differentiation. Chemical inhibitors of PI3K or mTOR strongly suppress proliferation and differentiation of T cells and B cells.
Our laboratory uses chemical and genetic approaches to understand how different components of the PI3K/mTOR signaling pathway control lymphocyte activation. Current work focuses on different effectors of mTOR, particularly S6 Kinases and eIF4F components, and their roles in promoting mRNA translation. We study these mechanisms in cellular immunology assays as well as in vivo models of adaptive immune responses and autoimmunity.
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The PI3K/mTOR signaling pathways is one of the most frequently activated in human cancer. Elevated PI3K signaling promotes tumor cell division, metastasis and resistance to apoptosis. PI3K activity in cells of the tumor microenvironment also modulates tumorigenesis. As pharmaceutical companies continue developing PI3K/mTOR inhibitors for oncology, it is crucial to understand how different components of this pathway function in cancer cells and the tumor environment.
Our work in this area is divided into three areas:
1) Which components of the PI3K/mTOR pathway are required for leukemogenesis? The lab focuses on pre-B acute lymphoblastic leukemia, mainly the Ph+ (BCR-ABL) and Ph-like subtypes. Recent work has highlighted the potential of third-generation mTOR inhibitors and compounds targeting the translation initiation complex eIF4F.
2) What mechanisms in leukemia or lymphoma cells confer resistance to PI3K/mTOR inhibitors? We have identified compensatory survival mechanisms and are studying drug combinations that can overcome resistance.
3) What effect do anti-cancer drugs have on lymphocytes? Distinguishing which candidate therapeutics enhance or suppress immune responses has important implications for successful application of these agents, especially in combination with immunotherapies.
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Most blood cancers (leukemia, lymphoma, multiple myeloma) maintain survival through elevated expression of BCL2 or related family members such as BCL-xL and MCL-1. This has led to new approaches to achieve blood cancer cell death using small molecule “BH3 mimetics” that inhibit specific BCL2 family members. One such BH3 mimetic, venetoclax (ABT-199), is FDA approved for treatment of CLL. However, venetoclax monotherapy does not cause complete remission in most CLL patients and is less effective in many other blood cancers. We are evaluating novel combinations that enhance apoptosis induced by venetoclax and other BH3 mimetics. We discovered that statins (HMG-CoA-Reductase inhibitors) that inhibit mevalonate production in cells, and are widely used to control cholesterol, are able to strongly enhance the efficacy of venetoclax in various leukemia and lymphoma cell types. In collaboration with AbbVie, developers of venetoclax, we analyzed clinical trial data and determined that background statin use is associated with improved responses to venetoclax in CLL. This work was published in 2018 (Lee at al., Science Translational Medicine) and has led to new project in multiple myeloma (funded by Leukemia & Lymphoma Society, Translational Research Program, published in Cancer Research Communications in 2023) and a new project in acute myeloid leukemia (funded by the Department of Defense, Impact Award). The latter award also supports a phase I clinical trial of pitavastatin in subjects receiving venetoclax as standard of care for CLL or AML (ClinicalTrials.gov identifier NCT04512105, PI: Elizabeth Brém).
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