Research Projects

 

Role of PI3K and mTOR in Lymphocyte Activation

Crosslinking of antigen receptors on T and B lymphocytes causes activation of PI3K 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 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 laboratories uses chemical and genetic approaches to understand how different components of the PI3K/mTOR signaling pathway control lymphocyte activation. Current work focuses on different substrates of mTOR, particularly S6 Kinases and 4E-BPs, 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.

Role of PI3K and TOR in Cancer

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? As a model oncogene we have focused on BCR-ABL, which causes chronic myeloid leukemia and acute pre-B lymphoblastic leukemia. Recent work has highlighted the potential of compounds targeting the active site of mTOR.

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.