The Graham lab focuses on the TAM family of receptor tyrosine kinases (Tyro-3, Axl, and Mer) and their roles in development and progression of human cancer. TAM-family tyrosine kinases regulate a spectrum of normal cellular processes, including proliferation/survival, adhesion and migration, blood clot stabilization, and regulation of inflammatory cytokine release. Signaling pathways downstream of TAM receptor activation have mediate diverse cellular functions, including macrophage clearance of apoptotic cells, platelet aggregation, and natural killer (NK) cell differentiation. Aberrant expression of the TAM-family receptors and their ligands has been demonstrated in a wide variety of human cancers.
Current projects include the study of TAM receptors in acute lymphoblastic leukemia, acute myeloid leukemia, melanoma, non-small cell lung cancer. Inhibition of Mer and/or Axl using shRNA leads to decreased signaling through these survival pathways, induction of cancer cell death, decreased colony formation in clonogenic or soft agar assays and decreased tumor growth in animal models. In addition, shRNA-mediated inhibition of Mer and/or Axl increases the sensitivity of tumor cells to traditional cytotoxic chemotherapies. Moreover, we have recently shown that Mer functions in the immune system to promote an anti-inflammatory phenotype that promotes tumorigenesis. These pre-clinical data identify and validate Mer as a potential therapeutic target for treatment of a wide spectrum of tumor types. Most recently, we have developed first-in-class, novel Mer-selective small molecule inhibitors in conjunction with our collaborators at the University of North Carolina. These Mer inhibitors in are now in a first in human clinical trial for relapsed/refractory solid tumors, and plans are in place to launch a clincal trial in acute leukemia later this year.