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Graham Lab

Welcome to the website for the Graham Laboratory at the University of Colorado at Denver Anschutz Medical Campus.

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 an intriguing mix of normal cellular processes, including proliferation/survival, adhesion and migration, blood clot stabilization, and regulation of inflammatory cytokine release. Signaling pathways employed by the TAM family have been recently elucidated and 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 in the lab include the study of TAM receptor activation and signaling in acute lymphoblastic leukemia, acute myeloid leukemia, melanoma, non-small cell lung cancer. Specifically, activation of Mer and/or Axl in these cancer types leads to downstream activation of pro-survival signaling pathways, including PI3K/AKT, p38 and ERK MAP kinases, and STAT5/STAT6. 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. In addition, the variety of mechanisms by which Mer inhibition may lead to anti-tumor activity, including direct tumor cell killing, sensitization to cytotoxic chemotherapies, and increased immune-mediated tumor rejection suggest that Mer inhibition may be a particularly effective strategy for treatment of cancers.

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 mediate anti-tumor activity in cell culture and animal models and are progressing toward clinical development.

​We have also generated several recombinant proteins that function as ligand sinks and thereby inhibit both Mer and Axl. These biologic therapies have been developed primarily for anti-thrombotic applications and are sufficient to inhibit platelet aggregation in vitro and reduce fatal clot formation in vivo, suggesting their therapeutic utility.