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Graham Lab

 

Contacts: 

Phone:     (303) 724-4006

Fax:          (303) 724-4015

Email:       doug.graham@ucdenver.edu

Website:  http://medschool.ucdenver.edu/peds/grahamlab


Research Interests:

 

The Graham lab focuses much of its research on the role of Mer and Axl receptor tyrosine kinases (RTKs) in development and progression of human cancer. Mer, previously cloned and characterized by Dr. Graham, is overexpressed in multiple human cancers and is transforming in vitro.  With a particular focus on leukemia, lymphoma, and non-small cell lung cancer, the Graham lab has elucidated pro-survival pathways which are activated as a result of abnormal Mer and Axl activation.  Specifically, the abnormal expression of Mer and/ or Axl leads to downstream activation of AKT and ERK 1/2 and mTOR, allowing cancer cells to survive even in the presence of apoptotic stimuli.   In solid tumors, the Mer and Axl RTKs are important in cancer cell invasion.  Using shRNA knockdown of Mer, a prolongation of survival has been found in xenograft studies. Recently, novel biologic inhibitors of Mer and Axl have been developed in the Graham lab and are being tested in preclinical in vitro and in vivo studies.

The Graham lab also studies the role of Mer and Axl in normal cellular functions. Recently, a truncated and soluble from of Mer (sMer) has been discovered which binds and sequesters the Mer/Axl ligand Gas6, thus preventing activation of membrane-bound Mer. Thus, sMer regulates Mer and Axl’s role in macrophage clearance of apoptotic cells and in platelet aggregation/clot formation. Current investigations are testing the potential use of sMer as a therapeutic agent in the treatment of patients with clotting disorders.

Selected Publications:

1. Linger MA, DeRyckere D, Brando L, Sawczyn KK, Jacobsen KM, Liang X, Keating AK, and DK Graham.   2009. The Mer receptor tyrosine kinase is a novel therapeutic target in pediatric B-cell acute lymphoblastic leukemia. Blood, 114:2678-87. PMID: 19643988.

2. Anwar AA, Keating AK, Joung D, Sather S, Kim GK, Sawczyn KK, Brandao L, Henson PM, and DK Graham.  2009.  Mer tyrosine kinase (MerTK) promotes macrophage survival following exposure to oxidative stress. J Leukoc Biol, 86:73-9PMID: 19386698

3. Linger RMA, Keating AK, Earp HS, and DK Graham. 2008. TAM receptor tyrosine kinases:  biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res, 100:35-83.  PMID: 18620092.

4. Sather SL, Kenyon KD, Lefkowitz JB, Liang X, Varnum BC, Henson PM, and DK Graham.  2007. A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation. Blood, 109:1026-33.  PMID: 17047157.

5. Graham DK, Salzberg DB, Kurtzberg J, Sather S, Matsushima GK, Keating AK, Liang X, Lovell MA, Williams SA, Dawson TL, Schell MJ, Anwar A, Snodgrass HR, and HS Earp. 2006. Ectopic expression of the proto-oncogene Mer in pediatric T cell acute lymphoblastic leukemia. Clin Cancer Res, 12:2662-69.  PMID: 16675557.

6. Keating AK, Salzberg, D.B., Sather, S., Liang, X., Nickoloff, S., Anwar, A., DeRyckere, D., Hill, K., Joung D, Sawczyn KK, Park J, Curran-Everett D, McGavran L, Meltesen L, Gore L, Johnson GL, and DK Graham. 2006. Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase. Oncogene, 25:6092-100.  PMID: 16652142.