Thomas J. Sayers, Ph.D.
Dr. Sayers is interested in characterizing molecular mechanisms by which cells of the immune system destroy cancer cells using the pro-apoptotic tumor necrosis factor (TNF) family proteins. A critical role for the anti-apoptotic protein cFLIP in protecting cancer cells has been established, and high-throughput screening has identified a number of natural products that can target cFLIP. These compounds may be useful in enhancing cancer immunotherapy. Dr. Sayers' lab is also isolating cancer stem cell populations in order to assess their sensitivity or resistance to standard chemotherapies, molecular targeted therapies as well as immunotherapy.
Identification of Factors Involved in Tumor Cell Destruction by the Immune System
Cytotoxic lymphocytes destroy tumor cells in vitro using 2 main mechanisms: 1) by the release of lytic granules from the lymphoid cells that contain toxic proteins including the pore-forming protein perforin as well as a family of enzymes known as granzymes, and 2) by the production of "death ligands" of the tumor necrosis factor (TNF) family which can trigger tumor cell suicide (apoptosis). The relative importance of these mechanisms for antitumor effects in vivo is being studied.
Our current studies are also concentrated on identifying the molecular events underlying tumor cell death, with a focus on rapidly developing knowledge of mechanism(s) of apoptosis. We are studying a possible role for the "death ligands" Fas-ligand, TNFalpha, and TRAIL in immune-mediated destruction of tumor cells in vivo and their role in controlling the development of tumor metastases. In addition, we are assessing the ability of some drugs to sensitize tumor cells to death ligands and the molecular basis of this sensitization. More recently, we have attempted to isolate minor subpopulations of cancer stem cells using DNA constructs where green fluorescent protein is responsive to the embryonic transcription factor Nanog.
Our overall goal is to better understand the molecular events operating during tumor cell death in tumor cells in various states of differentiation. This knowledge should be useful in the rational design of agents to trigger these "suicide" pathways in tumor cells.
Selected Key Publications
Tumor-specific CTL kill murine renal cancer cells using both perforin and Fas ligand-mediated lysis in vitro, but cause tumor regression in vivo in the absence of perforin.J Immunol. 168: 3484-92, 2002. [ Journal Article ]
Tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis is an important endogenous mechanism for resistance to liver metastases in murine renal cancer.Cancer Res. 63: 207-13, 2003. [ Journal Article ]
The proteasome inhibitor PS-341 sensitizes neoplastic cells to TRAIL-mediated apoptosis by reducing levels of c-FLIP.Blood. 102: 303-10, 2003. [ Journal Article ]
Treating metastatic solid tumors with bortezomib and a tumor necrosis factor-related apoptosis-inducing ligand receptor agonist antibody.J Natl Cancer Inst. 100: 649-62, 2008. [ Journal Article ]
- Cancer Res. 69: 6615-23, 2009. [ Journal Article ]
Dr. Thomas Sayers is a senior scientist with Leidos Biomedical Research, Inc. and works in collaboration with the Laboratory of Experimental Immunology in the Cancer and Inflammation Program. Dr. Sayers obtained his Ph.D. in biochemistry from the University of London and performed postdoctoral studies on purification of autoantigens at the Medical Clinic of the University of Tubingen, Germany. He also worked as a laboratory leader in the Department of Immunotherapy at the Sandoz Research Institute, Vienna, Austria, before coming to the NCI.
|Alan Brooks||Senior Research Assistant (Leidos)|
|Poonam Tewary Ph.D.||Scientist I (Leidos)|