Description of Research Expertise

Research Interests
1. Cancer drug discovery and development
2. p53 and TRAIL signaling
3. Novel anti-cancer therapeutics
4. In vivo molecular imaging
5. Cancer stem cells
6. Hypoxia and tumor microenvironment

Key words: Cancer, apoptosis, drug resistance, drug discovery, drug screening, tumor suppression, novel therapies, p53, p21, TRAIL, BRCA1, c-Myc, HIF.

Description of Research
A major interest of the El-Deiry lab has been to understand the mechanism of action of the tumor suppressor p53 and the contribution of its downstream target genes to cellular growth control. Analysis of this pathway led to the identification of a number of genes directly regulated by p53 and which can inhibit cell cycle progression (p21WAF1), induce apoptosis (KILLER/DR5, Bid, caspase 6, Traf4 and others) or activate DNA repair (DDB2). The discovery of p21(WAF1) as a p53 target gene led to publication of the the most highly cited original research article ever published in Cell. Further progress by Dr. El-Deiry's lab has led to insights into the tissue specificity of the DNA damage response in vivo as well as into the mechanism by which wild-type p53 sensitizes cells to killing by anti-cancer drugs or under hypoxic conditions. This led to publications in Nature Cell Biology on Bid and Cancer Cell on Bnip3L. An area of focus in the lab that emerged from the work on p53 currently involves analysis of the extrinsic cell death pathway and its activation by the death ligand TRAIL. Dr. El-Deiry's lab originally discovered and cloned TRAIL receptor KILLER/DR5 as a p53-regulated gene in work published in Nature Genetics in 1997. Recent efforts have led to characterization of the DR5 knockout mouse revealing a defect in radiation-induced apoptosis in vivo and a tumor-susceptibility phenotype. These results were published in MCB and the Journal for Clinical Investigation. An interesting and as yet uncharacterized novel phenotype is the discovery that TRAIL signaling suppresses the chronic 'late' side-effects of ionizing radiation. Further efforts are proceeding to characterize the DR5/Puma null mice with respect to radioresistance and tumor susceptibility. Dr. El-Deiry published a comprehensive review on the structural and functional basis for therapeutic targeting of p53 in Clinical Cancer Research in 2008. Efforts are continuing to exploit the emerging complexity of targeting human tumors with mutant p53 with the goal of identifying effective therapeutic candidates.

There is a particular focus on the tumor microenvironment including hypoxia and stem cell composition on therapeutic sensitivity. In this regard the laboratory has carried out high-throughput screening to identify novel hypoxia sensitizers and has tested them in vivo. Exciting directions include studies evaluating the role of bone marrow-derived cells in promoting tumor growth with intent to ablate such populations prior to or after their homing to tumors and the potential to use such strategies for tumor-specific delivery of therapeutics. The laboratory is developing strategies to image and target cancer stem cells in vivo, including exploitation of the TRAIL and p53 pathways in combination with targeted agents or classical cytotoxic agents for therapy.

The work on the TRAIL pathway has involved analysis of the mechanisms of sensitivity and resistance of cancer cells, exploration of intracellular signaling events involved in regulating caspase activation and studies of how cell death occurs with respect to mitochondrial involvement and preclinical in vivo studies. This has led to a paper published in Cancer Cell in 2007 describing the use of TRAIL plus Sorafenib as a potential therapeutic strategy and a paper in MCB describing c-Myc as a major determinant of TRAIL sensitivity. In the last several years the lab has developed and applied non-invasive in vivo imaging technologies for cancer research and Dr. El-Deiry has published two reviews in the Journal of Clinical Oncology on the topic in 2006 and 2008. The lab has used bioluminescence and flourescence to image tumors in vivo as well as molecular events occurring within the tumors. The lab was the first to combine gene silencing with non-invasive bioluminescence imaging and the first to publish on the use of molecular (optical) imaging in high-throughput drug screening. These capabilities and the new technologies are enabling the development of cell-based assays, small molecule screens, animal models and imaging probes to accelerate research on cancer biology, drug development, and drug target validation. A novel non-invasive vascular imaging method was published by the lab in 2008. The goal of the laboratory is to translate basic knowledge in the areas of tumor suppressor genes and cell death signaling into novel diagnostic and therapeutic capabilities in the clinic. Efforts are progressing to develop therapeutic agents and combinations including TRAIL, radiation, classical chemotherapy and novel small molecules targeting drug-resistant cancer for implementation through Phase I/II clinical protocols. The ability to translate basic discoveries into novel approaches to care for cancer patients is the goal of Dr. El-Deiry who is a translational physician-scientist, practicing medical oncologist, and an American Cancer Society Research Professor.

Recent Awards and Honors:

2005 ISI Highly Cited Researcher in Molecular Biology and Genetics

2006 American Association for Cancer Research Littlefield Award for research on metastatic colon cancer

2007- Associate Editor, Journal of Clinical Investigation

2008 Elected Member, Association of American Physicians

2008- Elected Secretary/Treasurer, Interurban Clinical Club, an honor society for physicians started by Sir William Osler in 1905 http://interurbanclinicalclub.org/

2008, 2009 Citation in "America's Top Oncologists" by the Consumers' Research Council of America

2009 American Cancer Society Research Professorship

Rotation Projects

Please make an appointment to discuss ongoing work and available projects.

Lab personnel:

Junaid Abdulghani, M.D. Ph.D., Post-doctoral Scientist (Jefferson)
Rosalyn Crowder, Ph.D., Post-doctoral Scientist; Penn-PORT (U. Alabama)
David T. Dicker, Research Specialist (Flow and Multispectral Imaging)
Nathan Dolloff, Ph.D., Post-doctoral Scientist (Drexel)
Niklas Finnberg, Ph.D., Post-doctoral Scientist (Karolinska Institute)
Lori Hart, Ph.D., Post-doctoral Scientist (Wake Forest U.)
Sharyn Katz, M.D., Assistant Professor (Penn Radiology)
Yvette Liu, Imaging Specialist (Bioluminescence & Fluorescence Tomography)
Elizabeth Matthew, Ph.D., Post-doctoral Scientist (U. Cincinnati)
Patrick Mayes, Graduate Student (Pharmacology)
Arunasalam Navaraj, Ph.D., Post-doc. Scientist (Northwestern U.)
Luv Patel, Undergraduate Vagelos Scholar (Penn)
Kimberly Scata, Ph.D., Staff Scientist (Penn)
Wenge Wang, M.D. Ph.D., Post-doctoral Scientist (Columbia U.)
Wensheng Yang, Ph.D., Post-doctoral Scientist (Clemson U.)
Lanlan Zhou, Graduate Student (Bioengineering)