Description of Research Expertise

Research Interests
1. p53 and TRAIL signaling
2. Novel anti-cancer therapeutics
3. In vivo molecular imaging

Key words: P53, apoptosis, transcription, cancer, p21, TRAIL, GI cancer, drug resistance, in-vivo bioluminescence imaging, BRCA1, transformation, repair, caspase activation, tumor suppression.

Description of Research
The major interest of the lab in recent years 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 our 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). Insights have emerged 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. Efforts have been directed at understanding regulation of p53 activity through control of its stability as well as its selectivity in target gene activation. An area of focus in the lab that emerged from our work on p53 involves analysis of the extrinsic cell death pathway and its activation by the death ligand TRAIL. Our work on the TRAIL pathway has involved analysis of 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.

A new direction for the lab within the last several years has involved the development and application of non-invasive in vivo imaging technologies for cancer research. We have used bioluminescence and fluorescence to image tumors in vivo as well as molecular events occurring within the tumors including chemotherapy-induced gene expression changes. Other exciting applications include the ability to image protein-protein interaction in vivo and the ability to image the effects of genetic changes on tumor cell transformation and tumor growth in vivo. Of particular interest are efforts to incorporate genetic alterations (oncogene overexpression into primary human epithelial cells from the human esophagus or human mammary gland; tumor suppressor gene silencing including inducible systems) and imaging reporters/probes for longitudinal multi-modality in vivo molecular imaging in small animals. Efforts include validation of models through studies involving microarray comparisons with human tumors. These capabilities and 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, drug target validation, as well as biomarker development for clinical use in cancer diagnosis and therapeutic monitoring.

The goal of the laboratory is to translate basic knowledge in the areas of tumor suppressor genes and cell death signaling into novel diagnostic/therapeutic modalities in the clinic. Recent efforts to develop small molecule therapeutics are proceeding in the direction of creating and testing structural analogues through medicinal chemistry and are involving collaborations and interactions with the NCI Developmental Therapeutics Program, the Broad Institute at MIT, The Penn MLSCN, as well as Biotech companies including Oncoceutics and Progenra. We are also investing efforts to understand the impact of the tumor microenvironment including hypoxia and stem cell composition on therapeutic sensitivity. Mechanistic studies, target validation, preclinical toxicology and pharmacokinetics are part of the effort that involves multiple collaborators to achieve specific translational goals. 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. This is a rich laboratory environment for learning about cancer biology, preclinical models of human cancer, and the complexities of translational drug development research targeting key molecular events required for transformation and tumor progression.

Rotation Projects for 2006-2007
Please make an appointment to discuss ongoing work and available projects.

Lab personnel:
Joe Ackerman, Ph.D., Post-doctoral Scientist (Penn State)
David T. Dicker, Research Specialist (Flow and Multispectral Imaging)
Jay Dorsey, M.D. Ph.D., Post-doctoral Scientist (Holman Pathway; Radiation Oncology)
Wafik S. El-Deiry, M.D., Ph.D. (Professor and Lab Director)
Niklas Finnberg, Ph.D., Post-doctoral Scientist (Karolinska Institute)
Renato Goreshi, Rotating medical student (Penn)
Christine Greiss, visiting medical student (NY)
Lori Hart, Post-doctoral Scientist (starting Fall 2006; Wake Forest U.)
Seok-Hyun Kim, M.D. Ph.D., Post-doctoral Scientist (Yonsei Medical University)
David Jee, visiting undergraduate student (Harvard)
Kageaki Kuribayashi, M.D. Ph.D., Post-doctoral Scientist (Sapporo Medical University)
Judy Liu, Undergraduate Vagelos Scholar (Penn)
Yvette Liu, Imaging Specialist (Bioluminescence & Fluorescence Tomography)
Elizabeth Matthew, Ph.D., Post-doctoral Scientist (U. Cincinnati)
Patrick Mayes, Graduate Ph.D. thesis Student (Penn Pharmacology)
Akiva Mintz, M.D. Ph.D., Post-doctoral Scientist (Nuclear Medicine)
Arunasalam Navaraj, Ph.D., Post-doc. Scientist (Northwestern U.)
Shannone Nicolson, Administrative Assistant
Kazuhiro Ogi, M.D. Ph.D., Post-doctoral Scientist (Sapporo Medical University; (Japanese Society for the Promotion of Science)
Kiran Patel, Rotation Student, Penn M.D./Ph.D. Program
John Plastaras, M.D. Ph.D., Post-doctoral Scientist (Holman Pathway; Radiation Oncology)
Ramji Rajendran, M.D. Ph.D., Post-doctoral Scientist (Radiation Oncology)
Laura Rozan, Ph.D., Post-doctoral Scientist (U. Michigan)
Kimberly Scata, Ph.D., Post-doctoral Scientist (Penn)
Robyn Sussman, Research Scientist (U. Michigan)
Xiaobing Tian, Ph.D., Post-doctoral Scientist (Medicinal Chemist; Jefferson Medical College)
Wenge Wang, M.D. Ph.D., Post-doctoral Scientist (Columbia U.)
Wensheng Yang, Ph.D., Post-doctoral Scientist (Clemson U.)