Current Research

The El-Deiry Lab is a translational drug discovery and development lab focused on unraveling cell death signaling downstream of tumor suppressors p53 and TRAIL and developing novel therapeutic approaches for colorectal cancer. The lab does screening to discover new drugs, molecular and cellular analysis of new drug mechanisms, live tumor growth and drug effectiveness studies, and clinical trial development for testing of new treatments for patients with colorectal cancer. A major translational goal is to develop personalized therapy for patients with colorectal cancer including appropriate screening, personalized pharmacokinetically-guided chemotherapy dose adjustment, recommendations for therapy based on tumor genetic signatures, and the identification of novel therapeutic combinations based on live circulating tumor cell culture and drug testing. Dr. El-Deiry is interested in the role of bone marrow-derived cells towards solid tumor growth, the impact of the tumor microenvironment and cancer stem cells on tumor growth and therapy resistance, and cross-talk between cells and pathways in tumor progression and therapy resistance. A number of collaborations with academia and industry facilitate the conduct and progress of this research.

The lab has focused on the how colorectal tumor cells die when treated with chemotherapy and how they become resistant to therapy. Dr. El-Deiry discovered the universal cell cycle inhibitor p21(WAF1) and the TRAIL death receptor DR5 as important ways cancers are suppressed following environmental exposures or treatment by chemotherapy. Dr. El-Deiry has worked to use the basic knowledge generated by his laboratory to develop new treatments and treatment strategies for patients with colorectal cancer. Dr. El-Deiry's lab created a knock-out mouse for TRAIL receptor DR5 (published in Mol. Cell. Biol. in 2005 and J. Clin. Invest. in 2008) and this mouse is tumor prone and develops a not yet studied inflammatory syndrome in the lungs and gut after sub-lethal irradiation that has previously been attributed to TGF-beta. Dr. El-Deiry looks forward to collaborative studies with immunologists to unravel this phenotype and to use the knowledge gained to suppress side effects of inflammation encountered with radiation therapy.

The approach for drug discovery and development is multi-tiered and involves understanding mechanisms of resistance through effects of the tumor microenvironment, hypoxia, cancer stem cells, repurposing available old drugs, finding new combinations to use recently approved drugs including ones active in other tumor types to bring them to patients with colorectal cancer, and conducting discovery work to find and develop new treatments for colorectal cancer patients. The expertise of Dr. El-Deiry and his laboratory in the mechanisms of tumor suppressor genes is opening up new ways of finding cancer treatments. For example, his group is trying to develop drugs to stimulate p73, a protein in the cell that is very similar to the p53 tumor suppressor but is not mutated in cancer. On the other hand p53 is often mutated and dysfunctional in cancer leading to uncontrolled growth and resistance to therapy.

Drug screening to restore p53 signaling in mutant p53-expressing colorectal tumors.
This project started in 2002 in the El-Deiry lab and has made progress to find chemicals that look promising. The challenge is to test the chemicals for their mechanism of action and to demonstrate that these chemicals are safe and effective in animals before bringing them to the clinic for further development. The lab has conducted large-scale 150,000 chemical compound screening and is trying to facilitate clinical testing of the most promising drug candidates and to pursue FDA approval. Among the most interesting leads are small molecules that can stimulate p73, disrupt mutant p53:p73 interaction, and target mutant p53 for degradation without genotoxic stress and in a manner that has superior attributes to mTOR inhibitors that have been proposed as agents that can stimulate p73.
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Development of TIC10 as a novel anti-tumor agent.
TRAIL-inducing compound TIC10 is a first-in-class TRAIL gene inducer that can be given orally and has the ability to cross the blood-brain barrier to treat brain metastases(in press, Science Translational Medicine, 2013). TRAIL and Foxo3a are required for the anti-tumor effect of TIC10. The compound shrinks tumors even when given as a single agent in multiple animal models including immunocompetent lymphoma models and subcutaneous models of colorectal cancer, has synergy with other agents as well as effects against cancer stem cells that often lead to relapse and resistance to chemotherapy. The compound has a bystander effect by stimulating TRAIL production by normal cells to achieve an anti-tumor effect. TIC10 has potential to impact on patients with cancer.
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Development of lapatinib in new combinations for colorectal cancer.
Dr. El-Deiry's group discovered and published in Science Translational Medicine in 2011 that lapatinib, a drug approved to treat breast cancer, at doses twice what is used in the clinic induces TRAIL death receptors leading to potent anti-tumor effects in colorectal cancer. Lapatinib has not been tested in colorectal cancer. The drug which is given orally fluoresces and accumulates in the colon. This suggests there is a good opportunity to develop it in combination with other drugs that are currently used to treat colorectal cancer. In addition, the lab has discovered a novel synergistic interaction between lapatinib and a BMS drug that targets IGF1R/IR pathways. This is an exciting direction for colorectal cancer drug development research because of the potential to combine lapatinib, an agent currently approved to treat breast cancer with an experimental agent from BMS to develop a new treatment for colorectal cancer.
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Repurposing drugs such as quinacrine for use in colorectal and other cancers.
Dr. El-Deiry's group reported single agent anti-tumor effects as well as synergistic anti-tumor effects between quinacrine and 5-Fluorouracil to treat colorectal cancer. Dr. El-Deiry obtained an IND for testing the combination of capecitabine (oral form of 5-Fluorouracil) plus quinacrine as a therapy for advanced colorectal cancer. The motivation for this direction was the need for more options for patients with advanced colorectal cancer coupled with known safety of quinacrine going back to world war II and its 20,000 fold accumulation in the liver over serum (suggestive of potential use for liver metastases), and $30 cost per month for quinacrine. The quinacrine mechanism does not involve autophagy inhibition but appears to involve inhibition of NFkB, STAT3, Mcl-1, an anti-angiogenic effect and effects seen in p53-deficient cells. Multiple mechanisms of action reduces the chances that resistance will develop. Dr. El-Deiry is applying for an IND for quinacrine plus sorafenib to treat hepatocellular and anaplastic thyroid cancers. This line of research has suggested a potential to develop quinacrine plus aspirin to prevent colorectal cancer to be tested in animal models.
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Targeting hypoxic regions of colorectal tumors.
The lab performed a chemical screen looking for candidate drugs that can act as hypoxia sensitizers and synergize with TRAIL or 5-Fluorouracil to kill colorectal tumors. The lab published in Cancer Research in 2011 the identification of sangivamycin-like molecules (SLMs), nucleoside analogues as novel hypoxia sensitizers in vivo with impressive effects in colorectal cancer. Hypoxia is a major mechanism for cancer resistance to therapy and this approach holds promise to improve the way current therapy is being used. Dr. El-Deiry is interested in translating these discoveries to the clinic and developing appropriate biomarker studies to facilitate the translation. Dr. El-Deiry's lab has preliminary data demonstrating a novel regulation of HIF stability through CDK activity, a here-to-fore unrecognized regulatory mechanism that has therapeutic implications.
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Personalized dose adjustment and studies of the p53-dependence of 5-FU metabolism.
This is a translational direction that involves measuring 5-FU levels in patients receiving infusional 5-FU chemotherapy for colorectal cancer. Measuring 5-FU levels reduces toxicity and improves outcome in our cohort of 84 patients with stage II-IV colorectal cancer. Dr. El-Deiry hypothesizes that p53 may be involved in how each individual patient metabolizes 5-FU and has data demonstrating regulation of 5-FU metabolizing enzymes in mice. His group is pursuing a genomic basis for variability in 5-FU metabolism among patients and the p53 connection.
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Analysis of circulating tumor cells (CTCs) from patients with advanced colorectal cancer to monitor response to therapy and to develop new personalized treatments.
The El-Deiry lab has collaborative interdisciplinary directions in the area of circulating tumor cells including immunophenotyping cancers of unknown primary, isolation and drug testing of live CTCs, and Dr. El-Deiry has an open clinical protocol evaluating stem cell markers and prognostic markers in CTCs isolated from patients with advanced colorectal cancer. The Lab is pursuing use of CTCs for the development of biomarkers for drug development and has data to support detection of various cell survival and other drug target phosphoproteins. The lab has been modeling CTC detection in mouse models and has recently become interested in testing some implications of the tumor self-seeding hypothesis.
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Impact of BMDC's on solid tumor growth.
The lab has published in 2011 in the Am. J. Pathol. An experimental model to investigate the effect of bone-marrow derived cells on solid tumor growth. This work was begun through syngeneic GFP(+)-bone marrow transplants to recipient tumor-bearing mice. Dr. El-Deiry is interested in understanding the impact of the BMDC's on solid tumor growth or growth suppression and in the future using cells that traffic to solid tumors to carry therapeutic cargo. This is a collaborative project that will involve interaction with immunologists over the next few years.
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Targeting BRCA1/repair-deficient cells.
The Lab has worked on BRCA1 for over 15 years with recent description of an in vivo model system demonstrating transformation of human mammary epithelial cells by H-Ras that causes EMT with subsequent invasive and angiogenic features endowed upon this by knockdown of BRCA1. The models are available for drug testing and are investigating cross-talk between BRCA1 and p53 pathways. The lab has conducted screening and has a number of small molecules that selectively kill BRCA1-deficient cells. The lab is characterizing the mechanism of action of molecules given the impact of PARP inhibitors in the clinic.
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