The Jeannik M. Littlefield-AACR Grants in Metastatic Colon Cancer Research are a joint effort of the Littlefield 2000 Trust and the American Association for Cancer Research. The two-year grants support innovative cancer research projects designed to accelerate the discovery and development of new agents to treat metastatic colon cancer and/or for preclinical research with direct therapeutic intent, with special emphasis placed on research that holds promise for leading to individualized therapeutic options for treatment in the near future or for developing promising new cancer therapeutics for metastatic colon cancer, which will translate into clinical applications within a one- to two-year period.
2008 GRANTEES
Nita Ahuja, M.D.
Assistant Professor, The Johns Hopkins University, Baltimore, MD
Developing Epigenetic Staging and Therapy for Colorectal Cancer
Dr. Ahuja's research focuses on epigenetic changes during colorectal cancer formation. Epigenetic changes are heritable but potentially reversible modifications of DNA, including abnormal DNA methylation and chromatin, which regulate gene transcription. DNA methylation of promoter-associated CpG islands is a frequent event in colorectal cancer. Colorectal cancer remains the second leading cause of cancer death worldwide. About 25 to 40 percent of patients who undergo curative surgery for localized colorectal cancer will recur with metastases but current staging does not tell us which patients will go on to recur. In addition, despite recent progress in therapy for metastatic colorectal cancer, most patients will progress and die of metastatic disease. Thus, there is a need for identifying the patients at highest risk for development of metastases, and development of novel treatments once metastases do occur.
Dr. Ahuja's laboratory is focused on development of molecular staging for colorectal cancer to stratify the patients at highest risk of recurrence. Her laboratory will utilize methylation profiles of a panel of genes for molecular staging of early-stage colorectal cancer to stratify patients at highest risk of recurrence. Recent studies in her laboratory in lung cancer have shown that molecular staging, of the primary tumor and its regional lymph nodes, using DNA methylation profiles of a panel of genes, can be successfully used to perform molecular staging. Molecular staging of early-stage colorectal cancers will be performed using methylation profiles of known genes and novel genes, identified recently, from an expression microarray approach to stratify patients into high- and low-risk categories. Her laboratory will also focus on developing epigenetic therapy for treatment of colorectal cancer. Epigenetic silencing of tumor suppressor genes is a heritable but potentially reversible modification and epigenetic therapy is already approved for treatment of myelodysplastic syndromes. Her laboratory has shown that combination epigenetic therapy with demethylating drugs and histone deacetylase inhibitors demonstrates synergy in reactivating genes. Dr. Ahuja and her group will plan to initiate a phase II trial to determine the therapeutic efficacy of combination epigenetic therapy in patients with metastatic colorectal cancer using a demethylating drug and an HDAC inhibitor.
The goals of her laboratory are to develop an effective molecular staging tool for colorectal cancer patients such that patients deemed high-risk receive adjuvant chemotherapy while low-risk patients can be spared the toxicity of chemotherapy. In addition, if the therapeutic efficacy of epigenetic therapy is also shown in metastatic colorectal cancer, we can anticipate that in the near future all colorectal cancer patients will undergo molecular staging after undergoing surgery and high-risk patients can be proscribed adjuvant epigenetic therapy.
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S. Gail Eckhardt, M.D.
Professor, University of Colorado, Denver, CO
Development of Individualized Therapy for IGF-1R Inhibition in Advanced CRC
Colorectal cancer (CRC) represents a major health burden, and is the second-leading cause of cancer deaths in the U.S. Although great progress has been made over the last decade with combinations of highly active chemotherapy regimens that include biological agents, patients still run out of options and salvage therapy results in only a few weeks of disease control. Therefore, new agents are needed that can either induce tumor regression or disease stabilization in these patients. Her laboratory is focused on the development of patient selection strategies for the use of novel targeted agents in metastatic CRC (mCRC). One interesting new biological target for CRC is the insulin-like growth factor (IGF-1R) signaling pathway. This pathway appears to be important for the growth and progression of CRC and there is extensive scientific data supporting its involvement in many kinds of cancers. Despite extensive drug development in this area, early clinical results are modest, indicating that patient selection strategies may be necessary for clinical advancement. Therefore, the overall goal of this proposal is to discover and validate a set of patient-selective biomarkers in preclinical and clinical systems, to enhance the efficacy of IGF-1R inhibition in patients with mCRC. Initially, she will utilize gene array profiling, IHC, and FISH to characterize the responsiveness of CRC cell lines to a small molecule IGF-1R tyrosine kinase inhibitor. Genes or proteins that are associated with sensitivity or resistance to IGF-1R inhibition in vitro will then be validated in vivo using cell lines as well as human tumor CRC explants. Concurrent with predictive biomarker development will be assessment of pharmacodynamic endpoints including changes in gene/protein expression and functional imaging. The clinical testing of the biomarker strategy will then be conducted using a tandem, two-stage phase II trial in mCRC. By pursing the above, this proposal seeks to move beyond combinations of standard agents in unselected patients into an era of individualized therapy, thus improving the care and quality of life of patients with mCRC.
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