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 pre-clinical 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.
2008-2010 Grants
Nita Ahuja, M.D.
The Johns Hopkins University, Balitmore, MD
Project: 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.
S. Gail Eckhardt, M.D.
University of Colorado, Denver, CO
Project: 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.
Lara R. Lipton, M.B.B.S., Ph.D.
Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Melbourne, AU
Project: siRNA synthetic lethal screens to improve EGFR-targeted therapy of colorectal cancer
"The LCCI is an international Ludwig initiative in translational research into colorectal cancer. It utilizes a resource of high quality clinical data and specimen collection from persons undergoing colorectal cancer treatment, and uses this to improve our understanding and treatment of colorectal cancer. In the LCCI Biomarker Laboratory scientists and clinicians work together to discover variations or biomarkers that will allow individualized risk assessment and treatment for patients with colorectal cancer.
Colorectal cancer (CRC) is the second most common internal malignancy in men and women in most western societies and is increasing in incidence in developing countries. Almost half of those diagnosed with colorectal cancer will die from the disease. At present, we have no robust methods for discerning risk of relapse after diagnosis and although a number of effective treatments exist, we cannot individualize treatment based on specific tumour and patient parameters. In the LCCI laboratory we are studying genetic material from persons with CRC to determine biomarkers associated with overall prognosis or response to therapy. Our studies of CRC biomarkers involve technologies relating to molecular biology, cell biology, epigenetic regulation, protein expression, and genetic models of disease. Critically, all molecular information on these cancers can be correlated with clinical data including demographic details, pathology, treatment and outcome, allowing us to determine which biomarkers may be most useful in the clinic.
The LCCI biomarker laboratory is involved in a number of collaborative projects with other Ludwig laboratories and branches, as well as with research institutions nationally and internationally and with industry partners, to facilitate development of novel therapeutics for CRC. In the AACR-funded project, we will establish an expression signature for stage three colorectal cancers predictive of outcome after potentially curative surgery and validate this signature in an independent group of colorectal cancers. It will be possible to compare genome wide expression profile of a set of stage three colorectal cancers with patterns of genomic gain and loss and global methylation and to compare expression profiles in primary colorectal cancer and corresponding liver metastases."
2007-2009 Grants
Michael Kahn, Ph.D.
University of Southern California, Los Angeles, CA
Project: Wnt/beta-catenin/CBP antagonists to treat colon cancer and metastasis
Dr. Khan has focused his research on the signaling pathways in colon cancer. "Eighty to ninety percent of colorectal cancers involve aberrant activation of the Wnt/β-catenin signaling pathway. Our central hypothesis is that increased CBP/β-catenin/TCF4 driven transcription at the expense of p300/β-catenin/TCF4-mediated is associated with colon cancer relapse, drug resistance and poor prognosis." To combat this, Dr. Kahn and his team have developed a specific small molecule antagonist of the CBP/β-catenin interaction, ICG-001, which disrupts a subset of Wnt/β-catenin driven transcription. "There is a clear need for drugs that attenuate the nuclear functions of β-catenin. ICG-001 is the first specific small molecule developed that attenuates the nuclear functions of β-catenin. Equally importantly, ICG-001 has virtually no toxicity to normal tissue." With the support of the Jeannik M. Littlefield-AACR Grant in Metastatic Colon Cancer Research, Dr. Kahn hopes that the clinical trials for the CBP/β-catenin antagonists will be initiated in 2009.
Michael Karin, Ph.D.
University of California, San Diego, La Jolla, CA
Project: Novel anti-inflammatory intervention for preventing colon cancer metastasis
"Despite considerable progress in surgical oncology and the application of new chemotherapeutic and radiotherapeutic modalities, mortality from colon cancer remains high due to the frequent emergence of secondary metasases after elimination of the primary tumor. Although our understanding of the pathogenic mechanisms that lead to development and progression of primary colorectal cancer is quite advanced, much remains to be learned about the mechanisms that underlie the emergence and growth of metastasis. Without a better understanding of the mechanistic basis for metastasis, it will be difficult to develop specific therapies that target metastatic colon cancer. Using several different mouse model systems of metastatic cancer we found that inflammatory cells, such as macrophages and dendritic cells, activated either by extrinsic factors, for instance post-operative microbial infections, or intrinsic factors produced by the cancer cell itself, make important and very critical contributions to the growth of metastases formed by colon and lung carcinomas. We now propose to extend these studies to human colon carcinomas grown in mice. The proposal is divided into two parts. In the first part, we will examine whether tumor necrosis factor (TNF-alpha) plays a critical role in the ability of microbial products to stimulate the metastatic growth of colon carcinomas and whether anti-TNF and anti-NF-kappaB therapy can potentiate the tumorocidal activity of either the apoptotic cytokine TRAIL, which is currently under clinical development, or the TRAIL-inducing cytokine interferon beta. Second, we will examine whether human colon carcinomas secrete factors that lead to macrophage activation and production of pro-metastatic cytokines. We will characterize the signaling mechanisms used by these factors, focusing on the role of Toll-like receptors, and will develop neutralizing antibodies that block the ability of these carcinoma-generated factors to promote the formation of pre-metastatic niches and stimulate metastatic growth in vivo. In addition to a better understanding of the basic mechanisms that control the emergence and growth of metastases this work should within a relatively short time lead to development of new anti-metastatic therapies."
Makoto Mark Taketo, M.D., Ph.D.
Kyoto University, Kyoto, Japan
Project: Inhibition of CCR1 to suppress colon cancer invasion and metastasis
Dr. Taketo has focused his research on the process of cancer invasion and colon cancer metastasis. Dr. Taketo and his laboratory have recently discovered that cancer cells recruit a special type of bone marrow-derived cells (iMCs) that travels from the bold stream to an initial tumor site, aiding the metastasis of the cancer. Dr. Taketo has found "that iMCs produce proteolytic enzymes needed for invasion. Importantly, these iMC are recruited because the colon cancer secretes an attractant "chemokine" whose receptor "CCR1" is carried by iMCs." Dr. Taketo's research, with the aid of the Jeannik M. Littlefield-AACR Grant in Metastatic Colon Cancer Research, aims to suppress the invasion and subsequent metastasis. "In this project, we shall examine colon cancer invasion at the metastatic liver and lung for involvement of iMCs, and test a CCR1 inhibitor in mice for its ability to block colon cancer invasion and metastasis. The results should give us a convincing proof of concept to treat human colon cancers metastasis with this type of drugs; CCR1 inhibitors."
Louis M. Weiner, M.D.
Fox Chase Cancer Center, Philadelphia, PA
Project: siRNA synthetic lethal screens to improve EGFR-targeted therapy of colorectal cancer
Dr. Weiner and his collaborators are interested in improving the effectiveness of treatments for cancers of the colon and rectum by identifying the factors that make cancer cells more sensitive to the effects of monoclonal antibodies. Monoclonal antibodies are proteins that are designed to specifically attach to targets such as the Epidermal Growth Factor Receptor (EGFR), which is located on the surfaces of many of these cancer cells. When antibodies target the EGFR, cancer cells are deprived of critical signals that they need to proliferate, survive, invade and spread to other sites in the body. However, treatment with these antibodies is not uniformly effective. Weiner's group is identifying the genes in cancer cells producing the proteins that are needed for cancer cell-related EGFR signaling to proceed despite exposure to these antibodies. Such proteins thus will be targets for drugs that can be combined with antibody therapy to improve the effectiveness of treatment for cancers of the colon and rectum. The findings of this research can be rapidly applied to the development of new treatment strategies for these cancers.
- View the list of 2006 Jeannik M. Littlefield-AACR Grantees in Metastatic Colon Cancer Research