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VANDERBILT UNIVERSITY GI CANCER SPORERobert L. Coffey, M.D., Principal Investigator For more information on Vanderbilt University’s SPORE in GI Cancer, please visit: http://www.vicc.org/spores/gi/ At Vanderbilt-Ingram Cancer Center, three NCI SPORE grants support research in GI, breast and lung cancers. The SPORE in GI Cancer is one of only five in the country and focuses on innovative, translational research to reduce and prevent colorectal cancers, a leading cause of cancer deaths in both men and women. Vanderbilt-Ingram Cancer Center was the fourth cancer center in the United States to receive an NCI GI SPORE grant in 2002 and received a second round of support from the NCI in 2007.
OVERVIEWThe Vanderbilt-Ingram Cancer Center SPORE in GI Cancer is committed to innovative translational research to reduce and prevent colorectal cancers. The GI SPORE interdisciplinary team consists of clinical and basic science investigators with expertise in genetics, cellular and molecular biology, pathology, medical, surgical and radiation oncology, clinical trial design, epidemiology, mass spectrometry, biostatistics and biomedical informatics. The goal of the GI SPORE is to apply the translational research strengths of Vanderbilt University toward reducing the incidence, morbidity and mortality of colorectal cancer. THE OBJECTIVES OF THE GI SPORE INCLUDE:Translate discoveries in EGF receptor (EGFR) biology into improved therapies for patients with colorectal cancer; Develop and use biological assays for a high throughput screen to identify antagonists of canonical unit signaling and drugs that restore cell surface E-cadherin; Understand and control genetic and epigenetic changes in colorectal tumors that lead to malignancy with a special emphasis on p120; Identify biomarkers to assess individual risk for developing colorectal neoplasia. THE SPORE IN GI CANCER TEAMRobert J. Coffey, M.D., Program Director
RESEARCHThe Vanderbilt SPORE in GI Cancer consists of several initiatives including four scientific research projects, five cores that provide essential services to SPORE projects, a developmental research program to support pilot projects and career development opportunities for physician-scientists in training. Vanderbilt’s GI SPORE extends major translational research accomplishments of the previous grant cycle and redirects resources into emerging areas of opportunity identified in SPORE-supported pilot projects. Four projects and five cores represent a continuation of successful projects and establishment of new projects focused entirely on colorectal cancer, the second leading cause of cancer deaths in the United States. The advancement of translational research in the GI SPORE is supported by additional initiatives including the Mouse Models of Human Cancers Consortium, the Ayers Institute for Pre-cancer Detection and Diagnosis, unique imaging techniques and proteomic screening.
PROJECT 1: BIOLOGICAL AND THERAPEUTIC IMPLICATIONS OF BLOCKADE OF EGFR AXIS AND SRC IN COLORECTAL CANCERClinical PI: Mace L. Rothenberg, M.D. The goal of this project is to translate discoveries in EGFR biology into improved therapies for patients with colorectal cancer (CRC). Two complementary strategies will be employed: combined inhibition of the EGFR axis and inhibition of EGFR and complementary signaling pathways, as exemplified by Src. We previously identified the important role of EGFR signaling in gastrointestinal neoplasia based on genetic and pharmacological studies in the mouse (Roberts RB, Min L, Washington MK, Olsen SJ, Settle SH, Coffey RJ, Threadgill DW. Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis. Proc Natl Acad Sci U S A 2002;99:1521-6). A notable translational research accomplishment of our GI SPORE was the design and conduct of a randomized Phase II trial of two dose levels of gefitinib (IressaTM) in patients with advanced CRC recruited through collaboration with the Eastern Cooperative Oncology Group (ECOG) (Rothenberg ML, LaFleur B, Levy DE, Washington MK, Morgan-Meadows SL, Ramanathan RK, Berlin JD, Benson AB, 3rd, Coffey RJ. Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. J Clin Oncol 2005;23:9265-74). In this trial, gefitinib was clinically inactive and paired tumor biopsies confirmed that gefitinib failed to inhibit key biological targets including phosphorylated EGFR, Akt and MAPK. The concordance of laboratory and clinical findings and the ability to obtain paired tumor biopsies in a cooperative group setting were important accomplishments and provide a foundation upon which current and future translational research studies can - and are - being rationally designed. Although gefitinib alone is not an active drug in this disease, cetuximab (Erbitux, C225) monotherapy has demonstrated modest, but consistent, activity in this setting. We and others have generated preclinical data and championed the notion that one can combine blockade of discrete steps in the activation of the EGFR - cell surface ligand cleavage, ligand uptake by the receptor and receptor tyrosine kinase activity - to achieve cooperative growth inhibition in CRC (Merchant NB, Voskresensky I, Rogers CM, Lafleur B, Dempsey PJ, Graves-Deal R, Revetta F, Foutch AC, Rothenberg ML, Washington MK, Coffey RJ. TACE/ADAM-17: a component of the epidermal growth factor receptor axis and a promising therapeutic target in colorectal cancer. Clin Cancer Res. 2008 Feb 15;14(4):1182-91). A Phase I/II trial combining cetuximab and erlotinib (TarcevaTM) has been approved by the Cancer Therapy Evaluation Program (CTEP) and is evaluating the biological and clinical effect of this strategy. Should this approach prove promising, we plan to add a selective inhibitor of TACE, the enzyme that cleaves cell surface TGFα and amphiregulin, two EGFR ligands that are frequently upregulated in CRC, to further block the EGFR axis in a translational research trial planned for Years 3-5 of this grant. Aim 1: To evaluate the clinical and biological effects of inhibiting the EGFR axis in advanced CRC; Aim 2: To evaluate the clinical and biological effects of inhibiting EGFR and Src in a neoadjuvant trial of CRC patients with liver-limited metastasis prior to surgical resection; Aim 3: To explore utilizing novel imaging modalities in the mouse that will assess tumor volume, DNA replication, apoptosis, angiogenesis and EGFR status in a non-invasive manner. The most promising of these imaging modalities will be advanced to human application during the course of this funding cycle.
PROJECT 2: CHEMICAL GENETICS APPROACH TO INTERROGATE AND REGULATE E-CADHERIN EXPRESSION AND CANONICAL WNT SIGNALINGClinical PI: R. Daniel Beauchamp, M.D. Loss of E-cadherin function is a critical event that is associated with epithelial-to-mesenchymal transition, invasiveness and the metastatic phenotype in human colorectal cancer and other carcinomas. Inappropriate activation of the canonical Wnt pathway is another critical event in the transition from normal epithelium to the neoplastic phenotype in colorectal cancer. Although it is well accepted that perturbation of these pathways represent important hallmarks of neoplastic tranformation, their mechanisms of transduction and regulation under normal and pathological conditions are poorly understood. We have developed highly reliable and sensitive assays for re-expression of E-cadherin in the SW620 colorectal cancer cell line that normally expresses very low levels of E-cadherin. Similarly, we have also developed a robust biochemical assay that recapitulates activation of the canonical Wnt pathway by the Wnt coreceptor, LRP6. Both of these assays have been adapted for a 384-well format. We now propose to interrogate regulation of E-cadherin expression and canonical Wnt signaling using a chemical genetics-based approach in a high-throughput screen to identify compounds that induce expression of E-cadherin in SW620 cells and that perturb degradation of beta-catenin and Axin, two key regulators of signaling through the canonical Wnt pathway. Our initial screen of 6,400 small molecules has already identified several lead compounds in both of these assays and we propose screen a total of 160,000 compounds. We propose to validate lead compounds from this initial screen in a variety of in vitro and in vivo assays. Our preliminary studies indicate that the small molecule trichostatin A, a histone deacetylase inhibitor, acts to induce E-cadherin expression in SW620 cells. We will explore its role in E-cadherin expression as well as its potential for regulating Wnt signaling. Finally, we will identify the mechanisms of action and potential targets of validated compounds by testing their effects on candidate cellular pathways as well as in biochemically reconstituted reactions. Aim 1: Identify compounds that induce expression of E-cadherin or regulate stability of Axin and/or β-catenin through high-throughput screening of a small molecule library; Aim 2: In vitro and in vivo validation of “hits” identified by HTS for the re-expression of E-cadherin or perturbation of canonical Wnt signaling; Aim 3: Determine the role of histone deacetylases in the repression of E-cadherin and Wnt signaling in colon cancer cells; Aim 4: Determine the mechanism of action for validated compounds and identify compound targets.
PROJECT 3: UNDERSTANDING AND CONTROLLING P120 DYSFUNCTION IN COLORECTAL CANCERClinical PI: Mary Kay Washington, M.D., Ph.D. Tumor progression in colorectal cancer (CRC) involves accumulation of genetic and epigenetic changes that ultimately lead to malignancy. E-cadherin downregulation occurs frequently and is widely believed to be a pivotal event in the transition to metastasis. In the majority of E-cadherin-defi cient CRCs, p120 localizes aberrantly to the cytoplasm, and both E-cadherin-loss and cytoplasmic p120 are tightly associated with metastasis and poor prognosis. p120 itself is downregulated in a subset of CRC but the significance is not yet clear. We have found that p120 is essential for E-cadherin retention at the cell surface. p120 ablation in vitro and in vivo destabilizes and/or eliminates E-cadherin (and associated catenins) causing severe defects in cell morphology and adhesion. In addition, we have found that cadherin-association is required for p120-dependant regulation of Rho by a novel mechanism that may directly mediate contact-dependent inhibition. Interestingly, in vitro p120-ablation in various cell types induces constitutive activation of Rho, cell growth in the absence of serum, and loss of contact inhibition. Moreover, the same or similar pathways in vivo appear to mediate activation of a ROCK/NFkB/COX-2 signaling cascade and chronic inflammation. These observations reveal novel co-dependent interactions between p120 and E- cadherin that are likely required for contact inhibition, suppression of metastasis, and control of inflammation. Our progress report describes these observations, along with preliminary data based on a novel mouse model for limited conditional p120-ablation in the small intestine and colon. The aims below seek to apply these observations to tumor progression and clinical intervention in human CRC. Aim 1: To evaluate pharmaceutical blockade of signaling pathways activated by p120 and/or E-cadherin dysfunction as targets for suppression of tumor progression or metastasis; Aim 2: To determine the pattern and signifi cance of observed defects in p120 protein and mRNA expression as they pertain to CRC type and tumor progression; Aim 3: To Identify by high throughput screening (HTS) novel compounds that reverse p120-dependent defects in E-cadherin activity.
PROJECT 4: TENNESSEE COLORECTAL POLYP STUDYClinical PI: Reid M. Ness, M.D., M.P.H. Colorectal cancer is one of the most common malignancies in the United States and many other countries. Most colorectal cancers arise from adenomatous polyps, pre-malignant lesions that can be removed during an endoscopic procedure to reduce cancer incidence and mortality. Despite considerable research conducted over the past few decades, very few biomarkers have proven useful in assessing individual risk for developing colorectal neoplasia. As part of the renewal for the Tennessee Colorectal Polyp Study (TCPS), we propose to evaluate whether high endogenous production and signaling of prostaglandin PGE2, a key mediator of COX-2 pathway, may be related to the risk of colorectal adenomas and whether the PGE2 –related association may be independent of a low-grade, systematic inflammation, as measured by blood C-reactive protein (CRP). Urinary PGE2 metabolite and blood CRP will be measured in approximately 1000 adenoma patients and polyp-free controls to evaluate the utility of these biomarkers in risk assessment. A two-phase study involving approximately 4600 subjects will be conducted to evaluate polymorphisms in genes affecting PGE2 production (PTGS2, PTGES, 15-PGDH) and signaling (PTGER1-PTGER4) in relation to adenoma risk. Expression levels of genes related to PGE2 production in polyp tissues will be quantified using RT-PCR and correlated with the level of urinary PGE2 metabolite. In addition, we will also investigate risk factors for sessile serrated adenomas (SSA), a group of newly-defined adenomas that may have a different risk profile compared to conventional adenomas. The TCPS is a large, on-going colonoscopy-based epidemiologic study of colorectal adenomas. The resources established in this study will provide exceptional research opportunities to test the hypotheses proposed in this application. Results from this study will be valuable for identifying high-risk individuals for cost-effective colorectal screening and chemoprevention. Aim 1: To measure urinary PGE-M and blood CRP in cases and controls to evaluate case-control differences in these biomarkers. Aim 2: To conduct a two-phase study to evaluate the risk for colorectal adenomas with polymorphisms in the candidate genes described above. Aim 3: To conduct RT-PCR assays to quantify the expression levels of the PTGS2, PTGES, 15-PGDH genes in polyp tissues.
CORESCORE 1: ADMINISTRATIVE COREDirector: Robert J. Coffey, M.D. The Administrative Core supports SPORE projects and investigators by managing SPORE resources and facilitating communication and interaction among SPORE components and collaborators, other SPORES, the community and the NCI. Management and support are accomplished through a series of oversight committees, as well as organized administrative and scientific meetings of SPORE investigators, institutional representatives and external advisors.
CORE 2: TISSUEDirector: Mary Kay Washington, M.D., Ph.D. The primary mission of the Vanderbilt GI SPORE Tissue Core is to provide high-quality human tissue and body fluid samples collected and processed according to standard protocols, research histology and research immunohistochemistry service to GI SPORE investigators and for interSPORE collaborations. The specific aims of this proposal are:
CORE 3: CLINICAL TRIALSDirector: Mace L. Rothenberg, M.D. The role of the Clinical Trials Core is to provide expertise in the development, implementation and coordination of the laboratory-clinical translational research trials performed in the SPORE. The ultimate goal is to develop improved therapies for patients with or at risk of developing gastrointestinal cancers through a better understanding of the biology of those cancers. To achieve this goal, the major responsibilities of the Clinical Trials Core will be:
During the first year there will be 3 trials open for accrual. These trials will serve to further the scientific knowledge regarding the roles of:
Knowledge and insights gained from these trials will be used to design follow-up trials to be conducted within this SPORE and, when appropriate, assist in the development of larger, confirmatory trials to be conducted as inter-SPORE or cooperative group collaborations.
CORE 4: BIOSTATISTICS/BIOINFORMATICSCore Director: Yu Shyr, Ph.D. The purpose of the Biostatistics/Bioinformatics Core is to provide professional expertise in statistics and bioinformatics for all Vanderbilt University GI Cancer SPORE projects, investigators and participants. Functions provided by this core include development of experimental designs, data acquisition and database development, data quality control, statistical analysis and interpretation of findings, and collaboration on presentation of results. To achieve these functions, the core directors and core biostatisticians are constantly available to investigators, and are in regular contact with the project and core leaders. The primary objectives of the Biostatistics/Bioinformatics Core are:
CORE 5: HIGH THROUGHPUT SCREENINGDirector: Charles David Weaver, Ph.D. High-throughput screening (HTS) is a means of rapidly assessing the ability of hundreds of thousands of chemical compounds to affect biological systems for the purpose of accelerating medical research. We propose an HTS core the goal of which is to enable GI SPORE investigators to discover chemical tools to promote better understanding of colorectal cancer physiology and potentially to help reveal novel targets and therapeutic opportunities through the following aims:
DEVELOPMENTAL RESEARCH PROGRAMDirector: Robert J. Coffey, MD The Developmental Research Program has been a major vehicle by which Vanderbilt’s GI SPORE has promoted translational gastrointestinal cancer research. To date $840,669 has been allocated to support 25 Pilot Projects. We have been able to sustain this Program through the generous institutional support despite reductions in the overall GI SPORE budget. A special effort has been made to attract young investigators into the field of gastrointestinal cancer research (Drs. Dixon, Dhawan, Fingleton, Franklin, Li, Kenworthy and Kaverina). In the case of Drs. Dixon, Dhawan, Fingleton and Kenworthy, the Developmental Research Program was instrumental in helping to secure their first independent peer review grant support. The GI SPORE has supported research in gastrointestinal neoplasia outside of CRC (colorectal cancer) with special emphasis on gastroesophageal cancer (Drs. Goldenring, Peek, Polk, El-Rifai and Schneider). This support has contributed significantly to Dr. Peek’s R01 application studying the link between inflammation and the development of gastric cancer. Efforts have been made to further strengthen existing programs and to bring together basic scientists and physician investigators.
CAREER DEVELOPMENT PROGRAMDirector: Mace L. Rothenberg, M.D. The Career Development Program is charged with recruiting and supporting talented investigators interested in focusing on GI cancer translational research. These could either be promising new investigators or established investigators wishing to redirect their research focus to translational research in GI cancer. This is accomplished by salary and research support for these investigators granted after identification of an established mentor, submission of a detailed plan of studies, personal interviews and rigorous peer review.
THE SPORE IN GI CANCER ADVOCACYJane Condon, MSSW, Manager, Patient Advocacy Research advocates have a unique and important contribution to make to cancer research and are increasingly playing an important role in the cancer care setting. By participating in the development and oversight of research, advocates can truly influence the nature of cancer research and the future of patient care. At Vanderbilt-Ingram Cancer Center (VICC), research advocates participate in the NCI’s Specialized Program of Research Excellence (SPORE), bringing the patient perspective to the table, and helping scientists make the translation of cancer research to cancer patients efficient and effective. Research advocates may be cancer survivors, family members/caregivers, health professionals or community advocates who have an interest in cancer research and are willing to work directly with researchers in a specific SPORE program. Since 2003, research advocates have been an integral part of the GI SPORE team, offering patient experiences and perspectives into GI SPORE research at VICC. Four committed cancer survivors and caregivers are actively involved helping to bring the best science to those who are affected by colorectal cancer by contributing in the following ways:
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