Gastrointestinal Cancer Research Program
Program Leaders: Robert J. Coffey Jr., M.D., and Jordan D. Berlin, M.D.
- To support the basic, translational, and clinical research in gastrointestinal (GI) cancer and Vanderbilt-Ingram Cancer Center
- To develop investigator-initiated clinical trials in GI cancer with an emphasis on agents that target critical signaling pathways studied by GI members and other VICC investigators, and to diversify the clinical trials menu conducted in terms of disease type, source, and integration with other cancer centers
- To foster internal and external scientific interactions to develop innovative diagnostic and/or predictive markers of and therapeutic approaches to GI neoplasia
- To continue colorectal and gastroesophageal research and to launch a pancreatic cancer initiative
- To continue training students and postdoctoral fellows, and mentoring junior faculty to be the next generation of leaders in the field of GI cancer
Program Focus to Meet Scientific Goals
GI has leveraged existing and newly developed institutional strengths to advance its basic and translational goals. These include the Jim Ayers Institute for Precancer Detection and Diagnosis (Ayers Institute), Digestive Diseases Research Center (DDRC), Vanderbilt Institute of Chemical Biology (VICB), and Epithelial Biology Center (EBC). GI focuses on several themes that span the spectrum from basic mechanisms to clinical trials. Areas of interest include the following:
- Optimize EGFR blockade with emphasis on inhibiting complementary pathways, including COX-2, Src, and Notch
- Utilize chemical high-throughput screens (HTS) to identify antagonists of canonical Wnt signaling and to restore cell surface E-cadherin as a surrogate marker for reversal of epithelial-to- mesenchymal transition (EMT)
- Continue to develop pharmacodynamic and non-invasive imaging biomarkers predictive of response to established and novel anti-cancer agents
- Identify predictors of colorectal adenoma recurrence
- Evaluate the importance of epithelial polarity and vesicle trafficking in the maintenance of epithelial homeostasis and their dysregulation in GI neoplasia
- Elucidate the relationship between inflammation and cancer with a particular focus on the role of H. pylori in gastric cancer
- Develop prognostic and predictive biomarkers of colorectal cancer (CRC)
- Interrogate the relationship between normal colonic stem cells and colon cancer stem cells
- Continue patient advocacy, education, and outreach activities to inform patients and community about GI cancer research and enhance accrual into clinical trials
- Refine medical treatment of Ménétrier’s disease
Figure GI 1. Overview of the GI Program
Our most developed focus area is CRC. Vanderbilt’s GI Specialized Program of Research Excellence (SPORE), renewed in 2007, focuses exclusively on CRC. We also have made strong progress in developing a gastroesophageal initiative, recruitment of six new faculty members, funding of two Program Project Grants, 14 R01s, and an investigator-initiated trial (IIT) under development.
GI was instrumental in the establishment of the Ayers Institute, whose stated goal is to develop a serum marker for the early detection of CRC. VUMC and VICC have also made a large commitment to the newly launched EBC in terms of space and recruitment that will greatly aid the GI Program. Dr. Coffey is Director of the EBC and James Goldenring, M.D. is co-Director. The focus will be on establishment and maintenance of epithelial cell polarity, vesicle trafficking, and issues related to stem cell biology with a particular focus on the GI tract and GI neoplasia.
The laboratories of Drs. Coffey, Goldenring, and Anna Means have been relocated to new space on the 10th floor of MRBIV where the EBC is housed. The designated space is contiguous to the research space of the divisions of adult and pediatric gastroenterology where the DDRC is housed. This physical proximity further enhances the interactions among members of GI. The institution has committed to recruit five independent investigators to this location over the next five years, which will allow development of new basic and translational directions for GI. A high priority for VICC/EBC recruitment is a physician-scientist in pancreatic cancer. Other core technologies and services developed within the EBC include quantitative immunohistochemistry using an Ariol Scanner secured by M. Kay Washington, M.D., through a National Center for Research Resources Shared Instrumentation Grant, “Delta Vision” for live cell imaging and a colony counter. Institutional funds have been provided to purchase a custom flow cytometer for fluorescence-activated vesicle sorting (FAVS, a technology developed by Dr. Coffey) and a “microscope in a box” for HTS. All of these technologies and services are available to VICC members.
Drs. Berlin and Coffey meet weekly to discuss management of GI, new research data, and management of the GI SPORE. Collectively, these efforts (enhancing interactions within GI, stimulating new directions, training and mentoring the next generation of GI-cancer focused investigators) have had a major impact, locally and nationally.
About the Program Leaders
Program Co-Leader: Robert J. Coffey Jr., M.D., has led GI since its inception in 1993. He attended Princeton University and Georgetown Medical School. He trained in internal medicine at Emory University and then received fellowship training in medical oncology at Georgetown and gastroenterology at the Mayo Clinic. He was a staff member at the Mayo Clinic before coming to Vanderbilt as an Assistant Professor in 1986. He is currently Professor of Medicine (Gastroenterology and Medical Oncology) and Cell and Developmental Biology. He holds two endowed chairs and is Principal Investigator of the NCI-funded GI SPORE and MMHCC. Dr. Coffey also directs the newly formed VUMC EBC. He remains clinically active but devotes 90% of his effort toward basic research. He is a member of the American Society of Clinical Investigation and American Association of Physicians. His major research interests are in epithelial growth and differentiation, trafficking of EGFR ligands in polarized epithelial cells, GI malignancy, and Ménétrier’s disease. Dr. Coffey has trained 31 students and postdoctoral fellows, is actively training an additional 10 individuals, and has mentored seven junior faculty members.
Program Co-Leader: Jordan D. Berlin, M.D., is Ingram Associate Professor of Medicine in the Division of Medical Oncology. Dr. Berlin maintains a leadership role in a number of national GI cancer committees. He serves on the core GI committees at ECOG and American College of Surgeons Oncology Group (ACOSOG) and was selected for the ECOG Young Investigators' Award in 2004. He represents ECOG as Chairman of the Intergroup Task Force on Pancreas Cancer. He has served on the program committees of several national and international cancer meetings including the roles of non-colorectal cancer sub-chair for the 2004 ASCO meeting, and overall program chair for 2008 AGA/ASCO/ASTRO/SSO Combined GI Symposium (often called ASCO GI). He was an invited panel member on the FDA Workshop on Colorectal Cancer Endpoints in 2003, an ad hoc reviewer for the SBIR/SSTR study section for the NCI in 2005 and 2006, and a 2008 member of the NCI Think Tank on the coding, decoding, transfer, and translation of information in cancer. At Vanderbilt, Dr. Berlin is newly appointed as Director of the Phase I team, serves as Medical Director of the Clinical Trials Shared Resource, and is a member of the IRB, the Resource Allocation Committee, and the VICC DSMB. He has served on design studios for two projects as part of the Vanderbilt CTSA. He has served as a mentor to several GI fellows at Vanderbilt and previously at University of Wisconsin. Former fellows work at University of Wisconsin, Ohio State University, University of Tennessee-Knoxville, and two at Vanderbilt. He has represented Vanderbilt on the Guidelines Steering Committee for the National Comprehensive Cancer Network (NCCN) and serves on the Neuroendocrine Guidelines Panel. Recent/current mentees are: Drs. A. Craig Lockhart, Emily Chan, Laura Williams Goff, Dana Backlund, Melanie Dunlap, and Kristen Ancell.
Areas of Research Program Expertise
The GI has developed a three-pronged approach to CRC, with a dynamic, bi-directional, iterative interplay between in vitro and in vivo systems to advance innovative diagnostic and therapeutic approaches. First, we utilize a battery of polarizing human CRC cell lines developed from well-differentiated CRCs to examine the spatial compartmentalization of the EGFR receptor (EGFR) and its cognate ligands. We have identified the EGFR axis (defined as the proximal events in activation of the EGFR) as a tractable therapeutic target in CRC and established the importance of Naked2 in the delivery of TGFβ to the basolateral surface of polarized epithelial cells. This work is summarized in a review in Experimental Cell Research (Fiske, et al, 2008). The pace of this in vitro work will be greatly accelerated by the newly established EBC. A recent advance is our ability to flow sort cellular organelles and perform large-scale proteomic analysis by LC/LC-MS/MS (Cao, et al, 2008). Development of this methodology has been supported, by our Mouse Models of Human Cancer Consortium (MMHCC), and by VICC.
A second focus of our CRC efforts is the study of various aspects of colon cancer in the mouse. This work has been recognized by funding of an MMHCC grant. The renewal application highlights the inter-institutional nature of the GI program in that we will join forces with Dr. Kevin Haigis from Harvard (and a member of Harvard’s GI SPORE). Drs. Hans Clevers and Jeff Franklin will also be important collaborators. A major focus of the MMHCC renewal is to determine the cell-of-origin of colon cancer using tamoxifen-inducible Cre drivers that target 3 discrete compartments in the colon (stem cell, transient amplifying, and differentiated compartment) to create compartment-specific loss-of-function Apc or non-degradeable β-catenin. Of interest, one of these drivers is Lrig1-CreERT2. Lrig1 is a negative regulator of EGFR; it marks proliferative and quiescent stem cells in the colon (RJ Coffey, unpublished observation). As PI of Vanderbilt’s MMHCC and GI SPORE, Dr. Coffey has a unique vantage point to integrate mouse models and human disease. Dr. Washington has emerged as a leader within the MMHCC based on her expertise in the comparative analysis of mouse and human GI tumors.
Historically, COX-2 has been of great interest to GI members as a potential target for prevention and/or treatment of CRC, but COX-2 inhibitors have well-documented cardiovascular side effects. Glucocorticoids are potent endogenous COX-2 inhibitors. Dr. Harris’ lab showed that expression of 11ß-hydroxysteroid dehydrogenase type 11 (11ßHSD2), which converts active glucocorticoids to inactive keto-forms, is increased in human colonic and ApcMin mouse intestinal adenomas and correlated with the increased COX-2 expression and activity (Zhang et al, 2009). Pharmacologic inhibition or gene silencing of 11ßHSD2 inhibited COX-2-mediated PGE2 production in tumors and prevented adenoma formation and tumor growth and metastasis. Unlike systemic COX-2 inhibitors, 11ßHSD2 inhibition did not reduce systemic prostacyclin production or accelerate atherosclerosis, thereby avoiding major cardiovascular side effects seen with COX-2 inhibitors.
The final emphasis of our CRC efforts is our study of human CRC. A major accomplishment was the successful renewal of the GI SPORE in 2007. Dr. Coffey is PI and Dr. Berlin is Co-PI. A unique component of our application was judged to be our high-throughput screening (HTS) core. In fact, a successful screen has already been conducted for the restoration of cell surface E-cadherin as a surrogate marker for reversal of EMT (directed by Dr. Beauchamp). An epidemiological study within the GI SPORE is designed to identify factors that predict recurrence of colorectal adenomas [directed by Wei Zheng, M.D., Ph.D. (CE, BC)]. Al Reynolds, Ph.D. (ST), directs a SPORE project that is elucidating fundamental roles for p120 in the pathogenesis of CRC. Charles Manning, Ph.D. (HT and mentored by Dr. Coffey) is developing non-invasive imaging modalities to monitor response to targeted therapies in mouse models of intestinal cancer, and these are being rapidly advanced to the clinic.
VICC and the GI Program have also been instrumental in the establishment of the Meharry-Vanderbilt Alliance Colorectal Screening Project. This effort is led by Dr. Harvey Murff, GI member and a recipient of a GI SPORE Career Development award. He was recently awarded one of two planning grants to develop a full proposal in response to the Meharry–Vanderbilt Alliance Foundation “A Revolution in Healthcare Project.” The purpose of this proposal is to design and implement a novel system of care for a specific medical condition for a defined population within Middle Tennessee. Critical elements of this novel clinical system include healthcare cost control, improved quality of care, and improved clinical outcomes. Dr. Murff will coordinate efforts to enhance CRC screening in an underserved, predominantly African American inner-city population.
Gastroesophageal Cancer Initiative
Vanderbilt has assembled one of the strongest groups of investigators in the world that bring a complementary but multi-faceted approach to investigating the pathogenesis of gastric cancer. Drs. Correa, El-Rifai, Zaika, Wilson, Vaezi, and Andl were recruited to join Drs. Goldenring, Peek, Cover and Brent Polk, M.D.
A major focus of the gastroesophageal initiative has been on the role of H. pylori-induced inflammation in the pathogenesis of gastric cancer. A new PPG titled H. pylori and Gastric Cancer was funded in 2009. Dr. Richard Peek is PI of this grant; other key investigators include Drs. Goldenring, Cover, Correa, Wilson, and Polk (ST), Director of the Division of Pediatric Gastroenterology at Vanderbilt. A second PPG, Etiological Studies of Gastric Cancer (P01 CA028842), was successfully renewed in 2009 with Dr. Correa as PI; Dr. Wilson directs a project within this PPG.
Dr. Correa was recruited to VUMC and VICC in 2005, thanks to being awarded the Anne Potter Wilson Chair in Cancer Research by VICC. His PPG (Etiological Studies of Gastric Cancer) is in its 24th year of continuous funding. His seminal work identified and defined the precancerous stages of gastric cancer. Instrumental in the renewal was a GI SPORE pilot project that enabled him to conduct field-work in Colombia and assess the effectiveness of chemo-preventive strategies using Vanderbilt laboratory resources.
Dr. Goldenring continues to study the origin of a pre-neoplastic gastric metaplasia he has identified, spasmolytic polypeptide-expressing metaplasia (SPEM). He works closely with Dr. Coffey and is co-Director of the EBC. Dr. Goldenring has recently organized a monthly brainstorming session/focus group for those interested in gastric cancer.
Dr. El-Rifai, recruited to the Department of Surgery in 2005, is an integral member of the GI program. His group investigates the molecular basis of adenocarcinoma of the stomach and esophagus by applying integrated molecular biology and translational genomics and epigenomic approaches. Based on Dr. El-Rifai’s work with the MLN8237, the GI team approved for further development a trial of docetaxel and MLN8237 as second line therapy for gastric cancer (Dr. Goff, Chair; Dr. El-Rifai, Laboratory Correlates Chair). In 2009, Dr. El-Rifai became a member of the NCI Esophago-Gastric Task Force.
Pancreatic and Hepatobiliary Cancer
Data from Dr. Merchant’s laboratory show significant benefit by combining Src kinase inhibition and EGFR inhibition with gemcitabine both in vitro and in vivo. Based on these data, ACOSOG is considering a trial of neoadjuvant dasatinib (Src inhibitor), erlotinib (EGFR inhibitor), and gemcitabine in pancreatic cancer. In 2007, Dr. Merchant developed and now serves as Director of the Central Pancreas Consortium. This Consortium brings together surgeons from nine major academic institutions with an expertise in pancreatic surgery and pancreatic neoplasms. The group includes Vanderbilt, Emory, University of Cincinnati, University of North Carolina- Chapel Hill, University of Louisville, Washington University, Indiana University, University of Wisconsin, and Northwestern. The primary objective is to prospectively study the surgical treatment of pancreatic neoplasms in a multi-institutional setting. The group has already completed five major collaborative projects, has initiated its first randomized trials, and has submitted one R01 grant and a Society of Surgical Oncology Clinical Investigator Award and is complemented by extensive expertise in pancreatic development under the leadership of Drs. Wright and Means that provides basic and translational support for this work.
Clinically, three cooperative group trials have been completed in which GI investigators were PI or co-chair, with two studies pending. In 2009, Dana Backlund, M.D., a Vanderbilt-trained and GI-mentored medical oncologist, was recruited to focus on pancreatic cancer translational research. She is currently finishing her Masters of Science in Clinical Investigation (MSCI) degree. As a fellow, she authored GI0815, a Phase II IIT of erlotinib and sorafenib in second-line treatment of pancreatic cancer, under the mentorship of Dr. Berlin.
Early efforts in hepatobiliary cancer has been largely clinical, with efforts to increase patient recruitment through the development of clinical trials in hepatocellular cancer (HCC) and, more recently, biliary tract cancers. An investigator-initiated trial of selective internal radiation therapy (SIRT) is now closed to accrual. Dr. Berlin successfully completed his R21-supported HCC trial, conducted in ECOG (E6202) with correlative studies performed as an inter-programmatic collaboration with Ann Richmond, Ph.D. (HT). The preliminary results were reported at ASCO in 2008. A multidisciplinary focus group was established two years ago and has been very successful. It is attended by hepatologists, radiologists, interventionalists, surgeons, and medical oncologists. The clinical investigators have initiated relationships with basic science researchers within the Cancer Center to enhance the hepatobiliary program. Dr. Goff has worked with the Southeast Phase II Consortium to conduct trials of a novel MEK inhibitor in hepatocellular and biliary tract cancer. She is currently working with the Phase II Consortium on a new trial for temserolimus and bevacizumab for patients with HCC. One of Dr. Goff’s roles is to develop and foster relationships with scientists in and out of GI to increase our translational work in hepatobiliary cancers. Dr. Bill Russell uses mouse models to study growth regulation within the liver and Dr. Gordon is establishing mouse models of primary and metastatic liver cancer.
- Andl, Claudia D., Ph.D.
Assistant Professor of Surgery; Assistant Professor of Cancer Biology; Researcher
- Beauchamp, R. Daniel, M.D.
John Clinton Foshee Distinguished Chair in Surgery; Professor of Surgery; Professor of Cancer Biology; Chair of the Section of Surgical Sciences; Surgical Oncologist
- Berlin, Jordan D., M.D.
Professor of Medicine; Ingram Professor of Cancer Research; Clinical Director, GI Oncology Program; Director, Phase I Program; Medical Oncologist
- Chan, Emily, M.D., Ph.D.
Assistant Professor of Medicine; Medical Oncologist
- Coffey, Robert J., M.D.
Ingram Professor of Cancer Research; Prof Med (GI/Med Oncology) & Cell and Developmental Biology; Researcher
- Correa, Pelayo, M.D.
Professor; Anne Potter Wilson Endowed Chair in Cancer Research; Anatomic Pathologist
- Cover, Timothy L., M.D.
Professor of Medicine; Researcher
- Deane, Natasha G., Ph.D.
Research Assistant Professor; Researcher
- El-Rifai, Wael, M.D., Ph.D.
Professor; Director of Surgical Oncology Research; Cancer Geneticist; Molecular Biologist
- Franklin, Jeffrey L., Ph.D.
Research Assistant Professor; Researcher
- Goff, Laura Williams, M.D.
Assistant Professor of Medicine; Associate Director, Hematology/Oncology Fellowship Program; Medical Oncologist
- Goldenring, James R., M.D., Ph.D.
Paul W. Sanger Professor of Experimental Surgery; Vice-Chairman for Research; Researcher
- Gorden, David Lee, M.D. , F.A.C.S.
Associate Professor of Surgery; Liver and Hepatobiliary Surgeon
- Hanks, Steven K., Ph.D.
- Harris, Raymond C., Jr., M.D.
Ann and Roscoe R. Robinson Professor; Director, Divsion of Nephrology and Hypertension; Researcher
- Lee, Ethan, M.D., Ph.D.
Assistant Professor of Cell and Development Biology; Researcher
- Means, Anna L., Ph.D.
Assistant Professor of Surgery and Cell & Developmental Biology; Surgical Oncologist
- Merchant, Nipun B., M.D.
Associate Professor of Surgery (Surgical Oncology); Gastrointestinal Surgical Oncologist
- Murff, Harvey J., M.D., M.P.H.
Assistant Professor of Medicine (General Internal Medicine and Public Health); Researcher
- Nagathihalli, Nagaraj S., Ph.D.
Research Assistant Professor of Surgery; VICC Member
- Parikh, Alexander A., M.D.
Assistant Professor of Surgery; Surgical Oncologist
- Pearson, A. Scott, M.D., Ph.D.
Assistant Professor of Surgery (Surgical Oncology); Researcher
- Peek, Richard, Jr., M.D.
Director, Gastroenterology, Hepatology & Nutrition; Professor of Medicine (Gastroenterology, Hepatology, & Nutrition); Professor of Cancer Biology; Researcher
- Reynolds, Albert B., Ph.D.
- Russell, William E., M.D.
Director, Division of Pediatric Endocrinology; Associate Professor Pediatrics and Cell & Developmental Biology; Pediatric Endocrinologist
- Tarpley, John L., M.D.
Professor of Surgery (Surgical Oncology); Surgical Oncologist
- Vaezi, Michael F., M.S., M.D., Ph.D.
Professor of Medicine (Gastroenterology); Researcher
- Washington, M. Kay, M.D., Ph.D.
Professor of Pathology; Director, Gastrointestinal and Hepatic Pathology; Pathologist
- Williams, Christopher Shawn, M.D., Ph.D.
Assistant Professor of Medicine; Assistant Professor of Cancer Biology; Researcher
- Wilson, Keith T., M.D.
Professor of Medicine (Gastroenterology, Hepatology, & Nutrition); Professor of Cancer Biology; Director of Research and Director of Fellowship Training Program, Division of Gastroenterology, Hepatology, & Nutrition; Researcher
- Wright, Christopher V., Ph.D.
Professor of Cell & Developmental Biology; Researcher
- Zaika, Alexander, Ph.D.
Assistant Professor of Cancer Biology and Surgery; Researcher