eBriefing

The Beast in the Belly: Targeted Therapies for Gastrointestinal Cancer

The Beast in the Belly
Reported by
Catherine Zandonella

Posted May 22, 2008

Presented By

the Mushett Family Foundation, the New York Academy of Sciences, and Memorial Sloan-Kettering Cancer Center

Overview

Gastrointestinal cancers account for roughly 20% of all newly diagnosed cancers in the United States each year and include cancers of the esophagus, colon, rectum, and other parts of the gastrointestinal tract. Although these cancers are united by the fact that they start in the gastrointestinal (GI) tract, they arise in different cell types and detection and treatment vary according to the location and type of cancer.

In a full-day conference held at the Academy on March 14, 2008, researchers gathered to discuss recent findings that are enhancing our understanding of GI cancers and to promote new treatment approaches. The symposium brought together leading scientists and clinicians to present new research on potential biomarkers for identifying the preliminary stages of GI cancer, targeted therapies that could halt its progression, and the molecular pathways that contribute to tumorigenesis. The symposium culminated with a discussion of ways to foster collaborations between academic and industry.


Sponsorship

This conference and eBriefing were made possible with support from the Mushett Family Foundation and Memorial Sloan-Kettering Cancer Center.

 

Web Sites

American Cancer Society
A nationwide, voluntary health organization that compiles statistical information about cancer rates as well as information, advocacy, and public policy. General information about colorectal and stomach cancer is available on their site.

Cancer Stem Cell
Wikipedia entry describing definition and properties of a cancer stem cell.

Epistem
A company formed to explore the key regulators of epithelial stem cells and develop therapeutics that control cell production in the therapeutic areas of oncology (by killing cancer stem cells) and epithelial diseases.

Fred Hutchinson Cancer Research Center
A Seattle-based research organization dedicated to the elimination of cancer. Information about the Center's research in colorectal cancer is here.

Gastrointestinal Cancer Research Program at Vanderbilt-Ingram Cancer Center
A program dedicated to the study intestinal epithelial cell biology with the goal of studying the etiology, progression, and treatment of gastrointestinal cancer.

Memorial Sloan-Kettering Cancer Center
A cancer organization that conducts research, provides patient care, and educates and trains clinicians in the diagnosis and treatment of cancer. Learn more about their work on stomach and colorectal cancer.

Ohio State University
The Ohio State University Comprehensive Cancer Center, James Cancer Hospital, and Solove Research Institute (OSUCCC–James) has a patient information page explaining all about gastrointestinal cancer.

University of Pennsylvania School of Medicine Division of Gastroenterology
A project that seeks to define and elucidate the molecular mechanisms underlying squamous cell carcinogenesis in the esophagus with eventual translation to new strategies in diagnosis and therapy.


Books

Abbruzzese JL, Pollock RE, Ajani JA, Curley SA. 2004. Gastrointestinal Cancer (M.D. Anderson Cancer Care Series). Springer, New York.

Fujita R, Jass JR, Kaminishi M, Schlemper RJ. 2006. Early Cancer of the Gastrointestinal Tract: Endoscopy, Pathology, and Treatment. Springer, New York.

Griffin-Sobel J. 2007. Site-Specific Cancer Series: Gastrointestinal Cancer. Oncology Nursing Society, Pittsburgh.

Kelsen DP, Daly JM, Kern SE, Levin B. 2007. Principles and Practice of Gastrointestinal Oncology: Principles and Practice. Lippincott, Williams & Wilkins, Philadelphia.


Journal Articles

Albrecht B, Hausmann M, Zitzelsberger H, et al. 2004. Array-based comparative genomic hybridization for the detection of DNA sequence copy number changes in Barrett's adenocarcinoma. J. Pathol. 203: 780-788.

Egger K, Werner M, Meining A, et al. 2003. Biopsy surveillance is still necessary in patients with Barrett's oesophagus despite new endoscopic imaging techniques. Gut 52: 18-23.

Mueller J, Werner M, Stolte M. 2004. Barrett's esophagus: histopathologic definitions and diagnostic criteria. World J. Surg. 28: 148-154.

Rauser S, Weis R, Braselmann H, et al. 2007. Significance of HER2 low-level copy gain in Barrett's cancer: implications for fluorescence in situ hybridization testing in tissues. Clin. Cancer Res. 13: 5115-5123.

Walch A, Specht K, Bink K, et al. 2001. Her-2/neu gene amplification, elevated mRNA expression, and protein overexpression in the metaplasia-dysplasia-adenocarcinoma sequence of Barrett's esophagus. Lab Invest. 81: 791-801.

Walch A, Specht K, Braselmann H, et al. 2004. Coamplification and coexpression of GRB7 and ERBB2 is found in high grade intraepithelial neoplasia and in invasive Barrett's carcinoma. Int. J. Cancer 112: 747-753.

Christopher Potten

Bach SP, Williamson SE, O'Dwyer ST, et al. 2006. Regional localisation of p53-independent apoptosis determines toxicity to 5-fluorouracil and pyrrolidinedithiocarbamate in the murine gut. Br. J. Cancer 95: 35-41.

Cliffe LJ, Humphreys NE, Lane TE, et al. 2005. Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion. Science 308: 1463-1465.

Hendry JH, Booth C, Potten CS. 2001. Endothelial cells and radiation gastrointestinal syndrome. Science 294: 1411.

Potten CS. 1998. Stem cells in gastrointestinal epithelium: numbers, characteristics and death. Philos. Trans. R. Soc. Lond. B Biol Sci. 353: 821-830.

Potten CS, Ellis JR. 2006. Adult small intestinal stem cells: identification, location, characteristics, and clinical applications. Ernst Schering Res. Found. Workshop 60: 81-98.

Ruggero De Maria

Iannolo G, Conticello C, Memeo L, De Maria R. 2008. Apoptosis in normal and cancer stem cells. Crit. Rev. Oncol. Hematol. 66: 42-51.

Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. 2007. Identification and expansion of human colon-cancer-initiating cells. Nature 445: 111-115.

Ricci-Vitiani L, Pagliuca A, Palio E, et al. 2008. Colon cancer stem cells. Gut 57: 538-548.

Frank Diehl

Diehl F, Diaz LA Jr. 2007. Digital quantification of mutant DNA in cancer patients. Curr. Opin. Oncol. 19: 36-42.

Diehl F, Li M, Dressman D, et al. 2005. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc. Natl. Acad. Sci. USA 102: 16368-16373. Full Text

Li M, Diehl F, Dressman D, et al. 2006. BEAMing up for detection and quantification of rare sequence variants. Nat. Methods 3: 95-97.

Linda D. Siracusa

Baran AA, Silverman KA, Zeskand J, et al. 2007. The modifier of Min 2 (Mom2) locus: embryonic lethality of a mutation in the Atp5a1 gene suggests a novel mechanism of polyp suppression. Genome Res. 17: 566-576. Full Text

MacPhee M, Chepenik KP, Liddell RA, et al. 1995. The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell 81: 957-966.

Markova M, Koratkar RA, Silverman KA, et al. 2005. Diversity in secreted PLA2-IIA activity among inbred mouse strains that are resistant or susceptible to Apc Min/+ tumorigenesis. Oncogene 24: 6450-6458.

Silverman KA, Koratkar R, Siracusa LD, Buchberg AM. 2002. Identification of the modifier of Min 2 (Mom2) locus, a new mutation that influences Apc-induced intestinal neoplasia. Genome Res. 12: 88-97. Full Text

David Threadgill

Denning MF, Dlugosz AA, Threadgill DW, et al. 1996. Activation of the epidermal growth factor receptor signal transduction pathway stimulates tyrosine phosphorylation of protein kinase C delta. J. Biol. Chem. 271: 5325-5331. Full Text

Fujimoto N, Wislez M, Zhang J, et al. 2005. High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor. Cancer Res. 65: 11478-11485. Full Text

Reiter JL, Threadgill DW, Eley GD, et al. 2001. Comparative genomic sequence analysis and isolation of human and mouse alternative EGFR transcripts encoding truncated receptor isoforms. Genomics 71: 1-20.

Roberts RB, Min L, Washington MK, et al. 2002. Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis. Proc. Natl. Acad. Sci. USA 99: 1521-1526. Full Text

Threadgill DW, Dlugosz AA, Hansen LA, et al. 1995. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269: 230-234.

Joanna Groden

Boivin GP, Groden J. 2004. Mouse models of intestinal cancer. Comp. Med. 54: 15-18. Review.

Carson DJ, Santoro IM, Groden J. 2004. Isoforms of the APC tumor suppressor and their ability to inhibit cell growth and tumorigenicity. Oncogene 23: 7144-7148.

Kaiser S, Park YK, Franklin JL, et al. 2007. Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer. Genome Biol. 8: R131. Full Text

Lowy AM, Clements WM, Bishop J, et al. Beta-Catenin/Wnt signaling regulates expression of the membrane type 3 matrix metalloproteinase in gastric cancer. Cancer Res. 66: 4734-4741. Full Text

Qian J, Steigerwald K, Combs KA, et al. 2007. Caspase cleavage of the APC tumor suppressor and release of an amino-terminal domain is required for the transcription-independent function of APC in apoptosis. Oncogene 26: 4872-4876.

Reichling T, Goss KH, Carson DJ, et al. 2005. Transcriptional profiles of intestinal tumors in ApcMin mice are unique from those of embryonic intestine and identify novel gene targets dysregulated in human colorectal tumors. Cancer Res. 65: 166-176. Full Text

Steigerwald K, Behbehani GK, Combs KA, et al. 2005. The APC tumor suppressor promotes transcription-independent apoptosis in vitro. Mol. Cancer Res. 3: 78-89. Full Text

John P. Lynch

Calon A, Gross I, Lhermitte B, et al. 2007. Different effects of the Cdx1 and Cdx2 homeobox genes in a murine model of intestinal inflammation. Gut 56: 1688-1695.

Robert J. Coffey

Coffey RJ, Washington MK, Corless CL, Heinrich MC. 2007. Ménétrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach. J. Clin. Invest. 117: 70-80. Full Text

Crissey MA, Guo RJ, Fogt F, et al. 2008. The homeodomain transcription factor Cdx1 does not behave as an oncogene in normal mouse intestine. Neoplasia 10: 8-19. Full Text

Guo RJ, Huang E, Ezaki T, et al. 2004. Cdx1 inhibits human colon cancer cell proliferation by reducing beta-catenin/T-cell factor transcriptional activity. J. Biol. Chem. 279: 36865-36875. Full Text

Hinoi T, Gesina G, Akyol A, et al. 2005. CDX2-regulated expression of iron transport protein hephaestin in intestinal and colonic epithelium. Gastroenterology 128: 946-961.

Li C, Hao M, Cao Z, et al. Naked2 acts as a cargo recognition and targeting protein to ensure proper delivery and fusion of TGF-alpha containing exocytic vesicles at the lower lateral membrane of polarized MDCK cells. Mol. Biol. Cell 18: 3081-3093. Full Text

Mallo GV, Rechreche H, Frigerio JM, et al. 1997. Molecular cloning, sequencing and expression of the mRNA encoding human Cdx1 and Cdx2 homeobox. Down-regulation of Cdx1 and Cdx2 mRNA expression during colorectal carcinogenesis. Int. J. Cancer 74: 35-44.

Merchant NB, Voskresensky I, Rogers CM, et al. TACE/ADAM-17: A component of the epidermal growth factor receptor axis and a promising therapeutic target in colorectal cancer. Clin. Cancer Res. 14: 1182-1191.

Mizoshita T, Inada K, Tsukamoto T, et al. 2001. Expression of Cdx1 and Cdx2 mRNAs and relevance of this expression to differentiation in human gastrointestinal mucosa—with special emphasis on participation in intestinal metaplasia of the human stomach. Gastric Cancer 4: 185-191.

Nam KT, Varro A, Coffey RJ, Goldenring JR. 2007. Potentiation of oxyntic atrophy-induced gastric metaplasia in amphiregulin-deficient mice. Gastroenterology 132: 1804-1819.

Van Raay TJ, Coffey RJ, Solnica-Krezel L. 2007. Zebrafish Naked1 and Naked2 antagonize both canonical and non-canonical Wnt signaling. Dev. Biol. 309: 151-168.

Wafik El-Deiry

Corn PG, El-Deiry WS. 2007. Microarray analysis of p53-dependent gene expression in response to hypoxia and DNA damage. Cancer Biol. Ther. 6 [Epub ahead of print]

Finnberg N, Klein-Szanto AJ, El-Deiry WS. 2008. TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis. J. Clin. Invest. 118: 111-123. Full Text

Kim SH, Ricci MS, El-Deiry WS. 2008. Mcl-1: a gateway to TRAIL sensitization. Cancer Res. 68: 2062-2064.

Laguinge LM, Samara RN, Wang W, et al. 2008. DR5 receptor mediates anoikis in human colorectal carcinoma cell lines. Cancer Res. 68: 909-917.

Sussman RT, Ricci MS, Hart LS, Sun SY, El-Deiry WS. 2007. Chemotherapy-resistant side-population of colon cancer cells has a higher sensitivity to TRAIL than the non-SP, a higher expression of c-Myc and TRAIL-receptor DR4. Cancer Biol. Ther. 6: 1490-1495.

Wang W, El-Deiry WS. 2008. Restoration of p53 to limit tumor growth. Curr. Opin. Oncol. 20: 90-96.

David Hockenbery

Manion MK, Fry J, Schwartz PS, Hockenbery DM. 2006. Small-molecule inhibitors of Bcl-2. Curr. Opin. Investig. Drugs 7: 1077-1084.

Schwartz PS, Hockenbery DM. 2007. Targeted therapies for epithelial cancers: in vivo efficacy of the BCL-2/BCL-XL inhibitor 2-MeAA. Cancer Biol. Ther. 6: 465-466.

Schwartz PS, Hockenbery DM. 2006. Bcl-2-related survival proteins. Cell Death Differ. 13: 1250-1255.

Organizers

Joanna Groden, PhD

The Ohio State University
e-mail | web site | publications

Joanna Groden is a professor and vice chair for academic affairs, and associate dean for basic research in the Department of Molecular Virology, Immunology, and Molecular Genetics at the Ohio State University. Her lab is working to understand some of the factors that confer inherited susceptibility to cancer, with an emphasis in the area of gastrointestinal cancers. In particular, she studies Bloom's syndrome and familial adenomatous polyposis coli, two inherited syndromes which confer susceptibility to cancer. Through this work she is learning more about the mechanisms by which genomic integrity and appropriate cell growth and differentiation are maintained.

Groden completed her PhD at the Cornell University Graduate School of Medical Sciences, and did postdoctoral work at the University of Utah. Before joining Ohio State, she spent approximately 12 years at the University of Cincinnati College of Medicine.

Christoph Lengauer, PhD, MBA

Novartis Institutes for BioMedical Research
e-mail | publications

Christoph Lengauer studied human genetics and biology at the University of Salzburg, Austria, and received his PhD from the University of Heidelberg, Germany. Following postdoctoral studies at the IMP (Institute of Molecular Pathology) in Vienna, Austria, he joined Bert Vogelstein's group at the Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins University and worked there for eleven years. In 1998, he became faculty member of the School of Medicine at Hopkins, and later served as director of its Drug Discovery Laboratory at the Center for Cancer Genetics and Therapeutics.

Currently, Lengauer is executive director and senior unit head of oncology at the Novartis Institutes for BioMedical Research (NIBR). He is also adjunct associate professor of oncology at the Johns Hopkins University School of Medicine, and faculty associate of the Program for Evolutionary Dynamics at Harvard University. In addition to his science degrees, he holds an MBA in medical services management.

Martin Werner, MD

Albert-Ludwig University
e-mail | web site | publications

Martin Werner is the chairman of the Institute of Pathology and full professor at the Faculty of Medicine of the Albert-Ludwigs-University in Freiburg, Germany. He is also a member of the executive board of directors of the Tumorzentrum Ludwig Heilmeyer Comprehensive Cancer Center, Freiburg. Werner completed his MD at the University of Saarland in 1986 and his PhD at the University of Hannover in 1993. He received board certification of pathology and molecular pathology in 1995 and 1996. From 1996 to 2000, he held the position of senior chief pathologist at the Institute of Pathology, Klinikum rechts der Isar, in Munich, Germany.

Kathy Granger, PhD

The New York Academy of Sciences
e-mail | web site

Kathy Granger is program manager for conferences at the New York Academy of Sciences. Before joining the Academy she was a postdoctoral fellow at Weill-Cornell Medical College. A native of South Australia, she received her PhD in microbiology from Monash University, Melbourne.


Speakers

J. Carl Barrett, PhD

Novartis Pharmaceuticals
e-mail | publications

Robert J. Coffey, MD

Vanderbilt University
e-mail | web site | publications

Ruggero De Maria, MD

Istituto Superiore di Sanità
e-mail | web site | publications

Frank Diehl, PhD

Johns Hopkins University
Howard Hughes Medical Institute
e-mail | publications

Wafik S. El-Deiry, MD, PhD

University of Pennsylvania
e-mail | web site | publications

Stanley R. Hamilton, MD

The University of Texas
MD Anderson Cancer Center
e-mail | web site | publications

David Hockenbery, MD

Fred Hutchinson Cancer Research Center
e-mail | web site | publications

David S. Klimstra, MD

Memorial Sloan-Kettering Cancer Center
web site | publications

Silke Lassmann, PhD

Albert-Ludwig University
e-mail | web site | publications

John P. Lynch, MD, PhD

University of Pennsylvania
e-mail | web site | publications

Christopher Potten, PhD, DSc

Epistem, Ltd.
e-mail | web site | publications

Linda D. Siracusa, PhD

Thomas Jefferson University
Jefferson Medical College
e-mail | web site | publications

Laura H. Tang, MD, PhD

Memorial Sloan-Kettering Cancer Center
e-mail | web site | publications

David Threadgill, PhD

University of North Carolina, Chapel Hill
e-mail | web site | publications

Archie Ngai-chiu Tse, MD, PhD

Memorial Sloan-Kettering Cancer Center
e-mail | web site | publications


Catherine Zandonella

Catherine Zandonella is a science writer based in New York City, covering such topics as environmental science, public health, and applied technology. She has a master's degree in public health from the University of California, Berkeley. Zandonella has written for a number of publications, including New Scientist, The Scientist, and Nature.

Memorial Sloan-Kettering Cancer Center and the Mushett Family Foundation