Peter R. Holt, MD

Clinical Colorectal Cancer Prevention Program
Director, James E. Olson Colon Cancer Prevention Program
Senior Scientist, Strang Cancer Research Laboratory
Professor of Medicine (Emeritus), Columbia University
Adjunct Senior Scientist, Rockefeller University

Research Summary
Recent Publications
Contact Information
Lab Members

RESEARCH SUMMARY

Colorectal cancer is one of the commonest cancers in the United States and kills about 55,000 people each year. At least 70% of the risk of colon cancer derives from environmental factors rather than hereditary influences. These environmental factors have the potential to be modified and since the process of carcinogenesis—changes that occur from initiation of the process to the development of a neoplastic tumor—takes a considerable amount of time, this permits for interventions to lower the risk of developing precancerous polyps and colorectal cancer itself. Such an approach to risk reduction (cancer prevention) affecting the earliest changes in the process of carcinogenesis is called primary prevention.

Primary prevention of colorectal cancer is the aim of our studies to understand the basic molecular changes that are ameliorated by an intervention. The cancer preventive interventions that we have been primarily interested in are in natural products that are safe enough to use in the population at large.

Our basic approach is to evaluate the effects of an intervention upon an array of 28,000 genes in the colon in small groups of volunteer subjects who are at increased risk for developing colorectal cancer, because of a personal history of colon polyps or a family history of colon cancer or colon polyps. These genes which are measured in biopsies of the colorectum, can be quantified and organized into pathways to permit us to determine which pathways are altered by the intervention in individual volunteer subjects. The basic concept is that in order to develop active, useful, and effective risk reduction strategies for colorectal cancer, multiple cellular pathways must be altered simultaneously. By studying the effects of individual components such as calcium, vitamin D and folic acid we can plan more effective prevention strategies using several natural products simultaneously. Since the diet plays such a major role in carcinogenesis and in determining effective prevention, many of our studies are evaluating the effect of a “Western-style” diet upon the intervention.

Since using estrogen replacement therapy in post-menopausal women is accompanied by a dramatic reduction in colon cancer rates, we have studied the effect of estrogen repletion using various molecular techniques. Our studies to date suggest that estrogen may act to lower colon cancer rates, in part, by stimulating vitamin D action within colon epithelial cells.

SELECTED RECENT PUBLICATIONS

• Holt PR, Attilasoy EO, Gilman J, Guss J, Moss SF, Newmark H, Fan K, Yang K, Lipkin M. Modulation of abnormal colonic epithelial cell proliferation and differentiation by low fat dairy foods. JAMA. 280:1074-1079, 1998.
  
• Holt PR, Moss SF, Heydari AR, Richardson A. Diet restriction increases apoptosis in the gut of aging rats. J Gerontology. 53:B168, 1998.
  
• Agarwal B, Holt PR. Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac. Gastroenterology. 117:838-847, 1999.
  
• Holt PR. Studies of calcium in food supplemtns in humans. Annals New York Academy of Sciences. 889:128-137, 1999.
  
• Yang WC, Velcich A, Mariadason J, Nicholas C, Corner G, Houston M, Edelmann W, Kucherlapati R, Holt PR, Augenlicht LH. p21 WAF1/cip1 Is an Important Determinant of Intestinal Cell Response to Sulindac in Vitro and in Vivo. Cancer Research. 61: 6297-6302, 2001.
  
• Holt PR , Arber N, Halmos B, Forde K, Kissileff H, McGlynn K, Moss S, Fan K, Yang K, Lipkin M. Colonic Epithelial Cell Proliferation Decreases with Increasing Levels of Serum 25 Hydroxy Vitamin D. CEBP 11: 113-119, 2002.
  
• Agarwal B, Halmos B, Feoktistov S, Protiva P, Ramey WG, Chen M, Pothoulakis C, Lamont JT, Holt PR. Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells. Carcinogenesis 23(3):521-528, 2002.
  
• Tangpricha V, Flanaghan JN, Whitlatch LW, Tseng CC, Chen TC, Holt PR, Lipkin MS, Holick MF. 25-hydroxyvitamin D-1 a hyroxylase in normal and malignant colon tissue. Lancet 357:1673-1674, 2001.
  
• Saikali J, Picard C, Freitas M, Holt PR. Fermented milks, probiotic cultures, and colon cancer. Nutrition and Cancer, 49,14-24, 2004.