Forum 7: Rapid Development of New Agents to Treat Precancer: Fantasy or Reality? "Treatment and prevention of intraepithelial neoplasia: An important target for accelerated new agent development", Presented by Joyce O'Shaughnessy, U.S. Oncology, Dallas, TX. "The clinical development of new agents to treat intraepithelial neoplasia (IEN) has been slowed significantly and unacceptably by the requirement that effectiveness of a precancer treatment agent be demonstrated by reduction in invasive cancer incidence. Precancer treatment clinical trials that have cancer incidence as the endpoint are too large, time consuming, and costly to be feasible for most pharmaceutical companies and academic medical centers. Only 5 agents have been approved by the FDA for the treatment of IEN including topical 5FU and topical diclofenac for multiple actinic keratoses (AKs), intravesical BCG for bladder carcinoma in situ (CIS), tamoxifen ofr ductal carcinoma in situ (DCIS) following lumpectomy and breast radiotherapy, and celecoxib for adenomatous polyps in patients with familial adenomatous polyposis. The AACR IEN Task Force has made recommendations (Clinical Cancer Res.8:314-346, 2002) to stimulate discussion about which high risk populations to target, and which clinical trial designs and efficacy endpoints in IEN treatment trials are practical, feasible and worthy of pursuit. The major conclusion of the IEN Task Force is that in clinical situations where there is an established and close association between dysplasia and invasive cancer, a convincing reduction in the IEN burden provides patient benefit by reducing cancer risk and/or by decreasing the need for invasive interventions. In addition to there being a well established link between the IEN and invasive cancer, there must exist a reliable method of detecting and serially monitoring the burden of IEN, and demonstration of a convincing reduction of IEN burden. Precancer or IEN is a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer and which predicts for the substantial likelihood of deveopling invasive cancer. It is standard medical practice to endoscopically or surgically excise many forms of IEN to reduce invasive cancer risk. However, non-surgical treatments for IEN are urgently needed because of the low utilization of surgical interventions in eligible populations at risk (e.g. Colonoscopy), the morbidity associated wit the interventions, and because resection of clinically apparent lesions neglects treatment of the entire epithelial field at risk." "Demonstrating Clinical Effectiveness and Patient Benefit with a New IEN Treatment", presented by (no presenter name was shown on this abstract but it was probably Gary B. Gorndon, Ovation Pharmaceuticals, Lincolnshire, IL). "In addition, the IEN Task Force believes that eradication of clinically detectable high risk IEN in a substantial proportion of patients, e.g., complete clinical responses in 30% of patients, with a new treatment agent would also constitute effectiveness and patient benefit. In such case, patient benefit would be obtained whether or not the need for surgical intervention was decreased, because complete eradication of high risk IEN would substantially reduce patients' risk of developing invasive cancer. This scenario requires that the link between the high risk IEN and invasive cancer be well established such that eradication of one would substantially reduce the risk of the other." "IEN as the best surrogate endpoint for treatment and prevention of precancer", presented by Gary J. Kelloff,NCI, Bethesda, MD. "IEN is a near obligate precursor to cancer. It occurs in most epitheial tissue as moderate to severe dsyplasia, is on the causal pathway leading from normal tissue to cancer, and is close in stage of progression to cancer (invasive neoplasia)." An important area to look at is "prevention or treatment of subclinical IEN in patients at risk for recurrence. New adenomas occur within 1-3 years post-resection in approximately 30% of patients with sporadic colorectal adenomas or cancers. These patients are screened routinely at 1-5 year intervals, undergoing colonoscopies with removal of clinically apparent new lesions. Prevention or regression of subclinical adenomas and hyperplastic colorectal mucosa will reduce the number of clinically apparent adenomas and will supplement the clinical benefit obtained by screening (which routinely results in missed polyps). Successful treatment of this 'at-risk" epithelium could potentially provide benefit by increasing the screening interval, thereby decreasing associated morbidity and lowering health care costs. The FDA Gastrointestinal Drug Advisory Committee at its March 19, 2002 meeting supported the use of drugs to reduce sporadic colorectal adenomas as providing clinical benefit." Forum 8: Translating NCI Bypass Budget Priorities into Proposals (there were no abstracts). Plenary Session 5: Nuclear Receptors in Cancer and Metabolism. "The molecular actions of vitamin A (retinol) in cancer prevention", presented by Lorraine J. Gudas, (Chair, Pharmacology) Department of Pharmacology, Weill Medical College of Cornell University, NY, NY. "Retinoids (vitamin A, retinoic acid, and related compounds) inhibit the growth of many types of cells and induce cell differentiation. Retinoids act as cancer chemopreventive agents in many animal models and humans. We have identified numberous retinoid target genes in cultured normal human mammary epitethelial cells, prostate epithelial cells, and renal epithelial cells. We have analyzed differences in retinoid-regulated gene expression between normal epithelial cells and tumor cells. Our recent studies indicate that the metabolism of retinoid to reinyl esters is greatly reduced in human carcinoma cell lines of the oral cavity, skin, breast, and prostate compared to their normal epithelial counterparts." Ann's NOTE: In our section labelled Ann's Bio, there is discussion about my use of vitamin A, both retinol palmitate as tablets and liquid A, to reduce a chest wall tumor (local recurrence). The results included well differentiated, few malignant cells and a much higher ER and PR positivity. (as indicated by this and other discussions at this meeting). "Nuclear Receptors, Terpenoids and Cancer", presented by Michael Sporn, Dartmouth Medical School, Hanover, NH. From my notes: "Combinations are going to be increasingly important" - Dr. Sporn has been speaking of and encouraging the use of combination natural substances for years. There is a poster with information on this talk which will be shown in this summary. "INOS, COX-2, and ODC: Regulators of cellular signaling in colon cancer", presented by Bandaru S. Reddy, American Health Foundation, Vallhalla, NY. "Several natural products and nutritional agents, such as Omega-3 fatty acids, and curcumin that inhibity COX-2, iNOS and/or HMG CoA activities have been shown to prevent the formation and growth of colon tumors. Our recent results demonstate that DHA induces colonic cell differentiation partly through the inhibition of iNOS and modulation of retinoic and X receptor (RXR) suggesting that DHA is a promising naturally-occurring ligand for chemoprevention of colon carcinogenesis. Equally exciting are opportunities for effective chemoprevention by a combination of low doses of these agents, which are based on defnitive mechanisms relevant to tumorigenesis as means of obtaining increasing efficacy while minimizing toxicity." iNOS=inducible nitric oxide sythase, ODC=ornithine decarboxylase and HMG-CoA=3-hydroxy-3-methylglutaryl-coenzyme A. Thursday, Oct 17 Thursday afternoon Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.