Abstract ED02-01: Molecular targets of cancer preventive agents
Authors: Brown Powel H. 
Published: May 2019

Given the advances in targeted therapy for the treatment of cancer, there has been strong interest in treating early in the carcinogenic process. This has led to the use of targeted therapies in individuals who do not have cancer but who are at risk of this disease. Treatment of individuals without cancer with drugs, vitamins, or natural products to prevent cancer has been termed “chemoprevention” or preventive therapy. While many studies of natural products or non-specific preventive agents have been conducted in the past, more recent studies have tested molecularly targeted preventive therapies. Recent studies using such molecularly targeted drugs in women at risk of breast cancer, men at risk of prostate cancer, and men and women at risk of colon cancer has demonstrated that such treatment can greatly reduce the incidence of cancer in these individuals. Drugs targeting the estrogen receptor, including tamoxifen, raloxifene, and idoxifene, have been shown to reduce the risk of breast cancer by 50% in high-risk women. While these agents dramatically reduce this risk of breast cancer, their use has been somewhat limited by their side effect profile. Ongoing Phase III trials are testing drugs targeting the aromatase enzyme in an attempt to achieve even more effective risk reduction with reduced toxicity. Other targeted agents that have been shown to prevent breast cancer in preclinical models include cox-2 inhibitors, epidermal growth factor receptor (EGFR) inhibitors, the dual kinase inhibitor, lapatinib, and RXR selective retinoids (also termed “rexinoids”). Of these targeted agents, the rexinoids have the greatest cancer preventive activity in rodent models, preventing up to 90% of mammary tumors. In addition, the combination of a rexinoid and the anti-estrogen drug idoxifene is able to totally prevent mammary tumors in transgenic mice. Several of these agents are now being tested in early phase cancer prevention trials. The rexinoid bexarotene has been tested in women at high risk of breast cancer and was found to reduce cyclin D1 RNA expression in postmenopausal women. The dual kinase inhibitor lapatinib is currently being tested in a Phase II trial in women with EGFR-positive or ErbB2-positive non-invasive breast cancer (DCIS) to determine whether this drug will suppress the growth and progression of this non-invasive cancer. The current status of these trials will be presented. Other promising targets for breast cancer prevention include the PARP enzyme, other growth factor receptors (such as insulin-like growth factor receptor) and signaling molecules (AKT, mTOR, PI3K).

Several Phase III prostate cancer prevention trials have shown that targeting the 5-alpha reductase enzyme that conversion of testosterone to dihydrotestosterone using the 5-alpha reductase inhibitors finasteride or dutasteride. The PCPT prostate cancer prevention trial demonstrated that finasteride reduced the prevalence of prostate cancer in men over 55 years of age by 24%. The use of this agent has been limited by initial concerns about an apparent increase in high-grade prostate cancer in men taking finasteride; however, the increased incidence of high-grade cancers was later attributed to an artifact of the trial design. The results of another prostate cancer prevention trial, the REDUCE trial, were released earlier this year. In the REDUCE trial, men over the age of 50 were treated with the 5-alpha reductase inhibitor dutasteride to prevent prostate cancer. The results of this trial demonstrated a 23% reduction in prostate cancer in men taking dutasteride as compared to placebo. Notably in the REDUCE trial there was no increase in high-grade prostate cancer in men taking dutasteride. These two Phase III prostate cancer prevention trials provide compelling evidence that targeting the 5 alpha reductase enzyme can prevent prostate cancer in men. Current studies are attempting to define what population of men would most benefit from these cancer preventive drugs.

Major advances have also been made in testing targeted agents for the prevention of colon cancer. The Cox-2 inhibitor celecoxib has been shown to reduce the number of colonic polyps in individuals with familial adenomatous polyposis (FAP). These results led to the FDA-approval of celecoxib for use in FAP patients for polyp reduction, and also to the development of Phase III trials testing Cox-2 inhibitors in individuals at risk of sporadic colon cancer. Several of these polyp prevention trials did show that Cox-2 inhibitors reduced polyp formation; however, these trials also demonstrated that Cox-2 inhibitors had significant rare side effects of increased thrombosis and heart disease. The concern about these rare but potentially life-threatening side effects has limited further development of these active cancer preventive agents. More recently, the combination of the non-steroidal anti-inflammatory agent sulindac and the ornithine decarboxylase inhibitor DFMO has been shown to be extremely effective at reducing the recurrence of polyps in a Phase III polyp prevention trial. In this trial, individuals with previously resected polyps that were treated with low doses of sulindac and DFMO had a 70% percent reduction in total colonic polyps and a 92% reduction in advanced adenomatous polyps. These dramatic results have caused great interest in the cancer preventive activity of this drug combination, and have stimulated to the development of several confirmatory cancer prevention trials using sulindac and DFMO.

The above chemoprevention trials have conclusively shown that targeted drug therapy for cancer prevention is effective. However, rare significant side effects and a limited ability to accurately predict cancer risk in individuals greatly limits the general use of effective molecularly targeted preventive therapies. Future preclinical and clinical studies should focus on developing accurate cancer risk assessment tools and testing next generation targeted agents singly and in combination for their toxicity and ability to prevent cancer.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):ED02-01.