Scott M. Lippman, MD
Anderson Clinical Faculty Chair for Cancer Treatment and Research
Professor and Chair, Clinical Cancer Prevention
University of Texas MD Anderson Cancer Center
Houston, Texas
Increased technological prowess for characterizing the molecular changes associated with cancer development and major advances in gene characterization are revealing the molecular pathways that drive the tumorigenic process and are fundamental for tumor development. The assessment of these pathways in premalignant tissues is proving useful for the estimation of individual cancer risk and these pathways can be targeted for preventive intent. Major advances in this field involve molecular studies of cancer risk and targeted prevention.(1) Recent seminal studies in molecular targeting for cancer prevention provide support for this contention, including significant reductions in breast cancer risk with a selective estrogen-receptor modulator(2) and prostate cancer risk with a 5-a-reductase inhibitor(3), and significant reductions in adenoma number in patients with familial adenomatous polyposis (FAP) and sporadic adenomatous polyps (SAPs) with the use of nonsteroidal anti-inflammatory drugs.(4-6)
Advances in molecular prevention science have revolutionized drug development and blurred the distinction between malignancy and intraepithelial neoplasia (IEN), and between therapy and prevention.(1) Although it was first developed for cancer treatment, tamoxifen later became a major agent for cancer prevention, and almost certainly both treated and prevented microscopic, subclinical disease in the Breast Cancer Prevention Trial (BCPT). Drugs like COX-2 and aromatase inhibitors now cross from prevention into therapy, and molecular-targeting agents (e.g., epidermal growth factor receptor, tyrosine kinase inhibitors) are being developed simultaneously for cancer therapy and prevention in the same phase I program. Molecular surrogate endpoints will be critical in developing the burgeoning number of molecular-targeting preventive agents.
The retinoid-head and neck model provided the initial proof of principle of cancer chemoprevention and a translational paradigm for studying multistep carcinogenesis and preventive-agent mechanisms. As illustrated by RAR-a, LOH and cyclin D1 in head and neck IEN, molecular targets and markers for developing drugs, monitoring interventions, and assessing risk and pharmacogenomics are advancing cancer prevention research. Studies suggesting that retinoic acid can detour head and neck carcinogenesis at 11q13 (Figure 1) exemplify the novel concept of cancer delay by molecular detour, which is highly relevant to molecular-targeting preventive drug development.(7) As illustrated in Figure 1, an agent targeting cyclin D1 could cause a molecular detour at 11q13, and agents targeting p16 or p53 could cause other potential detours. It may be possible to enhance cancer delay through combinations of molecular-targeting agents that amplify drug effects on key targets and cause detours at multiple critical molecular junctures within multistep carcinogenesis.
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| Figure 1. Molecular detour at 11q13 (adapted from Lippman SM, Hong WK. Clin Cancer Res. 2002;8:305-313.). |
Common age-related pathologic processes, such as carcinogenesis, atherogenesis and neurodegeneration, have certain molecular alterations in common.(1) Emerging data on nonsteroidal anti-inflammatory drugs, selective-estrogen-receptor modulators, peroxisome proliferator-activated receptors, statins, and other drugs or targets suggest that it may be possible to prevent or delay a number of age-related diseases with a single multitargeted regimen.
References
- Lippman SM, Hong WK. Cancer prevention science and practice. Cancer Res. 2002;62:5119-5125.
- Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst. 1998;90:1371-1388.
- Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:213-222.
- Steinbach G, Lynch PM, Phillips RKS, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000;342:1946-1952.
- Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med. 2003;348:891-899.
- Sandler RS, Halabi S, Baron JA, et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med. 2003;348:883-890.
- Lippman SM, Hong WK. Cancer prevention by delay. Clin Cancer Res. 2002;8:305-313.
