Issues & Insights

Advances and Challenges in Developing Cancer Preventive Agents

Powel Brown, MD, PhD
Professor
Departments of Medicine and Cellular and Molecular Biology
Director
Cancer Prevention and Population Sciences Program
Dan L. Duncan Cancer Center
Baylor College of Medicine
Houston, Texas

Over the last few years, major advances have been made in demonstrating that drugs can prevent cancer in animals (1-3) and in high-risk individuals. (4-6) Despite these impressive advances, two primary questions remain: With all these advances, what can be done to develop agents for general use to prevent cancer and why aren’t these medications widely used for cancer prevention?

Cancer Prevention Drug Development

To develop effective cancer preventive drugs that can be used in clinical practice, several hurdles must be overcome. It will be necessary to have:

• preclinical data showing effective cancer prevention in animals
• a supporting rationale for targeting a particular molecule, pathway, or population
• regulatory approval from the Food and Drug Administration (FDA) to test the drugs in humans
• access to the at-risk population
• an infrastructure to conduct the phase I, II, and III cancer prevention trials that will support widespread use of the cancer preventive drugs
• an acceptable toxicity profile from long-term studies

Each of these points represents an essential step in the development of cancer prevention drugs. While some agents have successfully traversed this path (e.g., tamoxifen or retinoids)(4,7), the side effects of these agents have limited their widespread use. To identify effective yet tolerable agents for cancer prevention, we must speed up the process of cancer prevention drug development.

Rationale for Targeting a Pathway or Population

Large epidemiologic studies have demonstrated that certain medications or dietary nutrients are associated with reduced risk of cancer (e.g., reduced incidence of colon cancer in individuals taking aspirin or calcium (8-10)). With the phenomenal progress being made in genomics, proteomics, and systems biology, it is now possible to identify the target of a specific drug or dietary agent and to develop a designer drug for virtually any target. The combination of strong epidemiologic data showing that cancer risk reduction is feasible and molecular pharmacologic results that identify a potential target offers a strong rationale to develop agents targeted to these pathways for the prevention of cancer.

The recent focus on targeted therapy has led to the development of tyrosine kinase inhibitors such as trastuzumab (Herceptin®), imatinib mesylate (Gleevec®), erlotinib (Tarceva®), and lapatinib (Tykerb®). These agents have much lower toxicity and unique specificity compared to traditional chemotherapy, making them highly attractive for both cancer treatment and prevention. Preclinical studies have already shown that these targeted drugs can prevent cancer, (3) but their rare and potentially significant toxicities currently limit their general use.

Two approaches have been taken to overcome this problem. One is to continue drug development efforts to identify safer and less toxic drugs. Clearly, such efforts are needed. A second is to identify high-risk individuals who will benefit from existing cancer prevention drugs and who will accept the risk of rare toxicities. This second approach has the advantage that the currently available drugs can be used now; it is currently used for the treatment of women at high risk of breast cancer with tamoxifen or raloxifene. Both approaches need to be applied concurrently if progress is to be made. It will also be necessary to educate the general public, the regulatory agencies, and physicians that no drug is totally free of side effects, so that the decision to use any drug is essentially an assessment of expected risk versus benefit.

Preclinical Studies

One of the most important steps in developing cancer therapeutic or preventive agents is the demonstration that these agents are effective in preclinical models. Animal models of cancer such as carcinogen-treated rodent models and transgenic models have been used to study the effects of natural and synthetic chemopreventive agents. (11) With the availability of sophisticated animal model systems, the limiting step in the development of novel therapeutic agents is often the availability and access to promising new drugs. Many of these drugs are developed as therapeutic agents in pharmaceutical houses, and access to them is restricted by the interests of that particular pharmaceutical house, and by legal barriers of material transfer agreements, intellectual property rights, and marketing issues. If rapid progress is to be made, it will be necessary to create more streamlined approaches to distribution and testing of newly developed drugs for cancer prevention.

Regulatory Issues

Significant regulatory requirements also must be overcome. With recent concerns about the rare, but potentially serious toxicities of commonly used medications such as those seen with rofecoxib (Vioxx®) (12) or celecoxib (Celebrex®) (13), there is increased scrutiny of drugs that are to be used in “healthy” individuals. All drugs need to undergo rigorous preclinical and clinical toxicity studies before being used in healthy individuals. However, there is now increased concern about rare, late toxicities of cancer prevention agents. Such rare toxicities (often occurring at a rate of less than 0.1%) may only be appreciated after very large studies with long follow up. This has led to a new more rigorous safety benchmark for such agents. It is anticipated that in the future it will be more difficult to obtain FDA approval and New Drug Application (NDA) approval for the use of novel cancer prevention drugs. To make such drug development feasible, it will be necessary to realize that many “healthy” individuals are, in fact, at high risk of cancer (for example those carrying cancer susceptibility gene mutations), and thus should not be considered at equal risk with low-risk “healthy individuals”. For such high-risk individuals, the use of effective cancer prevention agents with significant but rare toxicity should be considered medically appropriate.

Access to High-Risk Populations

If testing and use of cancer prevention agents are to be based on risk/benefit issues, then it will be necessary to identify those “healthy” individuals at particularly high risk of cancer. It is now possible to do this for many types of cancer. Epidemiologic models, such as the Gail model for breast cancer risk assessment(14), are now available for this purpose. In addition, identification of cancer susceptibility gene mutations in individuals, such as in APC, BRCA1 or 2, or mis-match repair genes, predicts a 60%--100% lifetime risk of cancer. Such individuals can potentially benefit greatly from cancer preventive therapy. However, such genetic testing is expensive and not always accepted by individuals and families at risk. Continued progress is needed to make genetic testing and other cancer risk assessment techniques widely available to individuals and physicians for clinical trial purposes and ultimately for general cancer risk assessment.

Clinical Infrastructure to Test Drugs in Clinical Trials

To move promising drugs from preclinical studies to preventive clinical application, it is necessary to conduct trials to show that these drugs are effective in humans. Early phase cancer prevention trials can be done to assess the toxicity and biologic activity of novel agents, but large scale phase III trials are then necessary to show that these drugs have cancer prevention efficacy and are tolerable. Such trials have been successfully conducted for the prevention of breast cancer(4-6), prostate cancer(16), and colonic polyps.(12,13,15) These trials are typically long and expensive, but have the potential to change medical management. However, because of their expense and length, few such trials can be conducted at any one time. To make continued progress, it will be necessary to appreciate the importance of such trials and to make the difficult funding choices to support continuing these critical phase I, II and III cancer prevention trials.

Bringing Cancer Preventive Therapy to the General Population

The final hurdle is to introduce effective cancer preventive drugs into the population for more widespread use. This has been a significant challenge. While clinical trials have demonstrated that certain drugs can prevent head and neck cancer(7), breast cancer(4-6), prostate cancer(16), and colonic polyps,(12,13,15) none of these agents has gained widespread use for cancer prevention. This is primarily due to concerns about toxicities (either common bothersome toxicities or rare serious toxicities). It is thus essential to develop agents with reduced toxicity and also to accurately identify those individuals who are at high risk of cancer and who have less concern about toxicity than about their cancer risk.

Despite these challenges, there is now a unique opportunity for cancer preventive drug development to achieve a major public health advance. The potential for benefit certainly justifies a major effort to overcome these apparent barriers.

References

1. Pereira MA, Kramer PM, Nines R, et al. Prevention of mouse lung tumors by targretin. Int J Cancer. 2006;118:2359-2362.
2. Howe LR, Subbaramaiah K, Patel J, et al. Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res. 2002;62:5405-5407.
3. Lu C, et al. Effect of epidermal growth factor receptor inhibitor on development of estrogen receptor-negative mammary tumors. J Natl Cancer Inst. 2003;95:1825-1833.
4. Fisher B, 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.
5. Cuzick J, Forbes J, Edwards R, et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet. 2002;360: 817-824.
6. Vogel V, Costantino J, et al. Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes. JAMA. 2006; 295:2727-2741.
7. Hong WK, Lippman SM, Itri LM, et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med. 1990;20;323:795-801.
8. Cho E, et al. Dairy foods, calcium, and colorectal cancer: a pooled analysis of 10 cohort studies. J Natl Cancer Inst. 2004;96:1015-1022.
9. Schreinemachers DM, Everson RB. Aspirin use and lung, colon, and breast cancer incidence in a prospective study. Epidemiology. 1994;5:138-146
10. Wallace K, et al. Effect of calcium supplementation on the risk of large bowel polyps. J Natl Cancer Inst. 2004;96:921-925.
11. Shen Q, Brown PH. Transgenic mouse models for the prevention of breast cancer. Mutat Res. 2005;576: 93-110.
12. Bresalier RS, et al., Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352:1092-1102.
13. Solomon SD, McMurray JJ, Pfeffer M A, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352: 1071-1080.
14. Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81:1879-1886.
15. Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000;342:1946-1952.
16. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349:215-224.