About the project - Goals and Significance

General Problem Area to be Studied

Based on morbidity, mortality, economic burden, and emotional hardship, cancer may be considered the most onerous health problem afflicting the American public. As indicated by the most recent statistics published by the American Cancer Society [1], the birth to death probability of developing invasive cancer is 32.3% in women (1 in 3) and 43.48% in men (1 in 2). Worldwide, approximately 10 million people are diagnosed with cancer annually, and more than 6 million die of the disease every year; currently, over 22 million people in the world are cancer patients [2]. In the U.S., about 1,300,000 new cancer cases are expected to be diagnosed this year, in addition to approximately 1,000,000 cases of basal and squamous cell skin cancer, and over 550,000 deaths are expected. Incredibly, approximately 16,000,000 Americans have been diagnosed with cancer since 1990, and the current five-year relative survival rates for several malignant, metastatic cancers remain dismal (e.g., esophageal, liver, lung, pancreatic, and stomach cancers, all 2-3%; breast cancer, 21%). Even though significant progress has been made in the clinical management of certain cancers (e.g., childhood leukemia, Hodgkin's disease, and testicular cancer), and the consequences of chemotherapy can be managed with improved efficacy through the use of antiemetics and immunostimulants, it is apparent that a national priority must continue to focus on the innovation of more effective strategies of managing metastatic diseases.

Obviously, in addition to focusing on cancer therapy, primary prevention tactics should be invoked with the greatest possible expedience. It is intuitively clear that all tobacco-related cancers could be completely prevented. Similarly, other types of primary prevention schemes could readily be implemented, such as reducing exposure to harmful levels of sunlight. In the early 1980s, a comprehensive plan was developed by the National Cancer Institute in which the stated goal was to reduce the 1985 cancer mortality rate by 50% by the year 2000 [3,4]. Unfortunately, it was not possible to reach this goal. As noted above, cancer remains a problem of epidemic proportion. Nonetheless, these visionary strategies are extremely valuable for establishing overall priorities in national healthcare. As is now the case with heart disease, prevention must receive greater emphasis as a key management strategy for cancer.

A relatively new area of scientific endeavor concerns dietary or pharmaceutically-based approaches for the prevention of cancer. Cancer chemoprevention, a term coined by Dr. Michael B. Sporn as part of his classical work dealing with retinoids and cancer prevention [5], deals with the prevention or delay of carcinogenesis in humans by ingestion of dietary or pharmaceutical agents. In essence, delay of a disease or condition beyond a normal human lifespan is equivalent to a cure. Preventive tactics have been broadly implemented for management of heart disease [6], and it is now generally accepted that cancer can be managed to some extent through chemoprevention.

Contemporary aspects of chemoprevention have recently been described in a report to the American Association for Cancer Research [7]. As stated in the report, "The development of new and better drugs for chemoprevention remains a principal need." Various groups of compounds have been classified as cancer chemopreventive agents [8], largely based on the results of animal studies and epidemiological data [9-12]. Utilizing various chemopreventive agents, a number of clinical intervention studies are underway with humans at high risk for the development of certain cancer types [8,13]. Although the trend is to evaluate preneoplastic biomarkers in high risk groups, some impressive large-scale human clinical trials have been reported recently. In a five-year trial conducted with 13,388 women, tamoxifen reduced the risk of invasive breast cancer by 49% [14]. The agent was subsequently approved by the FDA for cancer prevention, thus establishing a proof-of-principle in the field of cancer chemoprevention. Another clinical success was recognized with Celebrex, currently approved by the FDA and prescribed for the prevention of familial polyps, a precursor of cancer [15]. Further, in a trial conducted with nearly 19,000 men, prostate cancer was reduced by approximately 25% over a seven-year period [16] through administration of finasteride. Similarly, with much smaller patient populations at high risk for lung, liver or head and neck cancers, various agents have been shown to reduce recurrence approximately 50% [17].

Clearly, however, in most cases the drugs are not ideal [7], and some disappointments have been experienced (e.g., β-carotene has failed to reduce the incidence of lung cancer [18,19]). Tamoxifen is known to mediate some undesirable side-effects, such as the promotion of endometrial cancer [20,21], and finasteride may promote a greater number of high-grade cancers [16]. Some high profile studies are ongoing, such as the SELECT (selenium and vitamin E cancer prevention trial), hoping to enroll over 32,000 men for the evaluation of prostate cancer prevention, and the STAR (study of tamoxifen and raloxifene) trial, designed to include 22,000 women in a comparison of tamoxifen and raloxifene. While it is clear that the concept of cancer chemoprevention is firmly entrenched, it is also clear that the full potential of this approach has yet to be realized.

Our primary research emphasis has focused on the front-end of the entire process - that of drug discovery. Although a number of organizations concentrate on the discovery, characterization, and development of various therapeutic agents, this is not the case in the area of cancer chemoprevention. As described herein, we have assembled a multidisciplinary team of investigators who concentrate on the discovery and characterization of natural product cancer chemopreventive agents. We have achieved success in this area and there is no other program of this type throughout the world. There is substantive interest in developing the products that are emerging as a result of the program, and we are confident that continuation, as requested in this application, will yield valuable information and materials that will aid in the overall national effort of defeating cancer.

Hypothesis to be Tested

It is well-established that numerous drugs used in modern day medical practice are either chemical modifications of natural products or natural products themselves. In fact, approximately half of the world's 25 leading drugs are natural product-based [22], and about 60% of approved anticancer drugs are of natural origin or are modeled on natural product parents [23]. As a prime example, some of the most useful antitumor compounds, vinblastine, camptothecin, and taxol, are derived from plants. Thus, it is indisputable that natural products are a viable source of novel lead compounds for the design, synthesis and development of drugs. As related to chemoprevention, it is fair to ask "Can additional agents be discovered that will be useful adjuncts or replacements for the drugs in the current armamentarium?" Certainly, a considerable number of known cancer chemopreventive agents are naturally occurring, so it is reasonable to assume that additional entities with desirable preventative activities do exist. Aside from our work, few if any broad-based systematic searches have been conducted for the discovery of novel cancer chemopreventive agents, and the structural diversity provided by nature presents a unique opportunity for continuous progress. Through a highly coordinated and focused effort, we are confident this program project will produce novel cancer chemopreventive agents of value for human utilization. No other experimental approach is known to be capable of facilitating such an achievement.

Long-term Objectives of the Research

The long-term objective of this research is to identify and characterize chemopreventive candidates that may be entered into clinical intervention trials. Based on the relatively short history of cancer chemoprevention drug discovery, it is unlikely that the most efficacious agents are presently known. We have therefore instituted a program project wherein natural products procured from throughout the world are used for activity-guided fractionation schemes that yield novel and otherwise unpredictable chemical entities with desirable biologic potential. These agents are fully characterized in terms of structure, and subjected to more advanced mechanistic evaluations. Through coordinated efforts of isolation and chemistry, the leads are characterized in well-established animal models for definition of cancer chemopreventive efficacy. With this knowledge base of structure, mechanism, and chemopreventive activity, the discoveries can logically be considered as candidates for clinical intervention trials. The provision of such agents is the long-term objective of this research.

Our ongoing efforts in this area suggest this objective will be achieved. Thus far, brassinin, deguelin, resveratrol, 4'-bromoflavone, brusatol, betulinic acid, and oxomate (a sulforaphane analog) have been shown to mediate chemopreventive activity in full-term animal studies. Some of these agents have been selected by the NCI for more advanced testing. In particular, betulinic acid is being developed under the RAID program of NCI, and 4'-bromoflavone and abyssinone are being developed under the RAPID program of NCI. Additional agents have demonstrated promising activity with in vitro or short-term animal studies, and full-term carcinogenesis inhibition work is slated. Various other promising leads have been identified and are currently being processed. We are confident of continued progress and productivity.

An additional objective is to continue our cooperation with investigators outside of this program project. Students who have acquired training in cancer chemoprevention have continued working in this area in other institutions. When possible, research quantities of active leads are supplied to interested investigators for the conduct of additional studies. Our work has also attracted considerable publicity which thereby heightens public awareness of the concept of cancer chemoprevention. Further, the Purdue Cancer Center (NCI-designated) is responding to our discoveries and developing a chemoprevention program. Major cancer centers outside of Purdue have also expressed considerable interest in our work, and we strive to cooperate to the fullest extent possible.

Another important aspect is the nature of the starting materials. Heretofore, we have concentrated on terrestrial plants. All systems of collection, selection, shipping, etc., have been perfected, and benefit-sharing agreements have been devised and accepted by the source countries. This approach has been productive and will continue. In addition, however, we will expand our effort to include drug discovery from marine microorganisms. This is a very exciting and novel aspect of this program project. In the recent past, the unique chemical diversity provided by marine organisms has been revealed, as well as the enormous potential of mediating physiological responses of relevance to human health. However, in the area of cancer chemoprevention, the marine world has not been well investigated. Based on the few existing precedents already established in this area, we are very optimistic regarding our ability to make rapid breakthrough discoveries in this area.