The Next Step In Cancer Research: Cancer Prevention?

In 2006, approximately 1,399,790 new cases of cancer were diagnosed (1). Current treatments and lifestyle changes have significantly improved the fate of these patients; the death rate from the most common cancers—prostrate, breast, lung, and colorectal—and other cancer types is decreasing (1). While the outcome for cancer patients has improved, overall, the incidence of cancer has remained relatively unchanged since the 1990s (1). But what if the incidence of cancer could be decreased, not by treatment or lifestyle change, but by a drug? Drs. Michael Sporn, Tadashi Honda, and Gordon Gribble, professors at Dartmouth College, may have synthesized such a drug: 2-cyano-3,12-dioxyooleana-1,9(11)-dien- 28-oic acid (CDDO), as well as two derivatives: the C-28 methyl ester of CDDO (CDDO-Me) and CDDO- Imidazolide (CDDO-Im) (1).

Both in vivo and in vitro laboratory experiments have demonstrated that CDDO and its methyl ester (Figure 1) have anti-carcinogenic activity that manifests in three fundamental ways. First, CDDO and CDDO- Me inhibit cell proliferation (2). In one in vivo study, 100% of a population of mice genetically engineered to develop breast cancer demonstrated tumorgenesis without treatment, while in a similar mouse population that received CDDO-Me treatment, only 12% of mice developed tumors (3). Other studies have shown that CDDO and CDDO-Me inhibit cell proliferation in non-malignant and malignant cells, implying that both the formation of tumors and the progression of tumor growth could be inhibited by these drugs (2). Second, CDDO reduces nitric oxide (NO) production in activated macrophages (2). Although inflammation induced by nitric oxide plays an important role in host defense, excessive production increases inflammation and carcinogenesis. By inhibiting NO production, CDDO may be an anti-inflammatory and cancer chemopreventive agent. Finally, CDDO prevents the development of cancer cells by inducing transformation (2). This effect has been seen in a variety of cell types, and thus, CDDO could be effective in preventing cancer from developing and progressing.

The development of CDDO has been a long, challenging process rooted in Asian medicine and its use of triterpenoids. Triterpenoids are natural products with 30 carbon atoms derived from cyclization of squalene (Figure 2). They are often found in rosemary, olive leaves, and Reishi mushrooms, plants which have been used for centuries in traditional Asian medicine due to their anti- inflammatory and anti-carcinogenic properties (4, Figures 2 and 3). Their natural potency, however, is weak.

Drs. Sporn, Honda, and Gribble recognized the huge potential of triterpenoids in treatment and prevention of cancer and began bioassay-directed drug design and synthesis of triterpenoids to improve their pharmacological potency. When Drs. Sporn, Honda, and Gribble started their project 12 years ago, the structure activity relationship (SAR) of triterpenoids was unknown, meaning that the functional groups responsible for their anti-carcinogenic activity were unidentified (5). In order to identify a lead compound, they began by randomly synthesizing about 70 derivatives from two triterpenoids: oleanolic and ursolic acid (5). Initially, several in vitro assays using cancer cell lines detected no significant potency differences. However, a very sensitive bioassay testing inhibition of NO production in activated mouse macrophages, developed by Dr. Carl Nathan at Cornell University, testing inhibition of NO production in activated mouse macrophages, was able to detect significant differences (5). Amongst these 70 derivatives, TP-46 was found to be the most potent compound (5).

Over the course of the next three years, Drs. Honda and Gribble modified TP-46 in various ways. From these modifications, two derivatives, each ten times as potent as TP-46, were identified: TP-189 and TP-82 (5, Figure 1). With the hope of achieving a combinatory increase in potency, Dr. Honda added the nitrile and enone functionalities to TP-46. On February 16, 1998, bioassays demonstrated the synergistic effect of these additions (5). Two compounds, CDDO and CDDO-Me, showed potency levels approximately 10,000 times as strong as that of the initial compound (5).

The potency and ability of CDDO and CDDO-Me to prevent the development and progression of cancer have been clearly established in the laboratory. Collaboration with Reata Pharmaceuticals, a company in Dallas, Texas, has been established and these compounds are now being tested by the Food and Drug Administration (FDA). Currently, both CDDO and CDDO-Me are in Phase I trials, which assess their toxicity on a population of 18 to 25 advanced stage cancer patients (5). If Phase I is successfully passed, CDDO and CDDO-Me will progress into Phase II clinical trials, and potentially Phase III and Phase IV. If all phases are passed, the FDA will then grant the approval for clinical use of CDDO and CDDO-Me.

Though several stages lay ahead for CDDO and CDDO-Me, the development of these drugs already represents a great achievement for Drs. Sporn, Honda, Gribble, and their co-workers. Additionally, these compounds represent advancement in cancer research, for their pharmacologic potential extends beyond treating existing cancer—to stopping cancer before it starts.

References
1. Cancer Trends Progress Report – 2005 Update (2005) Available at http://progressreport.cancer.gov/doc_detail.asp?pid=1&did=2005&ch id=23&coid=220&mid= (5 May 2007).
2. N. Suh, et al., Cancer Research, 59, 336 (1999).
3. J. Durgin, Dartmouth Medicine, 28 (2007).
4. M.B. Regan, Johns Hopkins Public Heath, (Spring 2006).
5. T. Honda, personal communication.