How is chemoprevention defined?
The basic idea of cancer chemoprevention is to arrest or reverse the progression of premalignant cells towards full malignancy, using physiological mechanisms that do not kill healthy cells.
The approach involves the use of either pharmacologic or natural agents that inhibit the development of invasive cancer either by blocking the DNA damage that initiates carcinogenesis or by arresting or reversing the progression of premalignant cells in which such damage has already occurred.
The ideal chemopreventive agent will be safe, orally bioavailable, and well tolerated so that it might be acceptable for routine use as an approach to reduce an individual’s cancer risk.
The term “chemoprevention” was coined nearly four decades ago. How much progress has been made since then?
Michael Sporn coined the term chemoprevention in a 1976 article in Federation Proceedings when writing about the work his group was doing with vitamin A analogues.
Dr. Sporn, then a member of the Carcinogenesis Program at the National Cancer Institute, led the first work with agents that could be used to prevent cancer.
Since then there has been tremendous progress in the realm of preclinical research where numerous studies by prominent investigators in the field have demonstrated the utility of this approach in experimental animals.
Indeed, in these preclinical models, it is now possible to prevent the onset of cancer in almost all the common organs in which human carcinoma occurs. However, this success has not been limited to models of human disease as chemoprevention has now been validated in people.
For example, the use of selective estrogen receptor modulators (SERMs), has afforded as much as a five-fold reduction in incidence of estrogen receptor-positive breast cancer in women.
These compounds — most notably tamoxifen, raloxifene and lasofoxifene — have the added benefit of suppressing osteoporosis. Fenretinide, for which we have nearly 20 years’ worth of data, provides significant prevention of breast cancer in premenopausal women.
Yet despite these successes, the general acceptance of chemoprevention remains a hurdle that must be overcome and there is real concern that the concept is not only misunderstood by the general public, but also not yet fully embraced by the cancer community.
Could you please give a brief introduction to the class of molecules you have been working on – synthetic triterpenoids?
Triterpenoids are a class of biologically active plant metabolites biosynthesized from six isoprene units and cyclized into a variety of skeletal scaffolds.
The natural triterpenoid oleanolic acid has been demonstrated to be an effective platform for synthetic derivitization to generate chemopreventive agents that target the antioxidant and cytoprotective nuclear factor-erythroid-2 (NF-E2)-related factor 2 (Nrf2) transcriptional pathway among other pathways involved in inflammation and cancer.
Indeed, the synthetic triterpenoid used in our study recently published in JCI was derived from oleanolic acid. This natural triterpene is representative of a broad category of molecules ubiquitously present in the plant kingdom, with many used widely in Asian medicine and continually isolated and studied for anti-inflammatory, hepatoprotective, analgesic, antimicrobial, immunomodulatory and tonic effects.
Because many of the plants containing triterpenoids are readily edible by wild animals and humans, it could be expected that the plant contents are relatively nontoxic and could serve as safe platforms for drug discovery.
In preclinical studies, these triterpenoids have also been shown to be neuroprotective. Our own published data show the ability of selected synthetic triterpenoids to completely reverse clinical signs of neurodegeneration in the murine models of multiple sclerosis. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242013/?tool=pubmed)
It was recently announced that these molecules carry enormous promise for suppressing colon cancer associated with colitis. Why do patients with inflammatory bowel disease have a greater risk of colon cancer?
It is well established that people with Crohn's disease and ulcerative colitis (the most common forms of IBD) are at a higher risk for developing colorectal cancer (CRC) than the general population. In fact, IBD with colon involvement is among the top three high-risk conditions for CRC, which accounts for nearly 15% of all deaths among IBD patients.
The link between inflammation and cancer is well established and inflammation undoubtedly contributes to other forms of sporadic and heritable forms of colon cancer.
A number of very elegant studies in preclinical models have shed enormous light on the mechanisms involved. The picture that is emerging is that there are distinct roles for specific immune cells, cytokines, and other soluble mediators in the initiation, promotion, progression, and metastasis of colon cancer.
One proposed mechanism is that the chronicity of bowel inflammation leads to colorectal dysplasia and eventually colorectal cancer. Chronic inflammation is characterized by production of proinflammatory cytokines that can induce mutations in oncogenes and tumor suppressor genes (for eg., p53, APC) and genomic instability via various mechanisms.
Chronic inflammation can act to promote CAC by activating proliferation and anti-apoptotic (pro-survival) properties of precancerous cells, and also enhance their potential for tumor progression and metastasis by influencing the microenvironment in which they grow.
This effect, in part, is related to the ability of inflammatory cytokines to activate mediators like STAT3 and NFkB that are important in multiple inflammatory pathways, but also intricately involved in regulating tumorigenesis.
The critical point is that all of these mediators can be modulated in strategies intended to interrupt disease progression. CRC is highly treatable in the early stage, thus it is important not only to understand this risk, but to also recognize its signs and symptoms -- and why regular screenings and early detection are crucial.
However, the potential that we can further reduce risk through the application of chemoprevention strategies that target these inflammatory mediators is very real and must be exploited for clinical benefit.
How are synthetic triterpenoids thought to help protect against colon cancer?
When discussing the mechanisms of activity for this class of small molecules, it is very important to know and understand their ‘multi-functional’ nature, i.e., their capacity to influence multiple targets within a cell. Indeed, it is this property that may underlie their unique potential as chemopreventive agents.
For example, triterpenoids directly inhibit the function of both STAT3 and NFkB, key intermediates in the process of colon tumorigenesis.
Dr. Sporn first began synthesizing triterpenoids in 1995, shortly after leaving the NCI for Dartmouth. Since then, Dr. Sporn has been a collaborator on over 100 publications that have described the mechanisms mediating the activities of several synthetic triterpenoids and we have demonstrated their efficacy in the chemoprevention of cancer in numerous preclinical models of epithelial cancers.
When I joined Case Western Reserve University in 2006, I began to interact with Dr. Markowitz, who first described 15-PGDH as an important tumor suppressor in colon cancer and as a molecule akin to ‘nature’s celecoxib’.
We were intrigued by the finding that inflammatory cytokines, like TNF-α, could suppress the expression of 15-PGDH and questioned whether the triterpenoids could reverse this repression.
This turned out to be true, pointing to potentially important mechanisms through which this class of small molecules might suppress colitis-associated colon cancer, and possibly enhance the response to COX-2 inhibitors.
What are the next steps in your research?
Our current studies are focused on the analysis of this triterpenoid (CDDO-Me/Bardoxolone Methyl) in other models of IBD and in additional models of colon cancer, and the data emerging from these studies are corroborating the findings reported in JCI.
We are also very interested in the potential that natural triterpenoids with similar properties might provide a similar benefit. Our effort in this regard involves both natural product isolation and characterization in similar in vitro analyses and through in vivo studies of cancer chemoprevention.
As our data with these natural triterpenes mature, we anticipate that these collective observations will set the stage for human trials in which cancer chemoprevention by triterpenoids can be achieved in patients who are at a significantly higher risk.
This may be particularly beneficial in patients with IBD, as the multiple mechanisms of triterpenoid activity (eg: suppression of NFkB and STAT3 signalling, induction of TGF-β signalling, activation of the Nrf2-antioxidant response), all may work in concert to effect the amelioration of many of the clinical manifestations of IBD.
Are there any plans to pursue human trials in cancer chemoprevention with triterpenoids?
The synthetic triterpenoids, including CDDO-Me (bardoxolone methyl) and a related analog (RTA 408) are currently being explored in clinical development in a wide range of indications by our collaborator Reata Pharmaceuticals.
Notably, Reata is presently evaluating the immuno-oncology applications of RTA 408 in early clinical trials in melanoma and non-small cell lung cancer, and we expect that with positive clinical data the histologies of interest will be expanded in the future.
In addition to this program, we also have an active effort focused on the isolation and derivatization of unique, natural triterpenoids.
This initiative involves a recently established academic-industry collaboration between Case Western Reserve University (CWRU) and Modularix, through which candidate molecules isolated and developed at CWRU are screened for their potential as immune modulators and for their capacity to suppress cancer metastasis.
What do you think the future holds for chemoprevention of colon cancer?
The argument for pursuing such cancer chemoprevention trials is strong, and has been elegantly championed by Dr. Sporn for many decades.
One could argue that we have an obligation to the patients who suffer from diseases like IBD and from other conditions that elevate cancer risk: an obligation to develop these safe and multi-functional agents as an approach to minimizing their risk for suffering the many clinical manifestations disease, including cancer.
There are many questions that remain to be answered:
- Which triterpenoid will be the safest and most effective in this setting?
- Can clinical benefit be achieved with intermittent exposure, rather than by continuous administration? This will likely be an approach to lowering the risk for complications.
- Can these triterpenoids be used in combination with other agents to achieve an even greater clinical benefit?
Carefully designed clinical trials and a collaborative approach between industry and academics will be needed to answer these questions, but there is no question that the data have led us to the point where we truly have an obligation to do so.
Where can readers find more information?
About Dr. John Letterio
John Letterio is the Director of the Angie Fowler Adolescent & Young Adult Cancer Institute and Chief of Pediatric Hematology/Oncology at University Hospitals Case Medical Center and Case Western Reserve University in Cleveland, Ohio. Dr. Letterio earned his medical degree from The Ohio State University College of Medicine in 1984 completed a fellowship in Pediatric Oncology at the National Cancer Institute in Bethesda, Maryland in 1993. At the NIH, Dr. Letterio became a tenured investigator and Chief of the Laboratory of Immunoregulation.
After 16 years at the NIH, he was recruited to Case Western Reserve University in 2006 to lead the development of programs for children, adolescents and young adults with cancer at blood disorders. As a member of the Case Comprehensive Cancer Center and the Jane & Lee Chair in Pediatric Cancer Innovation, he is leading a team of basic scientists and clinical investigators whose efforts are focused on the development and application of novel agents for the chemoprevention and therapy of cancer.
His research is actively funded by several NIH Institutes including the NCI, NHLBI and NEI, and by the Department of Defense. His research team has provided important insights into the mechanisms linking inflammation to cancer and other diseases. His most recent studies have demonstrated the potential of synthetic triterpenoids in the chemoprevention of colon cancer and appear in the Journal of Clinical Investigation in June 2014.
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