Steady advancements in cancer treatments over the past century have led to significant improvements in the expected lifespan of cancer patients. However, to this day, cancer is very rarely cured.
For more than 50 years, NCI has invested heavily in elucidating the fundamental biology underlying the formation of tumors in order to reduce the burden of cancer across the population. This support has equipped the cancer research community with a rich understanding of the fine distinction between normal and neoplastic cell growth, and an armamentarium of robust “omics” approaches.
Greater knowledge of the earliest events that precede the formation of invasive tumors is emerging and transforming the field of cancer prevention research, which is now well poised to capitalize on decades of investment. Excitingly, several cancer prevention trials in high-risk subjects are yielding very promising results.
Recognizing the vast need for rational preventive agent development, NCI recently established the new Cancer Prevention-Interception Targeted Agent Discovery (CAP-IT) Program. Fox Chase Cancer Center is one of two founding members of the CAP-IT Program, along with Weill-Cornell Medicine.
This initiative represents a significant milestone in the history of cancer prevention research, as it is the first national consortium dedicated to the preclinical development of molecularly and immunologically targeted agents for precision cancer prevention and early interception in populations at high risk for cancer.
Importantly, this basic research initiative underscores the feasibility of not only preventing cancer by attenuating the detrimental effects of known extrinsic risk factors, but of also performing precision cancer “interception” by effectively targeting those biological processes known to be essential for the growth of precancerous lesions.
The vision for establishing a formal and robust pipeline for the preclinical development of novel cancer preventive agents has been provided by Shizuko Sei, MD, director of the NCI CAP-IT Program, and her colleagues in the Division of Cancer Prevention, NCI. This initiative is deeply rooted in the pioneering work of many others in the field of prevention over decades.
Among these is the discovery of the preventive properties of tamoxifen and other Selective Estrogen Receptor Modulators (SERMS) by V. Craig Jordan, PhD, DSc, at the University of Leeds in the 1970s. This work provided the first definitive evidence of the feasibility of using therapeutic strategies to impact cancer development in high-risk subjects. Dramatic reductions in the incidence of breast cancer followed, paving the way for the repurposing of agents as cancer preventives.
The late Michael Sporn, MD, of NCI and later the Dartmouth Cancer Center, was unwavering in his commitment to establish chemoprevention—a term that he coined—as a discrete discipline within the broader field of cancer research at a time when his view of cancer as a chronic disease that could be impacted by early drug intervention was not widely accepted.
The NCI CAP-IT’s systematic approach of “checks and balances” is expected to increase the chances for success by proactively circumventing some of the speed bumps encountered in past decades that derailed the development of initially promising cancer preventive drugs.
This concept gained momentum as natural and synthetic compounds were identified that were able to disrupt the initial phases of carcinogenesis and the transition of premalignant cells to invasive cancer. His early vision served as a strong foundation for the establishment of the NIH Chemodietary Study Section and has come to full fruition with the new NCI CAP-IT Program.
Importantly, the CAP-IT Program expands the cancer prevention field’s focus beyond chemoprevention to include immunoprevention and emphasizes the discovery of vaccines and novel immunotherapeutics that can bolster the host immune system to enhance tumor immune surveillance.
This approach is firmly anchored in the Nobel Prize-winning discovery of the hepatitis B virus by Baruch Blumberg, MD, PhD, at Fox Chase and the neoplastic potential of HPV infection by Harald zur Hausen, MD, of Germany, both of which have broadly impacted global health.
Routine immunization of healthy subjects with cancer-preventive vaccines continues to lead to extraordinary reductions in the incidence of cervical and liver cancer, saving millions of lives worldwide.
The CAP-IT Program addresses the challenge of adapting these successes to populations at increased genetic risk for cancer by taking advantage of recent technological advances in harnessing the immune system. Exciting clinical research has begun with the study of cancer vaccines in individuals with heritable cancer syndromes, including those with Lynch syndrome.
Entering the field in the early 1990s, as one of the first basic research labs dedicated to the development of cancer-preventive agents and later as a founding member of the Chemodietary Study Section, I was inspired by the work of Sporn and others.
My research interests quickly evolved from an early focus on the use of detoxification enzyme inducers to confer protection from carcinogens and environmental exposures, to establishing biomarkers of cancer risk and developing novel strategies for therapeutic intervention, including targeted disruption of estrogen metabolism and inflammation-associated pathways.
My work, as well as the prevention field, continues to be driven by the insights of Alfred Knudson, my close colleague and collaborator at Fox Chase, who, in the 1970s, established the “two-hit theory” of cancer development.
This theory first recognized that germline alleles inactivating potent tumor suppressors increase the likelihood of some forms of cancer by requiring only a single additional “hit” to initiate tumor growth.
In later work, Knudson, in collaboration with Fox Chase investigators and the NCI, demonstrated that mutant tumor suppressor genes in a heterozygous state can alter the expression profile of phenotypically normal epithelial cells in a gene-specific manner.
These findings suggest that detectable effects of “one-hit” represent early molecular changes in tumorigenesis that may serve as novel targets for preventive intervention. The field is now well-equipped to identify and validate these targets for cancer prevention/interception in an unprecedented way.
For three decades, my colleagues in the Department of Clinical Genetics at Fox Chase have been intently focused on providing genetic counseling, cancer surveillance, and optimal care to cancer prone families, with over 15,000 high-risk individuals now enrolled in the Fox Chase Risk Assessment Program.
Cancer prevention and interception are key goals of this program. For many, prophylactic risk-reducing surgery remains the best option; a drastic approach that is often associated with life-altering side effects.
While this option is not feasible for patients with Lynch syndrome who are predisposed to colon cancer, high-dose aspirin is emerging as an efficacious preventive regimen. However, the risk of gastrointestinal bleeding sometimes outweighs the known benefit. Thus, a critical need exists to identify non-toxic, targeted agents and vaccines that can reduce cancer risk.
As a basic prevention researcher, the thought of potentially providing this large cohort of primarily younger men and women with an efficacious regimen to attenuate their high chance of developing cancer has always been extraordinarily motivating. With support from the NCI, this goal now moves a step closer to becoming a reality.
The focus of the new NCI CAP-IT Program on cancer interception, as well as prevention, reflects its ultimate goal of intervening very early in the carcinogenesis process to inhibit tumor development and/or the progression of precursor lesions to invasive cancers. Interception is essential in high-risk individuals who have already inherited a genetic predisposition—the population being targeted by the CAP-IT Program.
The number of individuals known to carry germline mutations that confer increased susceptibility to cancer, approximately 5-10%, is expected to rise in the future, as additional genetic variants of functional significance emerge from the application of state-of-the-art genomic technologies.
The NCI CAP-IT Program provides a long-awaited infrastructure to support the rational development of preventive agents and vaccines, from in silico drug design to in vivo testing.
Omics technologies will be employed to elucidate the complex cellular interactions required to support the growth of precancerous lesions, and provide fuel for the systematic identification and validation of critical molecular targets for interception, as well as potential biomarkers of cancer risk. These studies will benefit greatly from discoveries that emerge from other NCI initiatives, including the Precancer Atlas project.
The bar for approval of cancer preventives has always been much higher than for chemotherapeutics, as agents will most likely need to be taken by asymptomatic individuals for decades.
The NCI CAP-IT’s systematic approach of “checks and balances” is expected to increase the chances for success by proactively circumventing some of the speed bumps encountered in past decades that derailed the development of initially promising cancer preventive drugs (e.g., cyclooxygenase 2 inhibitors).
Agents and vaccines will be characterized comprehensively, and only those with advantageous profiles will enter in vivo efficacy testing in the PREVENT component of the NCI drug discovery pipeline, of which Fox Chase has been a Prime Contractor for more than two decades.
I anticipate that discoveries from the CAP-IT Program will accelerate the translation of novel cancer preventive and interceptive agents from the “bench to the bedside” and impact the high cancer risk faced by asymptomatic individuals with heritable cancer syndromes.
Furthermore, since many of these predisposing genes are also somatically mutated in sporadic disease, it seems plausible that the novel preventive/interceptive regimens developed under the CAP-IT Program may also be effective in inhibiting sporadic cancers in the general population.
Half a century after the introduction of chemoprevention, the field is now better poised than ever to meet these challenges and prevail.
