Elsevier

Seminars in Oncology

Volume 37, Issue 4, August 2010, Pages 345-358
Seminars in Oncology

Cancer prevention II
Drug Development for Cancer Chemoprevention: Focus on Molecular Targets

https://doi.org/10.1053/j.seminoncol.2010.05.012Get rights and content

With biomolecular evidence accumulating at an exponential rate, there will be a surge in the development of targeted cancer prevention drugs and interventions in the next decade. Promising results from clinical treatment trials identify a spectrum of targeted cancer therapies in several broad categories. These include both small molecule inhibitors of either key receptors or enzyme binding sites, as well as intravenously delivered monoclonal antibodies that block a specific binding interaction between ligands and their receptors. These targeted interventions conform to a basic translational algorithm: biomarker present, biomarker modulated, and biomarker clinically relevant. A review of solid tumor targets provides a manageable list of factors that are critical to cancer cell survival. As such, these targets represent factors that are not only clinically relevant but also may play a critical role in early tumor development prior to the evolution of frank invasive malignancy. This possibility qualifies these targets for consideration in the development of cancer prevention interventions. Among solid tumors, the treatment of breast cancer with targeted drugs has a long record benchmarked by the initial US Food and Drug Administation (FDA) approval of tamoxifen for metastatic breast cancer treatment in 1977. Since then, the list of oncology drug targets has expanded to include aromatase, androgen receptor, the epidermal growth factor receptor (EGFR) family, and others. It is not surprising that tamoxifen was the first of the modern targeted therapies to be approved for cancer risk reduction and additional approvals are anticipated. The focus of this review is the pharmacologic manipulation of targets within epithelial tumor cells and the implication of those targets for intervening to suppress and eliminate premalignant cells in human tissue. Major obstacles to prevention drug development can be addressed by attention to two important areas. One of these is the refinement of early phase prevention trials to identify drug targets in epithelial cells that are at demonstrated risk of evolving into cancer cells, ie, cells from a developmental niche in cancer ontogeny. Early results suggest that molecular risk signatures may allow the investigational identification of molecular targets in premalignant tissue, with the possibility that chemoprevention agents can be used to eliminate the risk signature. To the extent that this approach can be developed, it will allow for cancer risk reduction in a way that is analogous to the measurement of tumor response to treatment. Even with improvements in the efficiency of clinical trials that come from using molecular risk signatures, there is an ever-growing list of chemoprevention agents that are candidates for evaluation. Improved prevention drug screening methodologies are therefore needed to prioritize agents for clinical testing. In addition to drug targets located in epithelial tumor cells, another list of malignancy-associated targets could be generated by considering targets in tumor-associated stromal and endothelial cells (eg, fibroblast growth factor [FGF], vascular endothelial growth factor [VEGF]), as well as targets related to a systemic reservoir of circulating cells that can be recruited to carcinogenic influence by inflammatory factors such as nuclear factor (NF)κB. The complementarities of target-related processes within tumors cells, in the tumor microenvironment, and beyond suggests that there is great potential for multi-targeted approaches that may be more effective than single agents and also less prone to resistance. Additional options, related to drug dose and schedule, remain to be established. As long as multiple agents can be used in combination for optimal effect with acceptable toxicity, the co-targeting of the epithelial cell compartment along with other compartments of oncogenic activity is expected to expand the dimensions of targeted prevention and enhance the overall opportunity to eliminate precancer or cells at risk of eventually transitioning to invasive cancer.

Section snippets

Targeting the Estrogen Receptor

Among solid tumors, the treatment of breast cancer with targeted drugs has a long record benchmarked by the initial US FDA approval of tamoxifen for metastatic breast cancer treatment in 1977. Long-term experience with tamoxifen across the spectrum of breast oncogenesis from metastatic disease to pre-malignancy has been invaluable for the translation of data from tamoxifen clinical trials in support of an approved cancer prevention indication. It is consequently instructive to review the

Targeting the Androgen Receptor

As in the treatment setting, the potential effectiveness of AIs in the prevention setting remains a consequence of estrogen deprivation, an indirect but effective approach to limiting the function of the ER. Although the adverse events from drugs used in androgen receptor blockade for prostate cancer treatment did not allow androgen receptor blockers to be used in prostate cancer prevention,43 the androgen receptor still remains a target of testosterone deprivation just as estrogen deprivation

Cyclooxygenase, Inflammation, and Colorectal Cancer

The association linking NSAIDs with reduced colorectal cancer risk is much stronger than the association for NSAIDs and breast cancer. In a systematic review prepared for the US Preventive Services Task Force (PSTF), observational evidence from cohort studies was summarized as showing that the use of NSAIDs was associated with an approximate 40% reduction in colorectal cancer incidence.47 In this same report, observational evidence for the association between NSAIDs and colorectal adenomas was

Epidermal Growth Factor Receptor and Other Targets

Of the targets listed in Table 1, much of the work of targeted cancer prevention has focused on the ER and the androgen receptor with spin-off activities implicating related pathways mediated by enzymes such as aromatase, 5α-reductase, and COX. For these targets, a long history of effort has generated a large reservoir of preclinical and clinical experience, to the point that large, phase III prevention trials with a cancer incidence endpoint were facilitated. Extended experience with some of

Targeting Molecular Risk Signatures for Prevention

Although treatment trials have played a central role in identifying cancer prevention targets, it is critically useful to appreciate two important but related differences in the clinical investigation approach used in treatment versus prevention. First, every individual enrolled in a treatment trial has a diagnosis of cancer, and this point allows for testing the tumor tissue for the drug target of interest. This aspect of lesion availability is largely responsible for the more manageable

Risk Signatures and DNA Repair

One of the frustrations in conducting cancer prevention trials is the dilemma posed by individuals who are known to be at high risk of developing cancer without visually detectable tissue abnormalities (eg, metaplasia and dysplasia). Lacking tissue abnormalities that can be identified and followed as intervention response markers complicates the assessment of eligibility for prevention trials. In the absence of abnormal histological morphology, it now seems that prevention science is on the

Screening Prevention Drugs for Targeted Activity

In addition to the need for tissue-based molecular definition of cancer risk, another obstacle to developing cancer prevention agents is the plethora of leads that have acquired a modicum of plausibility for testing as prevention interventions. For example, in the category of flavonoid compounds (flavonols, flavones, anthocyanidins, catechins, flavanones and isoflavones), more than 5,000 compounds have been identified.79 Using traditional methods and approaches,80 it would easily be possible to

Conclusion

The focus of this review has been the pharmacologic manipulation of targets within epithelial tumor cells and the potential of those targets to mediate suppression and elimination of premalignant cells in human tissue. Early results suggest that molecular risk signatures may allow the investigational evaluation of premalignant tissue for risk reduction secondary to clinical intervention in a way that is analogous to the measurement of tumor shrinkage in response to treatment. Improved

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