Drug Development for Cancer Chemoprevention: Focus on Molecular Targets

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.