Trials and tribulations of interrogating biomarkers to define efficacy of cancer risk reductive interventions.
Abstact
The challenges of clinical screening of cancer risk reductive interventions ("chemopreventive") have slowed progress in deployment of therapeutics to reverse or delay the carcinogenesis process. The preoperative or window-of-opportunity design clinical trial design enrolls subjects rapidly, has short study periods, and quantifies tissue biomarkers that reflect both anti-carcinogenesis mechanism of the risk reductive intervention and key molecular events of the carcinogenesis process for a specific epithelial target. High subject screened to on study ratios reduce the efficiency and increase cost of this research strategy. Small-sized tissue samples obtained by minimally invasive endoscopic technologies limit the number of biomarkers that can be detected and quantified, forcing investigators into choosing either a broad-based but superficial multi-mechanism exploration of signaling intermediates or a more focused analysis of multiple molecular events in a linear signaling-specific pathway. More efficient strategies of the future might involve isolation and expansion of pluripotent cells from at-risk epithelium or intraepithelial neoplastic lesions. Such a strategy would allow interrogation of key carcinogenesis-associated pathways and mechanisms in representative primary single-cell cultures amenable to genomic, proteomics, or transfection-based technologies.