Journal
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 52
Volume 52, Issue -, Pages 549-+Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-pharmtox-010611-134532
Keywords
cancer genome targets; biomarkers; patient selection; the Pharmacologic Audit Trail; PI3K inhibitors; HSP90 inhibitors; PARP inhibitors
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Funding
- Cancer Research UK [11566] Funding Source: researchfish
- Cancer Research UK [11566] Funding Source: Medline
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Our biological understanding of the molecular basis of cancer has benefited from advances in basic research, accelerated recently by cancer genome sequencing and other high-throughput, genome-wide profiling technologies. Given the diverse heterogeneity among tumors, the traditional cytotoxic chemotherapy and one-size-fits-all approaches to cancer discovery and development are not appropriate for molecularly targeted agents. Selection of new drug targets is based on achieving cancer selectivity through exploiting specific dependencies and vulnerabilities predicted from tumor genetics. Discovery of highly target-selective agents is enhanced by integrating multiple modern technologies, particularly structure-based design. Efficient clinical evaluation requires smart, hypothesis-testing studies using validated pharmacodynamic and predictive biomarkers. We discuss and exemplify biomarker-driven clinical development and the concept of the Pharmacologic Audit Trail. We detail the exciting approaches offered by drugging the cancer genome, focusing on blocking oncogene addiction, drugging the oncogenic lipid kinome, addressing nononcogene addiction, exploiting synthetic lethality, and overcoming apoptotic resistance, leading to personalized molecular medicine.
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