TY - JOUR
T1 - Exploiting the cancer genome
T2 - Strategies for the discovery and clinical development of targeted molecular therapeutics
AU - Yap, Timothy A.
AU - Workman, Paul
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/1/20
Y1 - 2012/1/20
N2 - 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.
AB - 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.
KW - Biomarkers
KW - Cancer genome targets
KW - HSP90 inhibitors
KW - PARP inhibitors
KW - Patient selection
KW - PI3K inhibitors
KW - The Pharmacologic Audit Trail
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U2 - 10.1146/annurev-pharmtox-010611-134532
DO - 10.1146/annurev-pharmtox-010611-134532
M3 - Article
C2 - 22235862
AN - SCOPUS:84855881402
SN - 0362-1642
VL - 52
SP - 549
EP - 573
JO - Annual Review of Pharmacology and Toxicology
JF - Annual Review of Pharmacology and Toxicology
ER -