Exploiting the cancer genome: strategies for the discovery and clinical development of targeted molecular therapeutics.
Annu Rev Pharmacol Toxicol
; 52: 549-73, 2012.
Article
em En
| MEDLINE
| ID: mdl-22235862
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article