title: Is target validation all we need?
abstract: Targeted therapy for cancer treatment has required a shift in drug development approaches from broad treatment with chemotherapies, to the development of precision medicines that are specific for clinical targets. Cancer biology is widely studied and translating these findings into efficacious targeted therapies requires more than just target validation. Targets identified pre-clinically must be reproducible in other models that harbor the target. In addition, the extent and duration with which the target is modulated is at times essential for efficacy. Further, not only the target is of focus but also any inherent feedback mechanisms or mechanisms of acquired resistance should be understood to optimize chemistry of agents in development to target the tumor biology and to inform on combination approaches. Another element of a target that will likely contribute to successful clinical validation include the impact of target intra-tumor and inter-tumor heterogeneity on clinical efficacy. Taken together, to answer the question Is target validation all we need? We highlight a few elements of tumor biology and drug chemistry that if understood, may increase the successful clinical validation of new targets and therefore provide more targeted treatment options for this disease.
authors.affiliation: Oncology Translational Science, AstraZeneca, Waltham, MA, USA.
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Frigault
authors.affiliation: Oncology Translational Science, AstraZeneca, Waltham, MA, USA. Electronic address: carl.barrett@astrazeneca.com.
authors.forename: J Carl
authors.initials: JC
authors.lastname: Barrett
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D004347:Drug Interactions; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D057170:Translational Research, Biomedical
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors