The molecular heterogeneity of cancer poses great challenges for drug development, yet it also affords new opportunities for developing highly targeted therapies. In the second session, “Targeted Cancer Drug Development: Defining Molecular Profiles of Sensitivity,” Alan Ashworth (Institute of Cancer Research) will discuss harnessing genetic dependencies in cancer therapy. Many tumours harbour defects in their ability to maintain genomic integrity. His lab used a synthetic lethal approach to target the defect in DNA repair by homologous recombination in tumours with a BRCA1 or BRCA2 mutation. This strategy using PARP inhibitors is showing considerable promise in the clinic. Here, he will describe the approach as well as recent work defining determinants of sensitivity and resistance to PARP inhibitors.
Neal Rosen (Memorial Sloan-Kettering Cancer Center) will discuss molecularly targeted therapies for cancer. Among these targets, the Raf kinase is activated by mutation in several tumors, and inhibitors of B-Raf show great promise in treatment of tumors that harbor activating mutations, such as melanoma. However, in tumors with wild-type Raf genes, the effects of Raf inhibitors are complex, as they perturb feedback mechanisms in the MAP kinase pathway and can induce proliferative responses. Explaining these results requires careful molecular analysis of the dynamic behavior of the pathway in tumor models, which will be the topic of the presentation.
It has been known for many years that metabolism is perturbed in cancer cells. Recently, mutations in components of metabolic pathways have been identified that provide exciting new opportunities for drug development. Scott Biller (Agios Pharmaceuticals) will discuss how metabolism informs cancer drug discovery.
Finding new molecules and targets
Many exciting new technologies are being developed to identify new drug targets for cancer and other diseases. In the third session, “New Methodologies for Target Discovery and Target Validation,” William Hahn (Dana-Farber Cancer Institute) will discuss how functional genomic approaches now enable the interrogation of gene function at scale and how the integration of functional approaches with other high-throughput technologies permits the identification and validation of cancer targets.
Cancers can show a high degree of cellular heterogenity within tumors. Peter Jackson (Genentech) will discuss proteomic network building to discover new disease genes and drug targets.
Finally, the ubiquitin-proteasome system represents an exciting new opportunity for drug development, as inhibitors of the proteasome are in the clinic. Randall King (Harvard Medical School) will discuss the use of phenotypic screening to discover new inhibitors of ubiquitin ligases and their potential role as novel antimitotic agents.
Randall King (firstname.lastname@example.org) is an associate professor at Harvard Medical School, and Peter K. Jackson (email@example.com) is director of cell regulation at Genentech Inc.