Research translation and personalized medicine

The convergence of technological advances leading to affordable genome sequencing and an ever increasing arsenal of molecularly targeted drugs are revolutionizing oncology. These developments set the foundation for personalized cancer therapy, a tailored approach to cancer treatment that exploits precise knowledge about molecular alterations in tumors. This chapter contextualizes these developments and discusses their implications and practical applications for renal cancer. At the outset, two cases are presented in which information about the molecular genetics of the tumor impacted patient management. These cases illustrate the challenges and opportunities associated with this approach. Precedent was set by the identification of mutations in the VHL gene and the implication of the mTORC1 in renal cancer. Recent advances have begun to unravel the complex interplay between pVHL and mTORC1 pathways and have uncovered a role of mTORC1 in the regulation, not only of protein translation and cell growth but also of sequence-specific transcription factors and gene expression. mTOR remains an important therapeutic target, and catalytic inhibitors targeting both mTORC1 and mTORC2 as well as PI3K isoforms are under evaluation. Opportunities are emerging from cancer genome/exome sequencing studies. Mutations create vulnerabilities that can be exploited with chemical-genetic screens. Drug development may be accelerated with improved preclinical models that accurately reproduce the molecular genetics and treatment responsiveness of RCC in patients. Renewed emphasis is needed on correlative studies in clinical trials. A vision is presented for an integrated research translation program for the advancement of personalized genomic-based cancer medicine.