Clear cell renal carcinoma (ccRCC) compromises 75% of all renal cancer cases and is strongly related to inactivation of the VHL tumor suppressor gene. The protein product of VHL, pVHL, is responsible for targeting the hypoxia inducible factor alpha (HIFa) family of transcription factors for degradation. When pVHL is inactivated, HIFa subunits are stabilized and are capable of translocating to the nucleus to induce transcription of various target genes (i.e. VEGF, PDGF) associated with increased tumor progression. An array of pharmacological inhibitors has been approved by the FDA in the past 5 years for treatment of advanced RCC. These drugs can broadly be grouped into two classes: VEGFR tyrosine kinase inhibitors and inhibitors of the mammalian target of rapamycin (mTOR). We are however victims of our own success, as the range of therapeutic choices has made selecting appropriate treatment difficult and it is increasingly clear that only a subset of patients benefit while almost all patients experience toxicity. The ability to identify a priori which patients will benefit from which drugs would be invaluable information as these predictors would allow the personalization of therapy most likely to benefit an individual while minimizing unnecessary toxicity and maximizing quality of life. We have established a cohort of RCC patient- derived tumorgrafts (PDT) and propose to expand and test them for sensitivity to the currently FDA approved targeted therapies targeting the VEGF and mTOR pathways. We have begun to molecularly characterize pretreatment tumor tissue as well as evaluate early passage tumorgrafts for functional imaging characteristics such as vascular perfusion and FDG PET avidity. We hypothesize that examination of the pretreatment molecular markers (ie. gene expression) and functional imaging (ie. PET/CT) characteristics of tumors will allow us to identify novel molecular biomarkers that predict response to treatments in a significantly more rapid fashion than can be done in humans.
Renal cell carcinoma (RCC) is a deadly cancer and its incidence is on the rise in the United States. While there are now a number of FDA approved therapies for advanced RCC it is increasingly clear that only a subset of patients benefit while almost all patients experience toxicity. Personalization of therapy for RCC will allow the use of drugs that are most likely to benefit an individual while minimizing unnecessary toxicity and maximizing quality of life.
|Bailey, Sean T; Zhou, Bing; Damrauer, Jeffrey S et al. (2014) mTOR inhibition induces compensatory, therapeutically targetable MEK activation in renal cell carcinoma. PLoS One 9:e104413|