Research Abstract

My laboratory is involved in translational research activities in genitourinary malignancies, especially renal cell carcinoma (RCC), which is the most common form of kidney cancer. Our research efforts in this area have focused on the identification of novel oncogenes and tumor suppressor genes that could function as new drug targets and thus might lead to new therapeutic approaches for patients with RCC. We conducted the first genome-wide analysis of copy-number changes and gene expression profiles in both sporadic and Von-Hippel Lindau (VHL) disease-associated clear cell renal cell carcinomas (ccRCC) (Beroukhim et al, Cancer Res 2009). Results showed that sporadic tumors without biallelic VHL inactivation are heterogeneous and include tumors with genomic profiles highly dissimilar to the majority of ccRCC, suggesting that they represent a separate group of cancers that do not respond to treatments that target the VHL pathway. We subsequently continued to work on the molecular characterization ccRCC as part of the NCI-sponsored The Cancer Genome Atlas (TCGA) effort(Creighton et al, Nature 2013).

In the past decade, the availability of approved agents with distinct mechanisms of action (immunotherapy, vascular endothelial growth factor [VEGF] pathway, and mammalian target of rapamycin [mTOR] inhibitors) has complicated treatment decisions for patients with advanced RCC. For this reason, my group has been very interested in building predictive models (for either FDA-approved or investigational drugs) that can help medical oncologists select the most appropriate therapy for a given patient. Over the past years, we have extensively analyzed the role of the enzyme carbonic anhydrase IX (CAIX) and other elements of the VHL-HIF pathway both as diagnostic and predictive biomarkers for VEGF-targeted therapy in ccRCC. More recently, we performed a multi-institutional study, which demonstrated that mutations in MTOR pathway genes are associated with response to mTOR inhibitors in patients with metastatic RCC, providing a potential predictive biomarker for rapalogs in this tumor type (Kwiatkowski et al, Clin Cancer Res 2016). In the past few years, my laboratory has also been deeply involved in the characterization of the expression of immunomodulatory molecules, including PD-L1, in tumors form patients with RCC and bladder cancer. This work has provided important insights into the role of PD-L1 as a potential predictive biomarker and a target of immunotherapy in genitourinary cancers. For instance, our analysis of PD-L1 expression in non-clear-cell Renal Cell Carcinoma (non-ccRCC) tissue samples provided a rationale for conducting clinical trial testing the efficacy of PD-1 inhibitors in patients with metastatic non-ccRCC (Choueiri et al, Ann Oncol 2014). Moreover, our detailed comparison of PD-L1 expression in primary ccRCCs and corresponding metastases highlighted the heterogeneity of PD-L1 expression in this tumor type, implying that accurate assessment of PD-L1 as a predictive biomarker for PD-1 blockade in ccRCC may require analysis of metastatic lesions (Callea et al, Cancer Immunol Res 2015). Our current efforts in this field of research are directed at identifying biomarkers of response to PD-1/PD-L1 immune checkpoints blockade through the analysis of clinical trial patient cohorts.