Renal cell carcinoma (RCC) is a lethal disease and its incidence is on the rise. It is categorized into various subtypes, with clear cell RCC (ccRCC) representing about 85% of all ccRCC tumors. The introduction of vascular endothelial growth factor receptor (VEGFR) targeted tyrosine kinase inhibitors (TKIs) has achieved significant advances, resulting in a doubling of progression-free survival and significant gains in overall survival. However, complete and durable responses to TKIs treatment have been noted in only a few cases, necessitating chronic therapy for the majority of ccRCC patients.

The ability of TKIs to inhibit angiogenesis is well-established.  We and others have demonstrated that, in addition to the inhibition of angiogenesis, TKIs may also manifest a direct cytotoxic effect on tumor cells. In fact, TKIs modulate a series of complex interactions between tumor and the surrounding tissues, thereby influencing multiple cellular processes, such as angiogenesis, cell growth, and cell survival.

We apply CRISPR/Cas9 based high-throughput loss of function (LOF) screening approach to identify new targets, critical for TKIs resistant phenotype.  Our previous analysis revealed a number of new molecular factors whose depletion reversed sunitinib resistance.  One promising target gene is the enzyme farnesyltransferase (FTase). FTase catalyzes most isoprenylation reactions by adding a 15-carbon isoprenoid lipid (the farnesyl group) to proteins bearing a CAAX motif. Known FTase inhibitors (FTIs) such as lonafarnib and tipifarnib, have shown the most encouraging clinical results.  Importantly, multiple clinical trials confirmed the favorable tolerability and safety profiles of lonaparnib. Our preliminary studies demonstrate that the concomitant treatment of established 786-O and patient-derived PNX0010 RCC cells with lonafarnib potently augments the antitumor effect of sunitinib and pazopanib. Moreover, combined treatment with sunitinib and lonafarnib completely reversed the resistance of human RCC tumors to sunitinib in a xenograft model. Thus, our current studies are focused on defining the mechanisms by which FTase contribute to the antitumor effects and pre-clinical evaluation of potential use of FTIs as combinatorial treatment option for metastatic RCC.

The landscape of therapeutic approaches for advanced RCC has expanded rapidly in recent years. Given that RCC tumors are highly vascularized and immunogenic, the combination of VEGFR-targeting and immunotherapies have shown significant clinical promise and opened the possibility of a cure for this lethal disease. For example, the first phase III trial of combined BEGFR-targeting and PD-1 checkpoint blockade in metastatic RCC improved both progression free survival rates (by 26%), as well as complete responses (10%) over conventional approaches. However, such combined therapies have also conferred additional toxicities ranging from moderate to adverse, requiring dose interruptions or reductions, thereby limiting their efficacy. Indeed, the most common adverse events associated with systemic VEGF depletion using bevacizumab therapy are proteinuria, hypertension, hypercalcemia, bleeding. Thus, combinational therapeutic approaches targeting VEGF pathways have significant potential in advanced RCC, but systemic toxicity remains a major concern.

Our team is also focused on development of bispecific antibody-based strategies which will simultaneously engage an RCC-restricted antigen and inhibit VEGF/VEGFR signaling. Specifically, this bispecific agent comprises an Ab fragment targeting the RCC biomarker CD70 on one end and a VEGF ‘trap’ on the other. CD70 is transiently expressed and restricted to a subset of highly activated T, B, and dendritic cells, but is highly overexpressed (over 70% samples) in all RCC tumors and reaching almost 100% incidence in metastatic ccRCC. This makes it an excellent antigen for selective targeting of ccRCC. Thus, we developed a novel anti-CD70-VEGF trap fusion antibody which is expected to have two major advantages over existing VEGF neutralizing agents. By targeting the VEGF trap to tumors, it will (i) achieve higher intratumoral concentrations of the trap; and (ii) limit side-effects arising from off-target VEGF inhibition seen with systemic anti-VEGF approaches.

Additionally, we focus on design and generation of novel cytokine traps with improved functions using computational approaches.