The role of Angiopoietin-like 4 in clear cell renal cell carcinoma and its therapeutic potential

University Of Florida, Gainesville FL

Investigators

Abstract

Project Summary Renal cell carcinomas (RCC) are the 7th most common types of cancer in the world with over 400,000 new cases and 170,000 deaths worldwide each year. Clear cell renal cell carcinomas (ccRCC) are the most common (>80%) and most aggressive subtype of RCC. ccRCC are highly vascularized tumors with elevated levels of vascular endothelial growth factor A (VEGFA) due to frequent (>80%) loss of function the Van Hippel Landau gene. As such, the first line of therapy for ccRCC are tyrosine kinase inhibitors (TKIs) which target the VEGF pathway in combination with immune checkpoint inhibitors (ICIs). However, these therapies have shown to be effective in only a subset of patients. This highlights the need to identify which patient cohorts are likely to respond and to develop novel therapies to improve the efficacy of ICIs. Angiopoietin-like 4 (ANGPTL4) is a secreted protein with several functions including regulating angiogenesis and has been shown to promote breast cancer progression and metastasis. We found that ANGPTL4 is highly upregulated in ccRCC compared to normal kidney tissue and blocking ANGPTL4 or knockout of ANGPTL4 reduces tumor growth in a 786O ccRCC xenograft model. Knockout of ANGPTL4 also decreased tumor angiogenesis and increased expression of adhesion molecules on tumor associated endothelial cells – an indicator of vessel normalization which is a key mechanism for combination with ICIs. We also found that a subset of ccRCC patients express low levels of ANGPTL4 and these patients have a shorter overall survival and less frequency of VHL mutations. Correlated with this we found that knockout of ANGPTL4 in ccRCC cells with wild type VHL increased tumor growth while blocking antibodies against secreted ANGPTL4 had no effect. This indicates a cancer cell intrinsic function for ANGPTL4 that is relevant to this subset of ccRCC patient. Based on these findings, we hypothesize that ANGPTL4 has a dichotomous function in ccRCC where secreted ANGPTL4 promotes angiogenesis and tumor progression and cancer cell intrinsic ANGPTL4 suppresses tumor growth possibly through regulation of lipid metabolism. Targeting secreted ANGPTL4 in the tumor microenvironment in combination with ICIs is a rational therapeutic approach for treating ccRCC patients with high levels of ANGPTL4. The objective of specific Aim 1 is to define the role of ANGPTL4 in the tumor microenvironment in ccRCC progression, metastasis and tumor vascularization. The goal of Aim 2 is to use mouse models of ccRCC to preclinically test the efficacy of combining anti ANGPTL4 antibodies with immune checkpoint inhibitors. In Aim 3 we will determine the cancer cell intrinsic function of ANGPTL4 in ccRCC cell lines in regards to regulation of lipid metabolism. This project will establish the mechanistic role of ANGPTL4 in the pathophysiology of ccRCC and its potential as a therapeutic target in combination with immune checkpoint inhibitors.