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Purpose: Human serum albumin (HSA) is an attractive candidate as a carrier in developing novel albumin-bound nanoparticle therapeutic drugs. Gemcitabine has been used in the treatment of solid tumors, including non-small cell lung, pancreatic, bladder, and breast cancers. Our previous work in pancreatic and lung cancer models demonstrates that caveolin-1 (Cav-1) enhances uptake of albumin and albumin-conjugated drugs. The aim of this study is to investigate whether the presence of Cav-1 expression alters therapeutic efficacy of JNTX-101, a novel albumin encapsulated gemcitabine prodrug. Experimental design: We first determined the treatment efficacy of JNTX-101 in a panel of 4 pancreatic/lung cancer cell lines (MIAPaCa-2, PANC-1, H23, and HCC15) by alamarBlue cell viability assay. We further established 4 pairs of Cav-1 isogenic cells stably expressing shRNA targeting Cav-1 (shCav-1) or scrambled control shRNA (shCtrl). We investigated whether the absence of Cav-1 expression alters sensitivity of JNTX-101 using alamarBlue cytotoxicity assay and western blotting in both high and low serum conditions. In addition, we tested whether JNTX-101 treatment can alter expression and cellular distribution of Cav-1 as well as other caveolae resident proteins, such as Cav-2 and Cavin-1. Results: Differences in Cav-1 expression resulted in different uptake of albumin prodrug conjugate and Cav-1 depletion attenuated sensitivity of the cells to JNTX-101. Decreased Cav-1 expression markedly reduced JNTX-101-induced apoptosis in a panel of cells in both high and low serum conditions, but particularly in low serum conditions. In addition, our data showed both serum starvation and JNTX-101 independently increased Cav-1 expression in a time-dependent manner (24hrs, 48hrs, 72hrs) similar to gemcitabine, with peak level at 48 hrs post treatment, while other caveolae resident proteins were minimally affected. Conclusions: Our preliminary results suggest that JNTX-101 effectively inhibits cell viability in pancreatic/lung cancer cells and Cav-1 expression dictates sensitivity to JNTX-101, at least partially through reduced apoptotic cell death. These data indicate that Cav-1 may be a potential predictive biomarker of JNTX-101 sensitivity, especially in nutrient deprived conditions. Further study will be performed to explore the impact of Cav-1 expression on JNTX-101 sensitivity in mouse models of pancreatic/lung cancer. Citation Format: Tiantian Cui, Sergio Corrales-Guerrero, Dan Maneval, Curtis Monnig, Patrick Kearney, Sam Ellis, Terence M. Williams. Caveolin-1 functions as a potential predictive biomarker for JNTX-101, an albumin encapsulated gemcitabine prodrug [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4070. |
