Abstract 1074: Cellular uptake and metabolism of MT1-MMP-activated taxane prodrugs

Abstract

Abstract ICT3205 is a targeted cytotoxic agent, comprised of an MT1-MMP-specific peptide and a paclitaxel warhead. Paclitaxel, originally approved in 1992, is one of the most commonly used chemotherapies for various cancer types, but is often characterized by its dose-limiting toxicity and low aqueous solubility. Tumor-targeted prodrugs are a promising strategy for the selective delivery of taxanes to prostate tumors, especially given the results of STAMPEDE trial1. Previous work has shown that ICT3205 is selectively metabolized in tumor tissue over the normal tissue, and that this is specifically mediated by MT1-MMP2. In vivo studies have demonstrated that when administered at an equimolar dose to paclitaxel, ICT3205 has a superior anticancer effect, with an absence of systemic toxicity. In this study we aim to further investigate the cellular uptake and metabolism of ICT3205 and other taxane analogues in MT1-MMP +ve (HT1080) and MT1-MMP -ve (MCF-7) cells in vitro. The compound will be also studied in the PC3 prostate cancer cell line, since it has been demonstrated before that there is a good correlation between MT1-MMP protein and mRNA expression. ICT3205 and analogues have been synthesized, and purified by semi-preparative HPLC. We report the tumor-specific metabolism of ICT3205 in prostate tumors ex vivo, and we are currently studying its cellular uptake and metabolism in MT1-MMP +ve and MT1-MMP -ve cancer cell-lines using HPLC, mass spectrometry and immunofluorescent microscopy. Moreover, ex vivo metabolism studies are performed on the analogues, while they will be also assessed for their metabolism and cellular uptake. These data will provide a better understanding of the mechanism of uptake and metabolism of this type of peptide prodrugs, and will provide the basis for the future synthesis and optimization of these prodrugs. 1.James ND et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomized controlled trial. Lancet. 2016;387(10024):1163-772.Loadman PM et al. Improved delivery of paclitaxel to prostate tumors: a membrane-type matrix metalloproteinase (MT-MMP)-targeted approach. Cancer Res. 2016;76:3 Citation Format: Athina Polykandritou, Alexandra Serre, Hannah Spencer, Goreti R. Morais, Amanda Race, Steven Shnyder, Paul Loadman, Robert A. Falconer. Cellular uptake and metabolism of MT1-MMP-activated taxane prodrugs [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 1074.