Abstract 1663: Development of a novel oral microtubule targeting agent with pan-cancer efficacy

Abstract

Microtubule-targeting agents (MTAs) are among the most effective chemotherapeutics used in the treatment of cancer. However, the clinical utility of current MTAs, such as paclitaxel and vinblastine, are often limited due to adverse side effects or multidrug resistance (MDR) driving the continuous pursuit for the development of novel microtubule interactors. Here, we report the development of a novel non P-gp substrate MTA that is metabolically stable, and that displays broad-spectrum anti-cancer activity in vitro and ex vivo. Anti-cancer activity was assessed by screening a panel of 102 cancer cell lines and in a multi-tumor type panel of patient-derived organoids (PDOs). In vitro, double to triple digit nanomolar (ranging from 17nM to 318 nM) potency was observed in 101 cell lines, while viability was reduced by more than 70% in 76 cell lines out of 102. Similarly, 23 out of 34 (68%) of ex vivo treated PDOs were highly or partially responsive as indicated by a 37-73% decrease in viability. Studies using spindle assembly checkpoint (SAC) inhibitors demonstrated a mechanism at or before microtubule-kinetochore attachment in M phase of the cell cycle. Subsequent microscopic evaluation of kinetochore assembly revealed a lack of proper mitotic spindle formation highlighted with an increase in Mad1 signal intensity emphasizing metaphase arrest. Furthermore, in vitro tubulin polymerization assays demonstrated that the anti-cancer effect is a result of cytoskeleton targeting to inhibit microtubule assembly. Additionally, the antimicrotubule agent inhibited the formation of EBI (N,N’-ethylene-bis(iodoacetamide)):β-tubulin adducts indicating an occupied colchicine-binding site of tubulin. Six multi-tumor preclinical oncology models were evaluated for in vivo anti-tumor efficacy by oral administration of the compound. Further, tumor growth inhibition (%) was demonstrated in preclinical murine models of Acute Myeloid Leukemia (AML) (MV-4-11, 51%), colorectal (COLO205, 35%), prostate (DU 145, 38%), and gastric cancer (HS746T, 74%; SNU-5, 48%). Moreover, tumor tissue analysis for prominent mitotic cell cycle markers, Cyclin B1 and pHH3, revealed a dose-dependent elevation of both markers revealing mitotic arrest phenotype. Together, our data supports further preclinical and clinical development of a novel oral MTA notably in Taxane resistant and/or Taxane sensitive tumors. Citation Format: Maria-Dorothea Nastke, Jacob Matson, Andressa Mota, Archna Ravi, Alex Batrouni, Marcus O'Hara, Shiva Kazerounian, Arcan Guven, Nicole Pellegrino, Kashni Grover, Kayleigh Gray, Anne Diers, Michael Kiebish, Vivek Vishnudas, Stephane Gesta. Development of a novel oral microtubule targeting agent with pan-cancer efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1663.