A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma

Surein Arulananda,Justin R Cidado,Erinna F Lee,Laura J Jenkins,Walter D Fairlie,Trishe Leong,Marco Evangelista,Megan O’Brien,Ashleigh R Poh,Thomas John,Marzena Walkiewicz,Jonathan Cebon,John M Mariadason,Srividya B Balachander

doi:10.1038/s41420-021-00505-0

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer with treatment limited to Cisplatin and Pemetrexed chemotherapy. Recently, we showed that drugs targeting the BCL-2-regulated apoptosis pathway could kill MPM cell lines in vitro, and control tumor growth in vivo. These studies showed BCL-XL was the dominant pro-survival BCL-2 family member correlating with its high-level expression in cells and patient tumor samples. In this study we show another inhibitor, AZD4320 that targets BCL-XL (and BCL-2), can also potently kill MPM tumor cells in vitro (EC50 values in the 200 nM range) and this effect is enhanced by co-inhibition of MCL-1 using AZD5991. Moreover, we show that a novel nanoparticle, AZD0466, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer, was as effective as standard-of-care chemotherapy, Cisplatin, at inhibiting tumor growth in mouse xenograft studies, and this effect was enhanced when both drugs were combined. Critically, the degree of thrombocytopenia, an on-target toxicity associated with BCL-XL inhibition, was significantly reduced throughout the treatment period compared to other BCL-XL-targeting BH3-mimetics. These pre-clinical findings provide a rationale for the future clinical evaluation for novel BH3-mimetic formulations in MPM, and indeed, other solid tumor types dependent on BCL-XL.

Highlights

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer caused by exposure to asbestos[1]
Our studies showed that MPM cell lines can be potently killed with BH3-mimetics targeting BCL-XL, though this activity is enhanced by co-treatment with an MCL-1 inhibitor[9]
In this study we show that AZD0466 has potent activity in MPM, with less thrombocytopenia compared to that observed with other BH3-mimetics targeting BCL-XL

Summary

Introduction

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer caused by exposure to asbestos[1]. For over a decade the mainstay therapy for MPM has been Cisplatin plus Pemetrexed combination chemotherapy[3], the recent MAPS study showed a modest improvement in overall survival with the addition of Bevacizumab, an anti-angiogenic agent, In an attempt to provide a new avenue for MPM treatment, we and others[8,9,10] have recently investigated a more generic approach of targeting the BCL-2 pro-survival proteins (i.e., BCL-2, BCL-XL, BCL-W, MCL-1 and BFL-1) that frequently have deregulated expression in cancer cells, leading to increased tumor cell survival and treatment resistance[11]. BCL-XL and MCL-1 were shown to be the dominant BCL-2 pro-survival proteins expressed in MPM patient samples[9]

Methods

Results

Conclusion