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

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.

Targeting the BCL-2-regulated apoptotic pathway for the treatment of solid cancers

“…In squamous cell lung carcinoma, dual inhibition of MCL-1 and BCL-XL induced synergistic tumour cell death, and when combined with fibroblast growth factor receptor (FGFR)-targeted therapy, produced durable treatment responses in FGFR1- overexpressing lung squamous cell carcinoma [ 79 ]. Similar results were also observed in malignant pleural mesothelioma, NSCLC and colorectal cancer [ 8 , 12 , 19 , 40 , 80 , 81 ]. In these cancers, BCL-XL is the dominant survival factor as its sole targeting had a greater effect compared with the targeting of MCL-1 alone.…”

“…No combination trials of AZD0466 with either ‘unconjugated’ BH3-mimetics targeting for example MCL-1, or chemotherapeutic agents have yet been announced. However, pre-clinical studies investigating the co-administration of AZD0466 and Cisplatin in a mesothelioma xenograft model demonstrate improved tumour killing with minimal thrombocytopaenia associated with BCL-XL targeting [ 80 ]. Another approach that directs BH3-mimetics to tumour cells is to conjugate them with antibodies targeting unique or overexpressed antigens preferentially found on cancer cells.…”

BH3-mimetics: recent developments in cancer therapy

“…It also showed combined effectiveness against biomarker-specific and Venetoclax-resistant AML cells, highlighting its usefulness for cell line- or biomarker- specific cancers [ 365 ]. Of similar interest is AZD0466, which can also be administered using nanoparticle technology as novel delivery method [ 366 ]. Alternatively, S63845 [ 74 ] is also showing good promise, although its optimal use is not fully…”

BH3 Mimetics in Hematologic Malignancies

“…The combination of venetoclax and navitoclax was well tolerated in patients with AML and lymphoblastic lymphomas [ 169 ]. Novel, dual BCL2 and BCL-XL inhibitors, e.g., AZD0466 or pelcitoclax (APG-1252), are currently under clinical development [ 170 , 171 ].…”