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

Our plain-English summary of A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma, by S. Arulananda, M. O'Brien, M. Evangelista, et al (Cell Death Discovery, 2021).

The study

• Authors: S. Arulananda, M. O'Brien, M. Evangelista, L.J. Jenkins, A.R. Poh, M. Walkiewicz, T. Leong, J.M. Mariadason, J. Cebon, S.B. Balachander, J.R. Cidado, E.F. Lee, T. John, W.D. Fairlie
• Journal: Cell Death Discovery
• Published: 2021;7(1):122
• Cited by: 32 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study tested experimental drugs against malignant pleural mesothelioma (MPM). It did not study asbestos exposure. The authors treated two human MPM cell lines with AZD4320, a drug that blocks the survival proteins BCL-XL and BCL-2: MSTO-211H, which is biphasic, and NCI-H28, which is epithelioid. AZD4320 alone reduced cell viability with EC50 values of 150 to 220 nM. Adding the MCL-1 blocker AZD5991 lowered these to 3 to 55 nM. A caspase inhibitor reversed the effect, consistent with cell death by apoptosis. Mice carrying MSTO-211H tumors were given AZD0466, a dendrimer-linked form of AZD4320, on days 1 and 8. In these mice, median time to the tumor-size endpoint was 32 days, compared with 28 days for cisplatin and 21 days for vehicle controls. Cisplatin plus AZD0466 reached 36 days. Forty-eight hours after AZD0466 alone, there was no evidence of thrombocytopenia (low platelets). The combination group's mean platelet count was 597 per microliter, against 1066 in controls. The authors stated that a direct platelet comparison with other drugs was not possible. They concluded that future clinical evaluation of AZD0466 in MPM should be considered.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (pre-clinical) study: experiments on human mesothelioma cell lines in vitro and mouse xenograft experiments
• Who was studied: Two human MPM cell lines (MSTO-211H, biphasic; NCI-H28, epithelioid) from the American Type Culture Collection, and NOD-scid female mice aged 6 to 8 weeks carrying MSTO-211H tumors (n = 6 to 10 per group), studied in Australia
• Exposure: Not asbestos. The treatments studied were AZD4320 (BCL-XL/BCL-2 inhibitor), AZD5991 (MCL-1 inhibitor) and cisplatin in cell culture. In mice: AZD0466 (AZD4320 conjugated to a dendrimer) at 100 mg/kg intravenously on days 1 and 8, cisplatin at 4 mg/kg intra-peritoneally on day 1, the combination, or vehicle controls
• Main results:
  • AZD4320 alone reduced viability of the MPM cell lines with EC50 values of 150 to 220 nM
  • When AZD4320 was combined with the MCL-1 inhibitor AZD5991, EC50 values ranged from 3 to 55 nM, depending on the AZD5991 concentration; the effect was synergistic
  • The pan-caspase inhibitor Q-VD-OPh rescued the effect of AZD4320 alone and in combination with AZD5991, consistent with cell death through apoptosis
  • AZD4320 enhanced cisplatin's effect in a cell-line-dependent way: a 14-fold increase in response for NCI-H28 versus 2-fold for MSTO-211H, with 1 μM AZD4320. The authors described this as weakly synergistic
  • In mice with MSTO-211H xenografts, median survival (time to tumor size of 1000 mm3) was 32 days with AZD0466 alone, 28 days with cisplatin alone and 21 days with vehicle controls. The p-value printed with the vehicle comparison was p less than or equal to 0.01
  • AZD0466 combined with cisplatin increased median survival in mice to 36 days
  • Forty-eight hours after dosing, there was no evidence of thrombocytopenia in the AZD0466-alone group
  • In the AZD0466 plus cisplatin group, mean platelet count was 597 per microliter versus 1066 per microliter in controls. The authors described this as relatively mild, and platelet levels rebounded one week after treatment ended
  • No mice in the treatment groups lost weight beyond the limit in the ethics protocol (greater than 15%)
• The authors' conclusion: The authors concluded that nanomedicine delivery of BH3-mimetics such as AZD0466 can provide similar, if not increased, efficacy in MPM compared with unconjugated BH3-mimetics. They said it can potentially overcome thrombocytopenia, and that its future clinical evaluation in MPM should be considered
• Limitations the authors state:
  • Ethics approval prevented blood sampling within 48 hours of intravenous dosing, so a direct comparison of platelet effects with A-1331852 or Navitoclax (measured at 24 hours) was not possible
  • Only one cell line could be tested in mice; tumors could not be established with NCI-H28
  • Whether similar efficacy will be seen in other solid tumor types is unknown

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Cisplatin, Pemetrexed (Alimta), Chemotherapy, Apoptosis.

Related studies

• BCL-XL is an actionable target for treatment of malignant pleural mesothelioma — S. Arulananda, M. O'Brien, et al. (2020)
• The role of BCL-2 family proteins and therapeutic potential of BH3-mimetics in malignant pleural mesothelioma — S. Arulananda, E.F. Lee, et al. (2021)
• A novel mycobacterial Hsp70-containing fusion protein targeting mesothelin augments antitumor immunity and prolongs survival in murine models of ovarian cancer and mesothelioma — J. Yuan, S. Kashiwagi, et al. (2014)
• Targeting polyamine as a novel therapy in xenograft models of malignant pleural mesothelioma — S.K. Lam, S. Yan, et al. (2020)
• The novel BH3 α-helix mimetic JY-1-106 induces apoptosis in a subset of cancer cells (lung cancer, colon cancer and mesothelioma) by disrupting Bcl-xL and Mcl-1 protein-protein interactions with Bak — X. Cao, J.L. Yap, et al. (2013)
• CARP-1 functional mimetics are a novel class of small molecule inhibitors of malignant pleural mesothelioma cells — S. Jamal, V.T. Cheriyan, et al. (2014)

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