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    MS31 - Clinical Science in Mesothelioma (ID 809)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 205 AC
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      MS31.02 - Clinical Implementation of BAP1 Inhibitors (Now Available) (ID 11536)

      13:45 - 14:00  |  Presenting Author(s): Paul Baas

      • Abstract
      • Presentation
      • Slides

      Abstract

      Over the last few years BRCA associated protein 1 (BAP1) has attracted attention in the development of cancer[1-2].
      BAP1 is one of the molecular targets that has been identified as a novel target in this disease. The function of BAP1 is mainly regulatory, including its function as deubiquitinating enzyme (DUB) of H2A. Through its deubiquitinase activity and the effects on transcription, BAP1 functions as a tumor suppressor gene. It regulates transcription, cell cycle control, DNA damage repair and cellular differentiation [1-4].

      Patients with a BAP1 germline mutation often presents with skin disorders including skin tumors and uveal melanomas and are often diagnosed at an early age. BAP1 germline mutation in patients with mesothelioma was first reported in 2011 [5]. In these cases, prognosis seems to be better with a 5-year survival rate of 47%, as compared to 6,7% for patients who did not have the mutation [6].

      Although germline mutations are rare in mesothelioma [7], somatic BAP1 aberrations are more common in mesothelioma tumors. Studies showed that 47-67% of the mesothelioma tumors contain a BAP1 genetic aberration. BAP1 somatic mutations are more frequent in the epithelioid subtype than in the sarcomatoid subtype. Besides single point mutations in the BAP1 gene, copy number loss, rearrangements and multiple alterations have been reported. The somatic BAP1 mutation can easily be identified with immunohistochemistry.

      BAP1 as a drug target in mesothelioma

      The regulation of histones by BAP1 suggests that an interaction with histone deacetylase (HDAC) inhibitors could be beneficial. In mesothelioma, the effect of HDAC inhibitors on H2A is not known, but BAP1 knockdown in mesothelioma cell lines increases the sensitivity for HDAC inhibitors leading to cell death, a process known as synthetic lethality. In the VANTAGE 014 study, a phase III trial including 661 patients, the HDAC inhibitor vorinostat did not improve overall survival in an unselected group of patients compared to placebo [8].

      Enhancer of zeste homolog 2 (EZH2) is upregulated in mesothelioma and preclinical models have identified a possible association between BAP1 loss and EZH2 upregulation. Specific EZH2 inhibitors decreased cell proliferation, reduced invasion and reduced clonogenicity in mesothelioma cell lines and tumor bearing mice. Importantly, BAP1 mutant mice were more responsive to the EZH2 treatment compared to wild type mice. In different tumor types, phase I studies with EZH2 inhibitors showed promising results [9]. Currently a study in mesothelioma patients with the EZH2 inhibitor tazemetostat is ongoing (NCT02860286).

      Another interaction partner of BAP1 is host cell factor 1 (HCF1). This protein has a role in cell cycle progression by activating transcription of promotors bound by the E2F (transcription) family. BAP1 deubiquitinates HCF1 and recently multiple groups showed that BAP1 mutation results in increased HCF1 ubiquitination, impairing E2F activation. Decreased activation of E2F causes problems in cell cycle progression and results in the inhibition of cell growth. Although there are no drugs yet available to inhibit E2F, these interaction partners may provide options for new therapeutic interventions.

      Synthetic lethality.
      Due to its regulatory function in DNA repair damage, it is expected that in BAP1 mutated cases the homologous recombination (HR) DNA repair system is impaired. The use of PARP1 inhibitors could therefore be promising as is shown in ovarian and mammary carcinoma. Preclinical studies of nirapanib and olaparib in mesothelioma cell lines proved to inhibit the cell growth, but this effect was independent of the BAP1 mutation status [10]. Therefore it is expected that other pathways are more important in this approach.

      Conclusions.

      For the treatment of tumors with BAP1 protein loss, it is important to identify therapeutic agents that reverse the phenotypic effects. Multiple interaction partners and proteins under influence of BAP1 are reported and (pre)clinical data of new inhibitors targeting these partners is promising. Further research on BAP1 action is required before we define an optimal treatment plan. Due to the many interaction partners and different functions of BAP1 the future we will probably end up with a combination of agents to reverse the phenotypic effect of BAP1 protein loss.

      Reference

      1. Wang, A., et al., Gene of the month: BAP1. J Clin Pathol, 2016. 69(9): p. 750-3.

      2. Bononi, A., et al., Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies. Expert Rev Respir Med, 2015. 9(5): p. 633-54.

      3. Misaghi, S., et al., Association of C-terminal ubiquitin hydrolase BRCA1-associated protein 1 with cell cycle regulator host cell factor 1. Mol Cell Biol, 2009. 29(8): p. 2181-92.

      4. Scheuermann, J.C., et al., Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature, 2010. 465(7295): p. 243-7.

      5. Testa, J.R., et al., Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet, 2011. 43(10): p. 1022-5.

      6. Baumann, F., et al., Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival. Carcinogenesis, 2015. 36(1): p. 76-81.

      7. Sneddon, S., et al., Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma. Gene, 2015. 563(1): p. 103-5.

      8. Krug, L.M., et al., Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Oncol, 2015. 16(4): p. 447-56.

      9. Kim, K.H. and C.W. Roberts, Targeting EZH2 in cancer. Nat Med, 2016. 22(2): p. 128-34.

      10. Gayathri Srinivasan et al. Synthetic lethality in malignant pleural mesothelioma with PARP1
      inhibition.
      Cancer Chemother Pharmacol. 2017; 80(4): 861–867.

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    WS02 - Mesothelioma Workshop (ID 996)

    • Event: WCLC 2018
    • Type: Workshop
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/23/2018, 08:00 - 11:15, Room 205 AC
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      WS02.07 - Session 2: Immunotherapy in Mesothelioma (Now Available) (ID 14750)

      09:05 - 09:05  |  Presenting Author(s): Paul Baas

      • Abstract
      • Presentation

      Abstract not provided

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