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N. van Zandwijk
Moderator of
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MS 08 - BAP1 Cancer Syndrome and Mesothelioma (ID 26)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 4
- Moderators:L.M. Krug, N. van Zandwijk
- Coordinates: 9/07/2015, 14:15 - 15:45, 702+704+706
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MS08.01 - Mesothelioma and BAP1 Germline Mutations (ID 1877)
14:15 - 15:45 | Author(s): M. Carbone
- Abstract
- Presentation
Abstract not provided
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MS08.02 - BAP1 and Ubiquitination (ID 1878)
14:15 - 15:45 | Author(s): E.B. Affar
- Abstract
- Presentation
Abstract:
The deubiquitinase (DUB) BAP1 recently emerged as a major tumor suppressor inactivated in several malignancies notably mesothelioma. With the aim of defining the BAP1 mechanism of action, we previously conducted a tandem affinity immunopurification of BAP1-associated proteins and found that most of the interacting partners are transcription factors and cofactors. Notably, BAP1 forms a complex with the Host Cell Factor (HCF-1), the O-linked N-acetyl-Glucosamine Transferase (OGT), the Lysine Specific Demethylase KDM1B, the Additional Sex Comb Like proteins ASXL1 and ASXL2 (ASXL1/2), the Forkhead Box transcription factors FOXK1 and FOXK2 as well as the zinc finger transcription factor Yin Yang 1 (YY1). We found that BAP1 regulates the expression of genes involved in cell proliferation and is recruited to gene regulatory regions to activate transcription. BAP1 is also recruited to the site of DNA double strand breaks to promote repair by homologous recombination. Moreover, this DUB appears to be also finely regulated by post-translational modifications including phosphorylation and ubiquitination. Interestingly, the ortholog of BAP1 in drosophila, named Calypso, deubiquitinates histone H2A on lysine 119 (H2Aub). H2Aub is a critical epigenomic modification involved in transcriptional and DNA repair, and is associated with stem cell function, development, cell proliferation and cancer. Calypso associates with Additional Sex Comb (ASX) and forms the Polycomb Repressive DUB (PR-DUB) complex. Recently, we provided insights into the importance of BAP1-interacting partners, ASXL1 and ASXL2 (two orthologs of ASX) in promoting H2A deubiquitination. We found that BAP1 forms two mutually exclusive complexes with ASXL1 and ASXL2. ASXL1 and ASXL2 use their highly conserved ASXM domain to interact with the C-terminal domain (CTD) of BAP1, and these factors regulate each other’s protein stability. Significantly, through mutational analysis, we found that ASXM enhances BAP1 binding to ubiquitin and stimulates its DUB activity. Importantly, these functions require intramolecular interactions in BAP1 that generate a Composite Ubiquitin Binding Interface (CUBI). Gain and loss of function studies indicated that BAP1, ASXL1 and ASXL2 play critical roles in the coordination of cell cycle progression. Notably, overexpression of BAP1 or ASXL2 trigger the p53/p21 DNA damage response and cellular senescence, and these effects are abolished by mutations of the CTD or ASXM interaction domains. Furthermore, we showed that cancer-associated inactivation of BAP1/ASXL1/2 DUB activity disrupts coordination of cell proliferation. Altogether, our results indicate that the mammalian BAP1 is an authentic DUB for H2A that regulates chromatin function and exerts a tight control on cell cycle progression. Moreover, our studies provide a mechanistic link between H2A deubiquitination, BAP1 interacting partners and tumor suppression.
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MS08.03 - Screening for BAP1 in Danish Families (ID 1879)
14:15 - 15:45 | Author(s): K. Wadt, L. Aoude, N.K. Hayward, A. Gerdes
- Abstract
Abstract:
Background: BRCA1 associated protein-1 (BAP1) is a tumor suppressor gene that encodes a deubiquitinase involved in cell cycle regulation, cellular differentiation, and cell death (Carbone et al., 2013; Murali, Wiesner, & Scolyer, 2013). BAP1 is recruited to double-stand DNA breaks and promotes error-free DNA-repair (Yu et al., 2014). Germline BAP1 mutations have been identified in around 40 families with accumulation of mesothelioma, uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and basal cell carcinoma (BCC) (Carbone et al., 2013; Wadt et al., 2014; Wiesner et al., 2011). Speculation exists as to whether BAP1 germline mutation carriers with mesothelioma, UM or RCC have different prognosis compared to non-carriers with the same types of cancer. Somatic BAP1 mutations have been identified in approximately 20% of pleural malignant mesotheliomas (Zauderer MG, Bott M, McMillan R, Sima CS, Rusch V, Krug LM, Ladanyi M, 2013), with most studies reporting no significant differences in the histopathological features or survival of patients with BAP1 mutant compared to wild-type tumors. A recent study of Portuguese siblings discovered a germline BAP1 mutation as the possible cause of the only known familial clustering of well-differentiated papillary mesothelioma (WDPM), a rare subtype of epithelioid mesothelioma (Ribeiro et al., 2013), and there has since been another report of WDPM in a carrier of a germline BAP1 mutation (Pilarski et al., 2014). Previously, some patients with germline BAP1 mutations and malignant mesotheliomas have been reported as long-term survivors, which is very rare for mesotheliomas, raising the possibility that such tumors may be associated with more favorable prognosis (Ribeiro et al., 2013; Wiesner T, Fried I, Ulz P, Stacher E, Popper H, Murali R, Kutzner H, Lax S, Smolle-Jüttner F, Geigl JB, 2014). In contrast, somatic BAP1 mutations or loss of BAP1 have been associated with high-grade tumors or disseminated disease in sporadic RCC and UM patients, which could indicate a worse prognosis for carriers of germline BAP1 mutations with these tumor types. Clearly, further studies are necessary to clarify whether BAP1 germline mutation carriers with various cancers have altered prognosis relative to individuals who acquire somatic mutations in BAP1. Here, we sought to determine the frequency of germline BAP1 mutations in cancer prone families with accumulation of mesothelioma, UM, CM and RCC. Methods: Families were collected through the Danish melanoma registry and through Clinical Genetic Departments in Denmark. Families, who previously had received genetic counselling regarding mesothelioma, CM, UM, and RCC, were contacted. Results: In total we analysed 152 Danish families and found five with BAP1 mutations, which are described in Table 1. We analysed 127 CM patients, who were either young onset (<40 years), had multiple primary CM, or had a family history of melanoma, and found no BAP1 mutation. We analysed 22 sporadic cases of UM or familial cases of CM, with one case of UM in the family and found no BAP1 mutation. However, in 6 melanoma families with two cases of UM, we found 4 families with BAP1 mutation, and 2 of 3 families analysed with 2 or more cases of mesothelioma carried BAP1 mutations. We found that the strongest indicator of a germline BAP1 mutation, were families with two or more cases of mesotheliomas or UM. In 40% of families with the occurrence of mesothelioma and CM we also found BAP1 mutations but did not find BAP1 mutations in families with only CM or RCC, or families with CM and RCC. Table 1: Characterization of Danish BAP1 mutation-positive families
13% of BAP1 mutation carries developed mesothelioma, 33% developed UM, and 13% developed CM. There were no cases of RCC in the 5 Danish BAP1 mutation-positive families. Conclusion: In the Danish BAP1 mutation carriers we observed rare tumor types (pericardial paraganglioma and malignant fibrous histiocytoma) and three cases of unknown primary tumors. At present there is no international consensus about a surveillance program for BAP1 mutation carriers. Since BAP1 contributes to a rare, recently discovered cancer syndrome, there is as yet no documented reduction of morbidity or mortality to persons following surveillance. To obtain such empirical data we offer persons carrying a pathogenic BAP1 mutation a surveillance program consisting of yearly ophthalmological and dermatological examination from the age of 15. In addition, from the age of 25, we offer ultrasound examination of the kidneys every second year. We inform the patient and their general practitioners of the increased cancer risk, and signs which should prompt further symptom-related investigations. At the moment, we have not established a surveillance program for mesothelioma. References: Carbone, M., Yang, H., Pass, H. I., Krausz, T., Testa, J. R., & Gaudino, G. (2013). BAP1 and cancer. Nature Reviews. Cancer, 13, 153–9. doi:10.1038/nrc3459 Murali, R., Wiesner, T., & Scolyer, R. a. (2013). Tumours associated with BAP1 mutations. Pathology, 45, 116–26. doi:10.1097/PAT.0b013e32835d0efb Pilarski, R., Cebulla, C. M., Massengill, J. B., Rai, K., Rich, T., Strong, L., … Abdel-Rahman, M. H. (2014). Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases. Genes Chromosomes and Cancer, 53, 177–182. doi:10.1002/gcc.22129 Ribeiro, C., Campelos, S., Moura, C. S., Machado, J. C., Justino, A., & Parente, B. (2013). Well-differentiated papillary mesothelioma: Clustering in a Portuguese family with a germline BAP1 mutation. Annals of Oncology, 24, 2147–2150. doi:10.1093/annonc/mdt135 Wadt, K. A. W., Aoude, L. G., Johansson, P., Solinas, A., Pritchard, A., Crainic, O., … Hayward, N. K. (2014). A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma. Clinical Genetics. doi:10.1111/cge.12501 Wiesner T, Fried I, Ulz P, Stacher E, Popper H, Murali R, Kutzner H, Lax S, Smolle-Jüttner F, Geigl JB, S. M. (2014). J OURNAL OF C LINICAL O NCOLOGY Toward an Improved Definition of the Tumor Spectrum Associated With BAP1. Journal of Clinical Oncology, 30(32), 2012–2015. Wiesner, T., Obenauf, A. C., Murali, R., Fried, I., Griewank, K. G., Ulz, P., … Speicher, M. R. (2011). Germline mutations in BAP1 predispose to melanocytic tumors. Nature Genetics, 43(10), 1018–21. doi:10.1038/ng.910 Yu, H., Pak, H., Hammond-Martel, I., Ghram, M., Rodrigue, A., Daou, S., … Affar, E. B. (2014). Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proceedings of the National Academy of Sciences of the United States of America, 111, 285–90. doi:10.1073/pnas.1309085110 Zauderer MG, Bott M, McMillan R, Sima CS, Rusch V, Krug LM, Ladanyi M. (2013). Clinical Characteristics of Patients with Malignant Pleural. Journal of Thoracic Oncology, 8(11), 1430–1433.Family Mutation Cases of UM/No. of mutation carriers Cases of mesothelioma/ No. of mutation carriers Cases of CM/No. of mutation carriers Other types of cancer in mutation carriers A c.1708C>G p.L570V 3/14 2/14 1/14 Paraganglioma, Sarcoma B c.581-2A>G Splice defect 7/9 0/9 1/9 Lung C c.1209_1210dupT p.D404X 0/8 3/8 2/8 BCC, Breast, unknown primary D c.178C>T p.R60X 3/10 0/10 2/10 BCC, ovary E c.178C>T p.R60X 2/4 1/4 0/4 BCC Total 15/45(33%) 6/45(13%) 6/45(13%)
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MS08.04 - BAP1: Lessons from Renal Cell Carcinoma (ID 1880)
14:15 - 15:45 | Author(s): J. Brugarolas
- Abstract
- Presentation
Abstract not provided
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Author of
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ORAL 26 - Clinical Trials 2 (ID 127)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:A. Scherpereel, C. Thomas
- Coordinates: 9/08/2015, 10:45 - 12:15, 702+704+706
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ORAL26.07 - Early Signs of Clinical Activity of a MicroRNA-Based Therapy in a Phase I Study in Recurrent Malignant Pleural Mesothelioma (ID 1101)
10:45 - 12:15 | Author(s): N. van Zandwijk
- Abstract
- Presentation
Background:
Recently we demonstrated that members of the miR-15/16 family of microRNAs are implicated as tumor suppressors in malignant pleural mesothelioma (MPM) (Reid et al, Ann Oncol, 2013). MesomiR 1 is a first-in-man study testing TargomiRs (miR-15/16-derived mimics packaged in EDV[TM]nanocells [EDVs] targeted with EGFR antibodies) in MPM patients.
Methods:
In this phase I study (ClinicalTrials.gov: NCT02369198) a standard 3-6 patient dose escalation cohort design examining weekly/twice weekly administration of TargomiRs is followed. Patients tolerating weekly/twice weekly TargomiR infusions well are allowed to continue experimental therapy for at least 8 weeks. Fifty percent of the MTD previously established for EDVs was chosen as the first dose level to be studied and corresponded to 5 billion EDVs containing 1.5 μg miR-15/16 mimics. Based on prior experience with EDVs, patients who presented with elevated IL-6 levels were given a dose adaptation period of two weeks before receiving phase I doses. Premedication consisted of dexamethasone, promethazine and paracetamol and patients were monitored for a minimum period of 3 hours after TargomiR infusion. Response assessment (CT, FDG-PET, pulmonary function) was scheduled for patients completing 8 weeks of treatment. Quality-of-Life (QoL) questionnaires (EORTC) were requested on a weekly basis.
Results:
Ten MPM patients have enrolled to date. The majority of patients receiving 5 billion TargomiRs experienced a period of shivering/rigor 80-90 minutes after the start of the infusion, sometimes associated with burning/painful sensations in the area of disease. Overall TargomiR treatment was well tolerated and no patient failed to complete the first (8 weeks) treatment period. Laboratory examination revealed a steep but transitory rise in inflammatory cytokines, neutrophilia and lymphopenia shortly after TargomiR infusion, sometimes accompanied by mild elevation of liver enzymes. QoL assessment (9 patients) showed improving scores in 3 patients, stabilization in 4 and slightly lower scores in 2 patients. Response assessment (modified RECIST) in the 6 patients completing 8 weeks of treatment to date: 1 PR (see Figure 1, reconfirmed after 12 and 16 weeks), 4 SD and 1 PD. Figure 1. FDG-PET scintigraphy before (left) and after (right) 8 weeksFigure 1 of TargomiR treatment (patient 5)
Conclusion:
Early MesomiR 1 data revealed that infusions with 5 billion TargomiRs were well tolerated. Transient inflammatory (cytokine-mediated) reactions were noted shortly after TargomiR administration. One objective response was recorded while stable disease and stable QoL scores were noted in the majority of patients completing 8 weeks of experimental treatment.
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P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.08-007 - Fibulin-3: A Potential Prognostic Biomarker in Malignant Pleural Mesothelioma? (ID 1668)
09:30 - 17:00 | Author(s): N. van Zandwijk
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a highly aggressive asbestos-induced cancer arising from the mesothelium lining the thoracic cavities. The definitive diagnosis of MPM in most instances depends on the availability of a biopsy. A number of biomarkers have been proposed to assist in making the MPM diagnosis but none of them has yet reached the accuracy required for routine clinical use. Among the candidates is the secreted extracellular glycoprotein Fibulin-3 (FBLN3) (Pass et al, NEJM 2012; 367(15)). In this study, we have further investigated the potential of FBLN3 to serve as a biomarker for MPM.
Methods:
Cellular and secreted FBLN3 was measured (ELISA) in MPM and normal mesothelial cell lines, plasma of xenograft tumour-bearing mice, plasma from two independent series of MPM and non-MPM patients, and in malignant and non-malignant pleural effusions. The diagnostic and prognostic potential of FBLN3 was assessed by receiver operating characteristics curve analysis and the Kaplan-Meier method, respectively.
Results:
FBLN3 levels were significantly higher in MPM cells than in mesothelial cells, with a strong correlation between secreted and cellular levels. Human FBLN3 was also detectable in the plasma of tumour-bearing mice, suggesting that MPM cells were the origin of circulating FBLN3. Plasma FBLN3 levels found in MPM patients were lower than previously reported (Pass et al, NEJM 2012; 367(15)), but were comparable to those appearing in subsequent validation studies (Creaney et al, Thorax 2014; 69(10), Corradi et al, Anticancer Res 2013; 33(12)). Plasma FBLN3 was significantly elevated in MPM patients from a Sydney cohort, but far less in a Vienna cohort and the diagnostic accuracy of FBLN3 was insufficient in both cohorts [63%, (95%CI: 50.1-76.4) and 56% (95%CI: 41.5-71.0), respectively]. FBLN3 levels found in pleural effusions were comparable to those reported in previous studies, but the difference between cases and controls did not reach significance. In our series low levels of pleural effusion FBLN3 were again associated (p=0.002) with prolonged survival. In multivariate analysis taking histological subtype, age and gender into account FBLN3 remained significant with a hazard ratio of 9.92 (95%CI: 2.14–45.93).
Conclusion:
FBLN3 is overexpressed in MPM cell lines and may point to a potential oncogenic role for this protein. In contrast to the initial report linking FBLN3 to diagnosis in MPM, the levels of FBLN3 measured in plasma and pleural fluid of our series of MPM patients lacked diagnostic accuracy. However, the potential prognostic value of FBLN3 levels measured in pleural fluid was confirmed and in line with previous validation studies. These data underline the importance of validation studies for newly proposed biomarkers.
