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Michele Carbone
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ES03 - BAP-1 and Other Novel Molecular and Metabolic Targets in Mesothelioma (ID 6)
- Event: WCLC 2019
- Type: Educational Session
- Track: Mesothelioma
- Presentations: 5
- Now Available
- Moderators:Michele Carbone, Miyako Satouchi
- Coordinates: 9/08/2019, 10:30 - 12:00, Tokyo (1982)
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ES03.01 - Targeting Altered microRNA Expression in Mesothelioma (Now Available) (ID 3161)
10:30 - 12:00 | Presenting Author(s): Glen Reid
- Abstract
- Presentation
Abstract
MicroRNAs (miRNAs) are an important class of noncoding RNA that post-transcriptionally regulate the expression of most protein-coding genes. In addition to central roles in normal biology, their aberrant expression in tumours contributes to all of the hallmarks of cancer. In common with other tumour types, changes in miRNA expression in malignant pleural mesothelioma (MPM) are characterised by a global downregulation, although elevated levels of some miRNAs are also found. While altered expression has been demonstrated for many miRNAs in MPM, relatively few have been functionally characterised. Early studies reported modest tumour suppressive activities of, among others, miR-29c, miR-31 and miR-145. More recently, miR-16, miR-193a and the miR-34 family were shown to have clear tumour suppressor activity; restoring the levels of these miRNAs leads to a range of effects including inhibition of cell growth, induction of apoptosis, reversal of drug resistance and reduced migration and invasion. In the case of miR-16 and miR-193a, targeted delivery of mimics to tumours in a xenograft model led to significant inhibitory effects on tumour growth. These results laid the foundation for the phase I MesomiR-1 trial, investigating the safety and optimal dose of a miR-16-based mimic delivered in anti-EGFR antibody-targeted bacterial minicells. This trial of 27 patients demonstrated safety of the treatment as well as initial signs of activity, with one objective response and stable disease in a further 15 patients. With miR-16 also impacting response to pemetrexed and contributing to PD-L1 regulation in vitro, restoration of miR-16 levels in combination with chemo or immunotherapy are potential future applications of this approach. Other miRNAs with pronounced tumour suppressor activity, including miR-137 and miR-193a, are further candidates for clinical development. The lower levels of miR-193a recently found to be associated with shorter overall survival in the TCGA study lend support to this notion.
In contrast to the use of mimics to restore levels of miRNAs downregulated in MPM, inhibition of overexpressed miRNAs with antisense oligonucleotides is an alternative strategy for modulating miRNA levels. This approach is attractive as it may be amenable to local delivery, avoiding the problems associated with tumour targeting via systemic administration. While the number of miRNAs found to be consistently overexpressed in MPM is relatively small, recent studies suggest that their inhibition can have profound effects on MPM growth. One such example was the report of the effects of inhibiting the overexpressed miR-182 and miR-183. They are upregulated in MPM cell lines where they promote proliferation and invasion, at least in part due to suppression of FOXO1. Reducing their levels with miRNA inhibitors reversed these effects, with dual inhibition showing additive effects. An oncogenic role for miR-182 was first demonstrated in melanoma, in which this miRNA enhances migration, invasion and metastasis via inhibition of FOXO3 and MITF. Upregulation of miR-182 in melanoma is due to amplification (at 7q31) of a miRNA cluster which also contains the related miR-183 and miR-96. As this region appears to be more frequently lost in MPM, the mechanism for overexpression remains to be determined. Another miRNA with oncogenic activity in MPM is miR-24, which was identified via a screen of polysome-associated miRNAs and is upregulated in cell lines and tumour samples. This miRNA regulates a range of genes involved in cell adhesion and communication, many of which are associated with good prognosis, and miR-24 knockdown reduced migration and invasion in vitro and in vivo. Although the targets of miR-24 identified in this study had no obvious link to MPM biology, it is intriguing that in other cancers miR-24 regulates both transcripts produced by the CDKN2A locus. Whether other well known oncogenic miRNAs such as miR-155, miR-10b and miR-21 promote MPM tumour progression remains to be seen, but the initial results with miR-182, miR-183 and miR-24 warrant further pre-clinical development.
Despite progress in the development of miRNAs as therapeutic targets for MPM, outstanding questions remain. Of particular relevance is the question of the cell of origin of dysregulated miRNAs. As tumour samples consist of a mix of cancer, stroma and immune cells, the source of miRNA contributing to changes in expression is unknown and thus impacts the interpretation of results. For example, altered expression of miR-223 was linked to changes in migratory behaviour of MPM, but in xenograft studies this miRNA is clearly derived from the stroma. Another confounding observation concerns the apparent contradictory findings from studies of the same miRNA. For example, miR-137 has clear tumour suppressor function in MPM cells in vitro, but its expression varies widely across MPM lines and is found at higher levels in tumours from patients with shorter survival. Similarly, miR-31 has growth inhibitory activity but higher expression is associated with poor prognosis in sarcomatoid tumours. There are also cases of different miRNAs showing apparent differences in MPM compared with other cancers. A prime example of this is miR-21; an oncomiR in most cancer types, but growth inhibitory when overexpressed MPM cell lines. Finally, because the activity of miRNAs typically leads to modest reductions in target genes, demonstrating in vivo effects is not trivial. In addition, because the miRNA being restored (or inhibited) is usually identical to its endogenous miRNA counterpart, measuring delivery can be difficult. Due to their short size, even novel sequences such as that used in the TargomiR study are difficult to definitively measure by RT-qPCR or RNA-seq.
In summary, the changes in miRNA expression in MPM provide avenues to develop new therapetuic approaches. The successful phase I trial of TargomiRs demonstrated that miRNA targeting is feasible in MPM and while the majority of miRNA studies in MPM have focused on miRNA mimics, recent studies suggest that antisense inhibitors have similar potential. Notwithstanding the ongoing difficulties in delivering nucleic acid-based drugs, the recent FDA approval of the first siRNA therapy – together with ongoing clinical trials of a number of miRNA mimic drugs – means that gene silencing drugs have moved from concept to reality. Continued preclinical studies and early phase clinical trials are needed to determine the true potential of miRNA targeting in MPM treatment.
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ES03.02 - Targeting CDKN2A in Mesothelioma (Now Available) (ID 3162)
10:30 - 12:00 | Presenting Author(s): Dean Anthony Fennell
- Abstract
- Presentation
Abstract
Interrogation of the genomic landscape in mesothelioma has revealed considerable inter-patient genomic heterogeneity, however development of molecularly targeted stratified therapy is currently in its infancy.
Somatic copy number loss involving the chromosome 9p21-3 locus occurs at high frequency (45% deep deletion in the TCGA cohort), and its expression may be further suppressed by DNA methylation. 9p21-3 harbours CDKN2A. Conditional Knockout of CDKN2A is sufficient to initiate mesotheliomas in vivo consistent with a role in tumorigenesis. This is supported by emerging phylogenetic analysis in which 9p21-3 occurs as an early (clonal or truncal) homozygous event during tumour evolution, in around 20% of cases. Late homozygous and heterogzyous losses also occur, with evidence of parallel evolution. Importantly, CDKN2A is a major negative prognostic factor associated with earlier progression following surgical resection.
CDKN2A encodes two genes; 1, the inhibitor of cyclin dependent kinases 4 and 6 known as p16ink4A, and 2. MDM2, an inhibitor of the p53-MDM2 interaction. Early preclinical studies showed that re-introducing p16ink4A transgene in a CDKN2A negative mesothelioma exhibited anti-tumour activity. Small molecule inhibition of CDK4/6 essentially phenocopies p16ink4a (in the presence of wild type RB1). Large scale drug-gene interaction studies have revealed CDKN2A dependent sensitivity to CDK4/6 inhibition suggesting a possible strategy in mesothelioma. We have therefore developed the MiST stratified umbrella trial (NCT NCT03654833) is therefore evaluating the CDK4/6 inhibitor abemaciclib in p16ink4a negative relapsed mesothelioma (arm 2)
Loss of p14ARF expression promotes MDM2, an E3 ubiquin ligase targeting p53. Given the low mutation rate for p53 in mesothelioma (around 16% in the TCGA), MDM2 inhibitors may, in the context of p14ARF loss, de-repress p53 to mediate tumour suppression. Preclinical data supports this hypothesis which has translational potential.
Co-deletion of the gene MTAP with CDKN2A is common, and coincident with around 80% of CDKN2A losses. MTAP (methylthioadenosine phosphorylase) may represent a potential molecular target in 9p21-3 deleted mesothelioma. This tumour suppressor salvages the essential amino acid methionine, as well as adenine, and plays a critical role in the polyamine salvage pathway. Recently it has been shown that loss of MTAP leads to an increase level in its substrate, methylthioadenosine (MTA). This metabolite directly interacts with and inhibits the epigenetic modifier, PRMT5 (protein arginine methyltransferase 5) that mediates symmetrical arginine di-methylation of histone H4 (H4R3me2s). A direct consequence of this is a reduction in the pool of functional PRMT5 enzyme, revealing a vulnerability to 1. Inhibition of PRMT5 expression or 2. Inhibition of PRMT5 substrate (SAM) synthesis via MAT2A (which converts methionine to SAM). 1st generation small molecule PRMT5 inhibitors are currently undergoing phase 1 clinical evaluation, however MTA dependent allosteric antagonism of such inhibitors presents a challenge to achieving efficacy. Small molecule transcriptional suppression may present a solution. Accordingly, using the connectivity map, we have identified quinacine as a PRMT5 transcriptional suppressor capable of suppressing PRMT5 transcription (which is c-jun dependent), mediating MTAP selective loss of viability with commensurate reduction in H4R3me2s, consistent with an on-target effect.
In summary, 9p21-3 loss encompassing CDKN2A and MTAP is one of the most common genomic aberrations in mesothelioma. Novel strategies are emerging with significant translational potential to deliver targeted therapies for mesothelioma.
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ES03.03 - Targeting NF2 in Mesothelioma (Now Available) (ID 3163)
10:30 - 12:00 | Presenting Author(s): Yoshitaka Sekido
- Abstract
- Presentation
Abstract
Malignant mesothelioma (MM), which arises from the pleural or peritoneal cavities, is a very aggressive tumor that is highly refractory to conventional therapies. Several key genetic alterations, including mutations of the CDKN2A/ARF, NF2, and BAP1 tumor-suppressor genes, are associated with the development and progression of MM. Notably, activating oncogene mutations are very rare; thus, it is difficult to develop effective inhibitors to treat MM.
Neurofibromatosis type 2 (NF2) encodes the tumor suppressor protein moesin-ezrin-radixin-like protein (merlin), which is a member of the Band 4.1 family of cytoskeletal linker proteins. NF2-inactivating mutations, deletions, or rearrangements are harbored in 40%–50% of MMs and result in bi-allelic loss of protein function. Somatic NF2 mutations are also frequently detected in sporadic schwannomas, meningiomas, ependymomas, and to a lesser extent, in other types of solid tumors. Merlin/NF2 primarily localizes to the plasma membrane where it mediates contact-dependent inhibition of proliferation in normal cells. Merlin/NF2 has also been shown to regulate multiple cell-signaling cascades including the Hippo pathway.
The Hippo signaling pathway is involved in critical biological processes, including organ size-control, development, differentiation, tissue regeneration (via cell-growth restriction), cell division regulation, apoptosis, and cancer development. The 4 core components in this pathway, MST1/2, SAV1 (also called WW45), MOB1, and LATS1/2, have all been shown to act as tumor suppressors. Since MMs also exhibit genetic or epigenetic inactivation of Hippo pathway components, including MST1/2 and LATS1/2, merlin-Hippo pathway dysregulation is thought to play a key role in MM development and progression.
Hippo pathway inactivation results in inactivation of the LATS1/2 kinases, which, in turn, induces constitutive activation (via underphosphorylation) of YAP1 and TAZ transcriptional coactivators. Underphosphorylation stabilizes YAP1 and TAZ and enables them to enter the nucleus where they bind to distinct transcription factors, including TEAD1-4, and regulate transcription of numerous target genes. We, along with other groups, have shown that constitutive activation of YAP1 and TAZ in vitro and in vivo confer malignant phenotypes in mesothelial cells, whereas their knockdown suppresses these phenotypes. Critical YAP1/TAZ target genes include prooncogenic cyclin D1 (CCDN1), forkhead box M1 (FOXM1), connective tissue growth factor (CTGF), and cytokine-encoding genes such as IL1B, which have also been shown to enhance the malignant phenotypes of MM cells.
Currently, several small molecules have been developed to directly target YAP1/TAZ coactivators, including YAP1-TEAD binding inhibitors. Targeting key YAP1/TAZ-inducible downstream genes, such as IL1B and CTGF, in the dysregulated Hippo pathway may also represent an alternative approach to inhibit MM progression. Furthermore, targeting stimulatory or inhibitory signaling pathways within the Hippo pathway, which include TGF-beta, Wnt, G-protein-coupled receptor (GPCR), mammalian target of rapamycin (mTOR) and mevalonate pathways, may be considered. Collectively, these evidences indicate that the Hippo pathway is a promising therapeutic target for MM treatment, particularly with regard to NF2-Hippo pathway inactivation, and supports the development of new strategies to effectively target YAP1/TAZ activation status as a promising therapeutic modality for this formidable disease.
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ES03.04 - Pegargiminase to Treat Mesothelioma (Now Available) (ID 3164)
10:30 - 12:00 | Presenting Author(s): Peter Szlosarek
- Abstract
- Presentation
Abstract
Treatments based on targeting metabolism remain central to the management of malignant mesothelioma, an intractable malignancy with a median overall survival (OS) of ~12 months. The standard of care since 2003 is an antifolate drug (pemetrexed or raltitrexed) paired with a platinum salt which provides a 2-3 month median survival benefit. Arginine metabolism is dysregulated in mesothelioma with deficiency of the rate limiting enzyme argininosuccinate synthetase 1 (ASS1) three-fold higher in sarcomatoid and biphasic compared to epithelioid tumours. ASS1 inactivation via promoter methylation diverts the precursor aspartate for enhanced pyrimidine synthesis via carbamoyl-phosphate synthetase 2 (CAD), accounting in part for increased tumorigenesis. However, loss of ASS1 generates a collateral dependence on exogenous arginine for growth (auxotrophy) that may be exploited with arginine-degrading enzymes, such as arginine deiminase and arginase.
A randomised phase 2 trial of pegargiminase (ADI-PEG20, pegylated arginine deiminase) monotherapy delivered as a weekly intramuscular (IM) injection (36mg/m2) in patients with ASS1-deficient mesothelioma (ADAM study; NCT01279967) revealed a 1.2 month progression-free survival benefit over best-supportive care (BSC) only (3.2 versus 2.0 months; hazard ratio of 0.56; and p=0.03). The restricted mean survival for OS, calculated due to early survival curve cross-over, was 15.7 months for the pegargiminase group versus 12.1 months for the BSC group, for a difference of 3.6 months (p=0.13). Pegargiminase was well-tolerated with a 13.6% grade 3-4 allergic rate, including anaphylactoid reactions and serum sickness, which were readily reversible and a low frequency of grade 1-2 reactions, mostly local skin irritation and discomfort due to the IM therapy. Pharmacodynamically, pegargiminase suppressed arginine plasma levels (measured on the day of and prior to drug dosing) for 4 weeks before a return to baseline with a reciprocal change in the degradation product, citrulline, a consequence of the production of drug-neutralising antibodies. Partial metabolic responses were documented by FDG-PET in almost 50% of patients by the third week of pegargiminase administration. Thus, while the PFS primary endpoint was modest, the ADAM trial is the first proof of principle study to show a survival benefit using an ASS1 biomarker-directed strategy.
More recent efforts in the arginine deprivation field have focused on rational drug combinations. Preclinically, pegargiminase reduces intracellular thymidine pools via inhibition of enzymes involved in de novo synthesis, specifically thymidylate synthetase and dihydrofolate reductase, and pyrimidine salvage via thymidine kinase 1, collectively enhancing pemetrexed cytotoxicity in arginine-auxotrophic tumour cell lines, including mesothelioma. This was tested in the phase 1 TRAP study (NCT02029690) combining pegargiminase with pemetrexed and cisplatin (ADIPemCis) in patients with ASS1-deficient mesothelioma (n=5) and non-squamous non-small cell lung cancer (NSCLC, n=4). The dose-escalation portion of the study revealed ADIPemCis was safe with a 78% (n=7/9) partial response rate and an overall 100% disease control rate. Moreover, partial responses were seen in biphasic and sarcomatoid mesothelioma considered to be largely chemorefractory. The overall PFS and OS in this small study was 7.5 and 13.9 months, respectively. A dose expansion cohort in mesothelioma at the maximum tolerated dose confirmed a similarly high disease control rate of 93.5% (29/31) and, with two-thirds of patients with non-epithelioid mesothelioma (10 biphasic and 10 sarcomatoid), an overall median PFS of 5.6 and OS of 10.1 months was observed. Although, a small series there was a 3 fold-higher survival at 12 months for patients with sarcomatoid mesothelioma compared with historical controls (30% versus 10% survival). These data supported the opening of a randomised double-blind phase 2/3 trial called ATOMIC-meso and the first to focus on the most aggressive subtypes of mesothelioma that is expected to report initial results by 2020 (NCT02709512).
Mesothelioma therapeutics are at a crossroads with increasing evidence for a key role of immunotherapy in a subset of patients. Objective responses of 10-30% have been reported in several phase 1-2 studies of PD1/PD-L1 antagonists with or without CTLA4 blockade in patients with mesothelioma. Pegargiminase increases PD-L1 expression on mesothelioma cells and leads to an influx of T cells in immunocompetent murine tumour models. Furthermore, urea cycle dysregulated cancers with increased aspartate flux and pyrimidine synthesis are hypothesized to generate genomic signatures more amenable to immune checkpoint blockade. Preliminary results of a phase 1 study of pegargiminase and pembrolizumab reveal activity in arginine auxotrophic cancers with good safety and tolerability (NCT03254732). Similarly, a first-in-man trial of platinum, pemetrexed combined with pegargiminase and atezolizumab (iTRAP study) is planned to start in 2019 focusing on patients with ASS1-deficient non-squamous NSCLC (NCT03498222). Pending these early data, and further ASS1 and PD-L1 biomarker analyses, additional studies are planned in patients with mesothelioma.
Recent preclinical work in our laboratory has revealed that arginine deprivation has a key role in remodulating the tumour microenvironment with an increase in macrophages involved in resistance to pegargiminase. Mesothelioma cells co-cultured with macrophages released several proinflammatory cytokines including IL-1alpha and the CXCR-2 dependent chemokines IL-8, CXCL2 and CXCL8 with a co-ordinate increase in ASS1 and ASL in macrophages and tumour cells, respectively bypassing sensitivity to pegargiminase. Moreover, analysis of blood from the ADAM study revealed an increase in argininosuccinate in the plasma of early metabolic progressors and paired biopsies from the TRAP mesothelioma expansion cohort revealed an influx of macrophages consistent with the preclinical work. Thus, re-education of macrophages with chemokine or “don’t’ eat me” inhibitors may be a viable strategy in mitigating stromal resistance to pegargiminase. Further optimisation of pegargiminase for the treatment of mesothelioma may come from manipulation of additional resistance pathways. Thus, antimalarial agents such as chloroquine inhibit autophagy, a common escape mechanism to nutrient deprivation, and have enhanced the effect of arginine depletion in various ASS1 negative tumour cell lines including mesothelioma. Lastly, synthetic lethal approaches targeting polyamine metabolism in ASS1-negative mesothelioma cells, also merit clinical investigation in combination with pegargiminase and may lead to deeper and more durable metabolic responses.
In summary, bench-to-bedside studies of pegargiminase have progressed to a phase 2/3 trial in mesothelioma. Combinations of pegargiminase with immune checkpoint blockade and modulators of resistance pathways appear promising areas for further development.
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ES03.05 - Inherited Predisposition to Mesothelioma, Biological and Clinical Differences with Sporadic Mesothelioma (Now Available) (ID 3165)
10:30 - 12:00 | Presenting Author(s): Jane E. Churpek
- Abstract
- Presentation
Abstract
Why less than 5% of those exposed to asbestos develop malignant mesothelioma,1 has long fueled the hypothesis that inherited genetic factors may contribute to risk. Studies in erionite exposed households in Turkey suggested that inherited genetic factors cooperate with shared exposures in mesothelioma development.2 In 2011, the discovery of inherited mutations in the gene BAP1 in families clustering multiple cases of mesothelioma3 and demonstration of further proof of causation in a mouse model, showing that mice with one abnormal copy of Bap1 develop mesothelioma more quickly, with lower asbestos doses, and at a higher proportion than wild-type mice4, 5 solidified the role of inherited genetics in mesothelioma risk. Failure to detect inherited BAP1 mutations in a substantial subset of cancer-prone and sporadic mesothelioma cases suggested, however, that BAP1 was not the only gene involved. A strong family history of many types of cancer has also been observed, suggesting that other broad cancer susceptibility genes were involved.6, 7 Recently, our group as well as groups at the NCI and in Italy all published results of targeted panel-based genomic sequencing of three unselected series of mesothelioma cases (Table 1).8-10 We all found a similar overall germline mutation frequency of 10-12%, placing mesothelioma among a growing number of solid tumors, such as metastatic prostate cancer, with mutation frequencies in this range. Clinical predictors of a germline mutation from all three series include: peritoneal compared with pleural disease, younger age, those with a personal history of other cancers, female gender, and lower level of prior asbestos exposure. By gene, BAP1 accounted for the most mutations, but overall more than half of those carrying a germline mutation carried a mutation in a gene other than BAP1. Biologically, most of these genes function predominantly in DNA repair pathways, especially the homologous recombination pathway involved in double strand break repair. These data may explain prior observations of complex cytogenetics and other features of genomic instability in mesothelioma tumors9-11 and could explain platinum sensitivity, a chemotherapy drug known to have increased efficacy in solid tumors, such as ovarian cancer, in those with germline mutations in genes in the same pathway. To investigate this possibility, we combined our data with data from the NCI series and together, our groups found that a germline mutation in any DNA repair gene was associated with improved OS after platinum based chemotherapy and that this effect was independent of age at diagnosis and gender, two key known prognostic factors.9 Interestingly, this effect was only present in those with pleural disease, in whom mutation carriers had a median OS of 7.9 vs 2.4 years in non-mutation carriers (p=0.0012). Further, among germline mutation carriers, OS for those with pleural or peritoneal disease was similar suggesting a similar biology is a more important predictor of OS than site in those cases. These data support the investigation of other DNA repair based therapies, such as PARP inhibitors, in patients with mesothelioma, especially among those with a relevant germline mutation. Further investigation of the full spectrum of inherited risk factors in mesothelioma, their interaction with response to various therapies, as well as how patterns of acquired mutations in mesothelioma tumors differ by germline mutation status and whether those without a germline mutation but whose tumors acquire similar gene mutations respond to similar therapies are all yet to be determined.
REFERENCES
1. Carbone M, Kratzke RA, Testa JR. The pathogenesis of mesothelioma. Semin Oncol. 2002;29: 2-17.
2. Roushdy-Hammady I, Siegel J, Emri S, Testa JR, Carbone M. Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey. Lancet. 2001;357: 444-445.
3. Testa JR, Cheung M, Pei J, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43: 1022-1025.
4. Xu J, Kadariya Y, Cheung M, et al. Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma. Cancer Res. 2014;74: 4388-4397.
5. Napolitano A, Pellegrini L, Dey A, et al. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene. 2016;35: 1996-2002.
6. Ugolini D, Neri M, Ceppi M, et al. Genetic susceptibility to malignant mesothelioma and exposure to asbestos: the influence of the familial factor. Mutat Res. 2008;658: 162-171.
7. Ohar JA, Cheung M, Talarchek J, et al. Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer. Cancer Res. 2016;76: 206-215.
8. Betti M, Casalone E, Ferrante D, et al. Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma. Cancer Lett. 2017;405: 38-45.
9. Hassan R, Morrow B, Thomas A, et al. Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy. Proc Natl Acad Sci U S A. 2019;116: 9008-9013.
10. Panou V, Gadiraju M, Wolin A, et al. Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma. J Clin Oncol. 2018;36: 2863-2871.
11. Betti M, Aspesi A, Ferrante D, et al. Sensitivity to asbestos is increased in patients with mesothelioma and pathogenic germline variants in BAP1 or other DNA repair genes. Genes Chromosomes Cancer. 2018;57: 573-583.
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Author of
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SH01 - Highlight of the Previous Day (ID 98)
- Event: WCLC 2019
- Type: Highlight of the Previous Day Session
- Track:
- Presentations: 1
- Now Available
- Moderators:Isabelle Opitz, Ritsuko Komaki-Cox
- Coordinates: 9/09/2019, 11:00 - 12:30, San Francisco (2009)
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SH01.05 - Mesothelioma (Now Available) (ID 3662)
11:00 - 12:30 | Presenting Author(s): Michele Carbone
- Abstract
- Presentation
Abstract not provided
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