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Dean Anthony Fennell
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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: 1
- Now Available
- Moderators:Michele Carbone, Miyako Satouchi
- Coordinates: 9/08/2019, 10:30 - 12:00, Tokyo (1982)
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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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P2.06 - Mesothelioma (ID 170)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.06-02 - Mesothelioma Stratified Therapy (MiST): A Phase IIA Umbrella Trial for Accelerating the Development of Precision Medicines (ID 2465)
10:15 - 18:15 | Presenting Author(s): Dean Anthony Fennell
- Abstract
Background
There are currently no approved therapies for the treatment of relapsed mesothelioma. Recent advances in our understanding of inter-patient genomic heterogeneity, identification of potential drivers, and application of high throughput -omic technologies to clinical trial samples , has created opportunities to explore novel treatments in prospectively biomarker-enriched cohorts.
Method
MiST is a British Lung Foundation funded, University of Leicester sponsored multicentre national clinical trial. Patients (Pts) harbouring either pleural (any histological subtype) or peritoneal mesothelioma are eligible. Pts must have ECOG performance status 1 or 0, received prior standard chemotherapy and progressed from their last treatment (in any line). The study is designed in three stages. Stage 1 comprises prospective molecular profiling of the tumour suppressors BAP1, BRCA1, p16ink4A and the immune checkpoint inhibitor PDL1 (22C3), using automated immunohistochemistry. Stage 2: Patients meeting eligibility criteria are presently stratified into Arm 1: Rucaparib (PARP inhibitor) for BAP1 inactivated (cytoplasmic or loss of expression) /BRCA1 negative mesothelioma. Arm 2: Abemaciclib (CDK4/6 inhibitor) for p16ink4a negative tumour, Arm 3, Pembrolizumab (anti-PD1) and Bemcentinib (AXL) to patients without biomarker specification. Arm 4, Atezolizumab (anti-PDL1) and Avastin (anti-VEGF) for PDL1 positive MM. Further arms are in development. The primary endpoint is 12 week disease control (12wDCR), with the secondary endpoints, 24wDCR, response rate (modified RECIST1.1) and safety/tolerability. 12wDCR>50% will be considered worthy of further investigation. Stage 3: Genome wide somatic copy number analysis and transcriptomic analysis with in-silico deconvolution of immune cell infiltrates will be used to refine molecular correlates of response. Gut microbiome 16RNA sequencing will be conducted in arms 3 and 4. Patients exhibiting a response to treatment who then progress, will be re-biopsied to facilitate molecular interrogation of acquired resistance mechanisms. MiST is coupled to our laboratory functional genomics programme, aimed at exploring co-clinical trial models, to robustly define or validate mechanisms that underpin drug responses.
Result
Section not applicable
Conclusion
In summary, MiST is a new clinical research platform that will support proof-of-concept studies capable of testing biomarker enrichment/efficacy hypotheses, with the aim of advancing personalised therapy for mesothelioma.
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P2.06-11 - MEDUSA: Phylogenetic Analysis of Mesothelioma Tumours by Multiregional Sampling, Whole Exome Sequencing, and Copy Number Analysis (ID 921)
10:15 - 18:15 | Author(s): Dean Anthony Fennell
- Abstract
Background
The Mesothelioma evolution: Drugging somatic alterations (MEDUSA) project aims to investigate the genomic evolution and heterogeneity of malignant pleural mesothelioma and identify genomic changes early in mesothelioma evolution that can be targeted by drugs. For 20 malignant pleural mesothelioma patients, we have analysed the exomes of at least four regions of the tumour and paired whole blood.
Method
Using paired tumour-normal analysis with the software Sequenza, we have called copy number alterations specific to the tumour, and used the software Tumult to reconstruct a phylogeny of the tumour for each of the 20 patients.
Result
We show that mesothelioma shows extensive heterogeneity in copy number changes, and accumulates typically between 100-200 copy number gains and losses while evolving in a branching pattern. We identify and validate copy number alterations that occur truncally, early in the evolution of the tumour, and are recurrent across patients, including homozygous loss of CDKN2A and MTAP in 4/20 patients, heterozygous loss of MTOR in 6/20 patients and heterozygous loss of BAP1 in 4/20 patients. Losses of these key genes are observed in some other patients, but only in a subset of regions, suggesting that they have occurred later in the evolution of the tumour compared to truncal changes.
Conclusion
As truncal changes are likely to be present throughout the tumour, identifying them highlights potential Achilles’ heels for drug targeting and treatment.
