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Orthotopic Implantation and Peripheral Immune Cell Monitoring in the II-45 Syngeneic Rat Mesothelioma Model
Published on: October 2, 2015
Integrated genomics point to immune vulnerabilities in pleural mesothelioma
Anca Nastase1, Amit Mandal1, Shir Kiong Lu1
1National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, SW36LY, UK.
Abstract:
Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.
Insights
New research identifies key genetic alterations in pleural mesothelioma, revealing potential therapeutic targets like SUFU deletions and RB1 mutations. These findings offer promising new avenues for treating this aggressive cancer.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Pleural mesothelioma is an aggressive cancer with limited treatment options.
- Identifying novel therapeutic targets is crucial for improving patient outcomes.
Purpose of the Study:
- To integrate multi-omics data (SNP genotyping, sequencing, transcriptomics) from tumors and patient-derived cells to discover therapeutic targets in pleural mesothelioma.
- To identify genetic alterations and their downstream effects on cellular pathways.
Main Methods:
- Integrated analysis of SNP genotyping, whole-exome sequencing, and RNA sequencing data.
- Utilized patient-derived cell models for functional studies.
- Investigated genetic alterations in SUFU, RB1, CDKN2A, and Hippo pathway components.
Main Results:
- Identified previously unrecognized deletions in SUFU (21% of tumors), impacting Hedgehog and T-cell synapse pathways (e.g., VISTA).
- Found co-deletion of Interferon Type I genes and CDKN2A in 50% of tumors, predicting poor survival.
- Detected RB1 deletions (26% of cases) and demonstrated sensitivity to PLK1, CHEK1, and Aurora Kinase inhibitors.
- Observed Hippo pathway defects (RASSF7 amplification, NF2/LATS1/2 mutations) in 50% of tumors, with sensitivity to YAP1 inhibitor Verteporfin.
Conclusions:
- Discovered novel genetic vulnerabilities in pleural mesothelioma, including SUFU and RB1 deletions.
- Highlighted the potential of targeting Hedgehog, T-cell synapse, and Hippo pathways for mesothelioma treatment.
- Identified specific genetic alterations as potential biomarkers for immunotherapy and targeted therapies.
