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EBioMedicine. 2018 Dec 20. pii: S2352-3964(18)30602-9. doi: 10.1016/j.ebiom.2018.12.025. [Epub ahead of print]

Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma.

Author information

1
Department of Pediatric Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands; Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands.
2
Department of Pediatric Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands; Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands.
3
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands.
4
Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Italy; CNR-Nano, Institute of Nanoscience and Nanotechnology, Pisa, Italy.
5
Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS - National Cancer Institute, Milano, Italy.
6
Department of Neurosurgery, Neuro-Oncology Research Group, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands.
7
H3 Biomedicine, Inc., 300 Technology Square, FL 5, Cambridge, MA 02139, USA.
8
Peritoneal Malignancy Program, National Cancer Institute, Milano, Italy.
9
Department of Radiology & Nuclear Medicine, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands.
10
Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands.
11
Princes Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.
12
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, location VUMC, Amsterdam, the Netherlands; Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Italy; CNR-Nano, Institute of Nanoscience and Nanotechnology, Pisa, Italy. Electronic address: elisa.giovannetti@gmail.com.

Abstract

INTRODUCTION:

Therapeutic options for diffuse malignant peritoneal mesothelioma (DMPM) are limited to surgery and locoregional chemotherapy. Despite improvements in survival rates, patients eventually succumb to disease progression. We investigated splicing deregulation both as molecular prognostic factor and potential novel target in DMPM, while we tested modulators of SF3b complex for antitumor activity.

METHODS:

Tissue-microarrays of 64 DMPM specimens were subjected to immunohistochemical assessment of SF3B1 expression and correlation to clinical outcome. Two primary cell cultures were used for gene expression profiling and in vitro screening of SF3b modulators. Drug-induced splicing alterations affecting downstream cellular pathways were detected through RNA sequencing. Ultimately, we established bioluminescent orthotopic mouse models to test the efficacy of splicing modulation in vivo.

RESULTS:

Spliceosomal genes are differentially upregulated in DMPM cells compared to normal tissues and high expression of SF3B1 correlated with poor clinical outcome in univariate and multivariate analysis. SF3b modulators (Pladienolide-B, E7107, Meayamycin-B) showed potent cytotoxic activity in vitro with IC50 values in the low nanomolar range. Differential splicing analysis of Pladienolide-B-treated cells revealed abundant alterations of transcripts involved in cell cycle, apoptosis and other oncogenic pathways. This was validated by RT-PCR and functional assays. E7107 demonstrated remarkable in vivo antitumor efficacy, with significant improvement of survival rates compared to vehicle-treated controls.

CONCLUSIONS:

SF3B1 emerged as a novel potential prognostic factor in DMPM. Splicing modulators markedly impair cancer cell viability, resulting also in potent antitumor activity in vivo. Our data designate splicing as a promising therapeutic target in DMPM.

KEYWORDS:

Mesothelioma; RNA-sequencing; SF3b modulation; Splicing; Therapy

PMID:
30581150
DOI:
10.1016/j.ebiom.2018.12.025
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