Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways

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Abstract

Background

Regorafenib is an inhibitor of multiple kinases with aberrant expression and activity in neuroblastoma tumours that have potential roles in neuroblastoma pathogenesis.

Methods

We evaluated neuroblastoma cells treated with regorafenib for cell viability and confluence, and analysed treated cells for apoptosis and cell cycle progression. We evaluated the efficacy of regorafenib in vivo using an orthotopic xenograft model. We evaluated regorafenib-mediated inhibition of kinase targets and performed reverse-phase protein array (RPPA) analysis of neuroblastoma cells treated with regorafenib. Lastly, we evaluated the efficacy and effects of the combination of regorafenib and 13- cis-retinoic acid on intracellular signalling.

Results

Regorafenib treatment resulted in reduced neuroblastoma cell viability and confluence, with both induction of apoptosis and of cell cycle arrest. Regorafenib treatment inhibits known receptor tyrosine kinase targets RET and PDGFRβ and intracellular signalling through the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Regorafenib is effective against neuroblastoma tumours in vivo, and the combination of regorafenib and 13- cis-retinoic acid demonstrates enhanced efficacy compared with regorafenib alone.

Conclusions

The effects of regorafenib on multiple intracellular signalling pathways and the potential additional efficacy when combined with 13- cis-retinoic acid represent opportunities to develop treatment regimens incorporating regorafenib for children with neuroblastoma.

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Most cited references 70

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Neuroblastoma.

Katherine K Matthay, John M. Maris, Gudrun Schleiermacher … (2017)

Neuroblastoma is the most common extracranial solid tumour occurring in childhood and has a diverse clinical presentation and course depending on the tumour biology. Unique features of these neuroendocrine tumours are the early age of onset, the high frequency of metastatic disease at diagnosis and the tendency for spontaneous regression of tumours in infancy. The most malignant tumours have amplification of the MYCN oncogene (encoding a transcription factor), which is usually associated with poor survival, even in localized disease. Although transgenic mouse models have shown that MYCN overexpression can be a tumour-initiating factor, many other cooperating genes and tumour suppressor genes are still under investigation and might also have a role in tumour development. Segmental chromosome alterations are frequent in neuroblastoma and are associated with worse outcome. The rare familial neuroblastomas are usually associated with germline mutations in ALK, which is mutated in 10-15% of primary tumours, and provides a potential therapeutic target. Risk-stratified therapy has facilitated the reduction of therapy for children with low-risk and intermediate-risk disease. Advances in therapy for patients with high-risk disease include intensive induction chemotherapy and myeloablative chemotherapy, followed by the treatment of minimal residual disease using differentiation therapy and immunotherapy; these have improved 5-year overall survival to 50%. Currently, new approaches targeting the noradrenaline transporter, genetic pathways and the tumour microenvironment hold promise for further improvements in survival and long-term quality of life.

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Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study.

Katherine K Matthay, C Patrick Reynolds, Robert C. Seeger … (2009)

PURPOSE We assessed the long-term outcome of patients enrolled on CCG-3891, a high-risk neuroblastoma study in which patients were randomly assigned to undergo autologous purged bone marrow transplantation (ABMT) or to receive chemotherapy, and subsequent treatment with 13-cis-retinoic acid (cis-RA). PATIENTS AND METHODS Patients received the same induction chemotherapy, with random assignment (N = 379) to consolidation with myeloablative chemotherapy, total-body irradiation, and ABMT versus three cycles of intensive chemotherapy. Patients who completed consolidation without disease progression were randomly assigned to receive no further therapy or cis-RA for 6 months. Results The event-free survival (EFS) for patients randomly assigned to ABMT was significantly higher than those randomly assigned to chemotherapy; the 5-year EFS (mean +/- SE) was 30% +/- 4% versus 19% +/- 3%, respectively (P = .04). The 5-year EFS (42% +/- 5% v 31% +/- 5%) from the time of second random assignment was higher for cis-RA than for no further therapy, though it was not significant. Overall survival (OS) was significantly higher for each random assignment by a test of the log(-log(.)) transformation of the survival estimates at 5 years (P < .01). The 5-year OS from the second random assignment of patients who underwent both random assignments and who were assigned to ABMT/cis-RA was 59% +/- 8%; for ABMT/no cis-RA, it was 41% +/- 8% [corrected]; for continuing chemotherapy/cis-RA, it was 38% +/- 7%; and for chemotherapy/no cis-RA, it was 36% +/- 7%. Myeloablative therapy and autologous hematopoietic cell rescue result in significantly better 5-year EFS than nonmyeloablative chemo therapy; neither myeloablative therapy with [corrected] autologous hematopoietic cell rescue nor cis-RA given after consolidation therapy significantly improved OS.

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The genetic landscape of high-risk neuroblastoma

Trevor J Pugh, Olena Morozova, Edward F. Attiyeh … (2013)

Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50% 1 . To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 cases using a combination of whole exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per megabase (0.48 non-silent), and remarkably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, an additional 7.1% had focal deletions), MYCN (1.7%, a recurrent p.Pro44Leu alteration), and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1, and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies reliant upon frequently altered oncogenic drivers.

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Author and article information

Contributors

Peter E. Zage: pzage@ucsd.edu

Journal

Journal ID (nlm-ta): Br J Cancer

Journal ID (iso-abbrev): Br J Cancer

Title: British Journal of Cancer

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 0007-0920

ISSN (Electronic): 1532-1827

Publication date (Electronic): 27 May 2020

Publication date (Print): 18 August 2020

Volume: 123

Issue: 4

Pages: 568-579

Affiliations

[1 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, Department of Pediatrics, Division of Hematology-Oncology, , University of California San Diego, ; La Jolla, CA USA

[2 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, Department of Family Medicine and Public Health, , University of California San Diego, ; La Jolla, CA USA

[3 ]GRID grid.39382.33, ISNI 0000 0001 2160 926X, Department of Medicine, Dan L. Duncan Cancer Center, , Baylor College of Medicine, ; Houston, TX USA

[4 ]GRID grid.286440.c, ISNI 0000 0004 0383 2910, Peckham Center for Cancer and Blood Disorders, , Rady Children’s Hospital, ; San Diego, CA USA

[5 ]GRID grid.468198.a, ISNI 0000 0000 9891 5233, Present Address: Department of Biostatistics & Bioinformatics, , H. Lee Moffitt Cancer Center & Research Institute, ; 12902 Magnolia Drive, Tampa, FL 33612 USA

Article

Publisher ID: 905

DOI: 10.1038/s41416-020-0905-8

PMC ID: 7434894

PubMed ID: 32457362

SO-VID: 9b0a862b-8edb-4bf9-b233-fae2fe0128c5

License:

Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

History

Date received : 25 September 2019

Date revision received : 26 March 2020

Date accepted : 29 April 2020

Funding

Funded by: Bayer Pharma, AG

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: paediatric cancer,targeted therapies

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: paediatric cancer, targeted therapies

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Regorafenib is effective against neuroblastoma in vitro and in vivo and inhibits the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways

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Abstract

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Methods

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Conclusions

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Karger: Oncology

Most cited references 70

Neuroblastoma.

Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study.

The genetic landscape of high-risk neuroblastoma

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