Preclinical investigation of novel therapies against neuroblastoma

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Neuroblastoma is a childhood tumor of the sympathetic nervous system and the most common tumor form diagnosed in infants. Patients with aggressive tumors are treated intensely with multi-modal therapy including chemotherapy, surgery, radiotherapy and immunotherapy. Despite this, many children suffer from incurable relapses and long-term side effects are common. Novel treatments are thus necessary for these patients. The aim of this thesis was to identify and test novel therapies against neuroblastoma. For this work, I have used patient-derived xenograft mouse models and neuroblastoma cells grown as 3D tumor organoids.

In paper I, we identified and tested novel inhibitors targeting the PIM, PI3K, and mTOR pathways. The inhibitors demonstrated promising effects in vitro with reduced viability, increased differentiation and cell death of neuroblastoma cells. Combinatory treatment of the inhibitors with chemotherapeutic agent cisplatin showed synergistic effects. In vivo, combination treatment resulted in slower tumor growth and increased survival of neuroblastoma PDX models.

In paper II, we performed a high-throughput drug screen to identify drugs that target neuroblastoma. We identified several drugs with previously unknown activity in neuroblastoma, among them the KSP inhibitor ARRY-520. Analysis of KSP expression across multiple tumor types demonstrated that neuroblastoma is highly dependent on this protein. Treatment of neuroblastoma PDX cells with ARRY-520 resulted in mitotic arrest and subsequent cell death. KSP inhibition caused tumor regression in vivo and resulted in increased survival of multiple PDX models.

In paper III, we investigated the effects of inhibitor rigosertib against neuroblastoma. Rigosertib reduced cell viability of neuroblastoma cells and caused cell cycle arrest in the G2/M phase. In vivo, rigosertib treatment resulted in decreased tumor growth and increased survival of PDX mice.

In paper IV, we performed a high-throughput combination drug screen with the aim of finding drugs that work synergistically with KSP inhibition. Using in silico synergy prediction tools, we identified drugs with synergistic activity against neuroblastoma. Our results suggest that Ras pathway inhibitors in combination with KSP inhibition represent a promising treatment strategy against neuroblastoma.

In summary, we identified and tested drugs which represent novel therapeutic opportunities against children with high-risk neuroblastoma.

Details

Authors
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • Cancer, Neuroblastoma, Translational research, Preclinical drug evaluation
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2020 Dec 4
Place of PublicationLund
Publisher
  • Lund University, Faculty of Medicine
Print ISBNs978-91-7619-992-3
Publication statusPublished - 2020
Publication categoryResearch

Bibliographic note

Defence details Date: 2020-12-04 Time: 09:00 Place: Hörsalen Medicon Village, Scheleevägen 2, Byggnad 302, Lund External reviewer(s) Name: Swartling, Fredrik Title: associate professor Affiliation: Uppsala University

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Research output: Contribution to journalArticle

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