BCL-2 targeting combination therapies for neuroblastoma

Lindy Vernooij

Research output: ThesisDoctoral thesis 2 (Research NOT UU / Graduation UU)

Abstract

High-risk neuroblastoma remains one of the most challenging pediatric cancers to treat, with survival rates below 50% and an even poorer prognosis for relapsed patients. Current treatment strategies heavily rely on chemotherapy, often causing severe side effects by targeting both cancerous and healthy cells. Precision medicine, which tailors therapies to the molecular characteristics of each tumor, offers a more personalized therapeutic approach that enables effective targeting of cancer cells while potentially reducing side effects. This thesis focuses on identifying targeted combination therapies for neuroblastoma patients with high BCL-2 expression. Venetoclax, a selective BCL-2 inhibitor, has shown promise in preclinical studies, but its effectiveness is limited by the development of therapy resistance. In the first part of this work, strategies to prevent or overcome venetoclax resistance were explored. Combining venetoclax with the MDM2 inhibitor idasanutlin was found to resensitize venetoclax-resistant cells, providing support for the clinical development of this combination. Additionally, MCL-1 inhibitors were shown to enhance the effectiveness of venetoclax by preventing therapy-induced resistance. In the second part of this thesis, we investigated targeted combination therapies for patients with high BCL-2 expression alongside mutations in the RAS-MAPK pathway or ALK. Combining venetoclax with the MEK inhibitor trametinib or the ALK inhibitor lorlatinib resulted in tumor regression across multiple preclinical models, suggesting that these are promising therapeutic strategies for these subgroups of neuroblastoma patients. In conclusion, the findings presented in this thesis highlight the potential of targeted combination therapies to improve treatment outcomes in high-risk neuroblastoma.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Utrecht University
Supervisors/Advisors
  • Molenaar, Jan, Supervisor
  • Dolman, Emmy, Co-supervisor, External person
Award date22 Oct 2024
Place of PublicationUtrecht
Publisher
Print ISBNs978-94-6506-434-5
DOIs
Publication statusPublished - 22 Oct 2024

Keywords

  • neuroblastoma
  • targeted therapy
  • combination therapy
  • precision medicine
  • BCL-2
  • venetoclax
  • MDM2 inhibitor idasanutlin
  • MCL-1 inhibitors
  • MEK inhibitor trametinib
  • ALK inhibitor lorlatinib

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