- Targeted therapy for pediatric glioma
L.J. van 't Veer
- Award date
- 25 November 2015
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
This thesis assesses molecular underpinnings of responses to promising targeted agents for pediatric tumors of Central Nervous System (CNS), incorporating preclinical testing of novel and translatable combination therapies to define the best therapy for each tumor cell specific molecular aberration. It addresses how to best target dysregulated components of signaling pathways in pediatric cancers, to prevent innate resistance, block emergent resistance and promote cooperative anti-neoplastic activity. As such, it aims to fill a critical unmet need for a pediatric patient population with few therapeutic alternatives, and change paradigms for pediatric gliomas treatment by incorporating personalized approaches.
The thesis is divided into three main areas of interest: (1) high-throughput exploration of human kinome in the context of malignant diseases; (2) preclinical investigation of targeted approaches for BRAF mutated carcinomas; and (3) combinatorial kinase inhibition strategies incorporating radiation therapy in pediatric CNS cancers. The latter part includes development of clinical protocol for DNA-damage and cell cycle arrest biomarker testing in patient blood samples.
Results obtained from the published work within this thesis have been pivotal in informing ongoing clinical trials, including combinatorial Wee1 with Radiation strategy for Diffuse Intrinsic Pediatric Gliomas (clinicaltrials.gov: NCT01922076), a study of Everolimus for recurrent Pediatric Low-Grade Gliomas (NCT01734512) and Vemurafenib for recurrent BRAFV600E-mutated Pediatric Gliomas (NCT01748149). The biomarker protocol developed as a part of the doctoral research and described in the thesis is currently implemented in numerous pediatric CNS cancer clinical studies spearheaded by the University of California, San Francisco.
- Research conducted at: Universiteit van Amsterdam