Molenaar J.J.: Targeted drug development in neuroblastoma

  • Eleveld, Thomas (Internal PhD candidate)
  • Hakkert, A (Internal PhD candidate)
  • Dolman, M (PostDoc)
  • Schild, Linda (Other)

Project Details

Description

Target validation in cell cycle and apoptosis signalling:
We are performing end stage development for several targeted cell cycle and apoptosis intervention compounds. CDK2 inhibiting small molecules, BCL2 inhibitors and BIRC5 inhibiting compounds have been identified as effective inhibitors of tumor growth in neuroblastoma in vitro and in vivo. Clinical implementation in phase 1/2 trials is currently considered in collaboration with the developing pharmaceutical companies. In parallel the identification and validation of selection biomarkers and biomarkers for efficacy are performed for these compounds. Extensive preclinical pharmacokinetics and pharmacodynamics should facilitate the clinical implementation.

Validation of new drugged target genes:
Several new tumor driving events have been identified in primary neuroblastoma. LIN28B signalling, Forhead box transcription factors, neuritogenesis regulating processes and the DNA damage response are all showing aberrations in neuroblastoma tumors and cell lines. These signalling cascades are currently validated in neuroblastoma model systems and potential interventions are studied in our targeted drug development pipeline.

Neuroblastoma tumor evolution:
Initial treatment can effectively induce complete remission but about 80% of high risk neuroblastoma relapse after which no curative treatment is available. The mechanism of this tumor evolution leading to therapy resistance is largely unknown. We hypothesize that prevention of tumor evolution and subsequent chemo resistance would yield a large therapeutic benefit. A series of primary neuroblastoma tumors and corresponding relapse samples are currently studied for events involved in tumor evolution. In addition chemoresistant neuroblastoma cell lines are generated and studied for additional genomic events that drive tumor evolution. Genes involved in tumor evolution are further validated in the targeted drug development pipeline.
StatusActive
Effective start/end date1/07/2012 → …