Title:In Vitro Sensitivity Profiling of Neuroblastoma Cells Against A Comprehensive Small Molecule Kinase Inhibitor Library to Identify Agents for Future Therapeutic Studies
Volume: 17
Issue: 6
Author(s): Anjali Singh, Vanessa Meier-Stephenson, Aarthi Jayanthan and Aru Narendran*
Affiliation:
- Departments of Pediatrics and Oncology, University of Calgary and Alberta Children's Hospital, Calgary, Alberta,Canada
Keywords:
Neuroblastoma, small molecule kinase inhibitors, IGF-1 Receptor, Bcr-Abl, Src, Ponatinib.
Abstract: Background: Neuroblastoma (NB) constitutes about 8% of all childhood tumors, yet accounts
for more than 15% of deaths, with an unacceptable overall survival rate. These rates are despite
the current multimodal therapeutic approaches involving surgery, radiation, chemotherapy and myeloablation
with hematopoietic stem cell rescue. Hence, efforts have intensified to identify new targets and
novel therapeutic approaches to improve cure rates in these children. Numerous new agents for adult
malignancies are developed and evaluated for cancer each year, providing an invaluable resource, with
the added advantage of available pharmacologic and toxicity data for consideration.
Methods: To identify potential therapeutic targets, we screened a small molecule library of 151
small kinase inhibitors against NB cell lines. Based on our initial screening data, we further examined
the potential of Bcr-Abl targeting small molecule inhibitors to affect the growth and survival of
NB cells.
Results: There is diverse activity among the currently available Bcr-Abl inhibitors, possibly reflecting
the molecular heterogeneity and off-target activity in each combination. In depth analyses of ponatinib,
an oral multi-target kinase inhibitor and effective agent in the treatment of refractory Philadelphia
chromosome (Ph) positive leukemia, show growth inhibition at sub-micromolar concentrations.
In addition, we also identified the potential of this agent to interfere with insulin-like growth
factor-1 receptor (IGF-1R) signaling pathways and Src activity, inhibit cell migration and induce
apoptosis.
Conclusion: Our findings provide initial data on ponatinib’s potential to target key growth regulatory
pathways and provide the rationale for further studies and evaluation in future early phase clinical
trials for the treatment of refractory NB.
