Ariad Pharmaceuticals Inc fka ARIA

[LUMA14]

In Vitro Sensitivity Profiling Of Neuroblastoma Cells Against A Comprehensive Small Molecule Kinase Inhibitor Library To Identify Agents For Future Therapeutic Studies.

link to abstract

Abstract
Solid tumors represent one of the most widespread causes of death in children across the world. Neuroblastoma (NB) constitutes about 8% of all childhood tumors, yet accounts for more than 15% of death, with an unacceptable overall survival rate. Despite the current multimodal therapeutic approaches involving surgery, radiation, chemotherapy with myeloablative therapy and hematopoietic stem cell rescue, there is growing realization of the limitations of conventional agents to improve the outcome in high risk metastatic disease. Hence, efforts have intensified to identify new targets and novel therapeutic approaches to improve cure rates in these children.
Among the significant number of new therapeutics that are being evaluated for cancer each year, the agents that have been developed for common adult malignancies have the added advantage of having usable toxicity data already available for consideration.
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.
Our findings confirm the diversity in 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 orally bioavailable multi-target kinase inhibitor and an 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.
Ponatinib also induced apoptosis, indicated by caspase-9 and PARP cleavage. Furthermore, at sub-lethal conditions ponatinib significantly inhibited the ability of these cells to migrate.
Our findings provide initial data on the potential of ponatinib to target key growth regulatory pathways and provide the rationale for further studies and its evaluation in future early phase clinical trials for the treatment of refractory NB.