Integration Of A Personalized Molecular Targeted Therapy Into The Multimodal Treatment Of Refractory Early Childhood Spnet

Background: Supratentorial primitive neuroectodermal tumors (sPNET) are highly-malignant and rare brain tumors that primarily affect young children. Despite multimodal treatment that includes surgery, radiotherapy and chemotherapy, less than half of affected patients will survive 5 years post-diagnosis. Moreover, neurocognitive impairment associated with current treatment protocols is a significant complication in survivors. Therefore, new molecular targeted therapies that are effective and less toxic are needed to further improve outcomes in sPNET patients. Tyrosine kinase inhibitors (TKI) have emerged as an important class of molecular targeted anti-cancer agents with demonstrated clinical efficacy and generally favorable toxicity profiles. Dasatinib, an orally-administered TKI that is FDA approved for Ph+ CML/ALL, has been reported in off-label use for cancers of the head and neck, breast, colon, prostate and lung. Dasatinib targets multiple tyrosine kinases that are involved in numerous cancers, including ABL, SRC family tyrosine kinases (SFKs), and receptor tyrosine kinases c-KIT and PDGFR. Notably, SFKs have been implicated in driving the development and progression of numerous solid tumors, including PNET and medulloblastoma. Methods: Here we report the successful use of dasatinib with informed consent in multimodal treatment of a 32 month old, ex-29 week twin B female patient. She was diagnosed with sPNET that demonstrated high tumor SFK-activity, had progressed on standard chemotherapy, and for whom irradiation was avoided due to the unwanted side effects of radiation on the developing brain. Multiplex kinase-activity profiling, and electron microscopy analysis was performed on pre- and post-dasatinib treatment tumor tissue after partial resections. Additionally, pre-and post-treatment MRI was done to quantitate the clinical response with dasatinib. Results: Ex vivo multiplex analysis revealed aberrant activation of SFKs SRC, LYN and FYN in the sPNET tumor, which was shown to be significantly reduced following dasatinib therapy. In addition, blockade of SFK activity with dasatinib correlated with greatly reduced activation of downstream proliferative transcription factors STAT1 and STAT3. Electron microscopy analysis of the tumor upon surgical resection revealed phenotypic changes with significant presence of autophagocytic vacuoles, indicative of cellular sequestration, and increased prominence of nuclear heterochromatin. Dasatinib therapy over a 4-month period was very well-tolerated by the patient and resulted in significant tumor reduction as determined by radiographic detection. Conclusions: We have demonstrated how tyrosine kinase activity-based tumor profiling can be utilized to devise a successful personalized molecular targeted multimodal treatment strategy in a patient for whom standard therapy had failed. Dasatinib was clinically and molecularly effective in the treatment of a progressive refractory sPNET displaying high-SFK activity. These results could aid future patient stratification schemes that direct targeted therapies based upon an aberrant molecular pathway strategy, therefore larger clinical studies using this approach are warranted. Citation Format: Lisa LR Hartman, Diba Farah, Arlynn F. Mulne, Bruce B. Storrs, Harry L. Wilson, Staci Bryson, Derrick M. Oaxaca, Robert A. Kirken, Jeremy A. Ross. Integration of a personalized molecular targeted therapy into the multimodal treatment of refractory early childhood sPNET. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B73.