Abstract B01: Sustained clinical response to treatment directed by genomic expression profiling suggests mTOR signaling is an effective target in choroid plexus carcinoma

Background: Choroid plexus tumors comprise 10-20% of intracranial tumors in children less than one year of age, the majority of these are benign papillomas, however some are highly aggressive carcinomas. Choroid Plexus Carcinoma (CPC) is derived from the choroid plexus which is neuroepithelial tissue that normally produces CSF and lines the intracranial ventricles. The prognosis of choroid plexus carcinomas is poor with 5 year event free survival rates varying between 10%-50% while relapsed or metastatic CPC is usually fatal. A patient with relapsed CPC who had progressed on 5 previous salvage chemotherapy combinations was enrolled on Neuroblastoma Medulloblastoma Translational Research Consortium (NMTRC) Molecular-Guided Therapy Trial for the Treatment of Patients with Relapsed or Refractory Childhood Cancer in which we performed genomic profiling allowing a targeted approach to therapeutic decision making. Methodology: The patient with multiply relapsed metastatic CPC enrolled on NMTRC Molecular Guided Therapy Clinical Trial after obtaining written informed consent. A tumor biopsy was sent to the Clinical Reference Laboratory (CRL) for mRNA expression analysis using U133 2.0 Plus GeneChip, and to Translational Genomics Research Institute (TGen) for high-performance RNA-seq analysis and DNA exome analysis. The differential expression data was interpreted in the context of systems biology annotation. Analysis of RNA expression results were discussed in a NMTRC tumor board leading to a therapeutic plan using study targeted treatments. Patient response was determined by clinical examination with serial MRI of the brain. Results: In this CPC specimen the PI3K/Akt/mTOR pathway was found to be highly expressed as well as PDGF, FGF2 and HDAC3 which were chosen by the tumor board for targeted therapy. Exomes analysis confirms mutation in RPTOR involved in mTOR activation. Treatment with sirolimus (mTOR), thalidomide (FGF2), Sunitinib (PDGF), and vorinostat (HDAC3) resulted in a 68% tumor reduction and the patient maintains a continuous response after 11 months while continuing to receive this therapy. This treatment combination has been well tolerated with no serious adverse events and excellent quality of life. Conclusion: Genomic Profiling analyses revealed activation of the mTOR pathway in this chemo-resistant Choroid Plexus Carcinoma. Targeted therapy has demonstrated clinical benefit suggesting a novel therapeutic approach. Further investigation of the mTOR pathway as a therapeutic target in CPC warranted. Citation Format: Albert S. Cornelius, Jessica Foley, Deanna Mitchell, Abhinav Nagulapally, Jeff Bond, Matthew Huntelman, Jason Corneveaux, Jeff Trent, Giselle Sholler. Sustained clinical response to treatment directed by genomic expression profiling suggests mTOR signaling is an effective target in choroid plexus carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B01.