Targetable Pathway Genome Sequencing for a Sinonasal Teratocarcinosarcoma and Xenograft Chemotherapeutic Testing for Personalized Medicine
Background: Characterization of common cancer (prostate, breast, etc.) transcriptomes, genomes, and exomes have identified chromosomal rearrangements, copy number gains and losses, and functional pathway mutations. To our knowledge, there has been no sequencing done for rare skull base tumors, including sinonasal teratocarcinomasarcoma. We describe exomic sequencing for such a tumor, as well as ongoing xenograft chemotherapeutic trials.
Methods: A 48 year old research professor presented with nasal obstruction and a rapidly growing unilateral sinonasal mass extending up to and thinning the cribriform. Biopsy and imaging revealed a T2N0M0 sinonasal teratocarcinosarcoma. The patient underwent an endoscopic craniofacial resection including cribriform resection with negative margins. Tissue was obtained at the time of surgery and was (1) flash frozen, (2) put into tissue culture for generation of in vitro cell lines, (3) implanted into mice for establishment of a xenograft model, and (4) sent for DNA and RNA analysis. Exomic, 'targetable pathway' sequencing was performed. Chemotherapeutic trials are ongoing in xenografts for controls (saline), traditionally used agents (platinum/taxane regimen), and our targetable mutation.
Current Results: In vitro cell lines are slowly growing. Mice xenografts were successfully created and expanded. Genome sequencing for 'targetable pathways' demonstrated a hotspot mutation in Beta Catenin, predicted to drive increased pathway activity. ICG-001 blocks the interaction of BCAT with a critical co-factor and has been used in xenografts at 5mg/kg daily IP. We are currently expanding our xenograft population and will begin a treatment experiment with saline control, platinum/taxane, and ICG-001 regimens. Data from these trials will be presented.
Conclusion: A unique mutation was found in Beta Catenin, and ongoing xenograft chemotherapeutic trials may provide exciting new avenues for personalized treatment of this rare skull base tumor. This technique is being refined for further testing of other rare skull base cancers at the University of Michigan.