Radiosensitization Through Targeting Molecular Alterations in Adenoid Cystic Carcinoma

Abstract

Adenoid cystic carcinoma (ACC) is a relatively rare cancer that typically arises in salivary tissues of the head and neck. There are currently no approved systemic agents for ACC and no data supporting the delivery of chemoradiation for ACC patients. The scarcity of validated model systems has hampered research efforts. We report the establishment and propagation of an ACC patient–derived xenograft (PDX), genomic evaluation of cancer-associated mutations, and in vivo response profiles to personalized radiosensitization agents based on next-generation sequencing. An ACC PDX was established and maintained in NOD-SCID gamma (NSG) mice directly from the patient. Common cancer-associated mutations were identified using the Illumina TruSeq Amplicon Cancer panel. PDXs were treated with focal radiation or chemotherapy selected based on the genomic profile of the cancer. Focal radiation was delivered at 5 Gy x 8 fractions twice weekly for 4 weeks. Tumor size was measured over time and comparisons between treatment groups made by repeated measures ANOVA. Target inhibition in vivo was confirmed via western blot of tumor lysates and IHC of FFPE tissue. The histologic and physical characteristics of the primary human tumor are maintained in this ACC PDX. Mutations in the receptor tyrosine kinases (RTKs) cKit and KDR/VEGFR2 were identified. No mutations were identified in EGFR, RAS, or PIK3CA. Several targeted therapies were selected including dovitinib, a multi-RTK inhibitor, BEZ235, a PI3K/mTORC inhibitor, and cetuximab, an EGFR mAB. Target inhibition was confirmed by western blot and IHC. Radiation temporarily halted tumor growth. Treatment with molecularly targeted agents prolonged time to tumor doubling compared to control treatment (p<0.05 for each). Chemoradiation resulted in significant tumor regression which persisted more than 2 months after the end of treatment. PDXs are a powerful model system for investigating potential radiosensitizers based on individual tumor characteristics. Our ACC PDX represents one of only a handful of tools for studying this rare disease. These preliminary data identify the rationale to investigate selected molecular drug/radiation combinations for ACC, particularly when driven by tumor-specific genetic biomarkers. Expansion of these studies may be valuable to advance the design of new treatment strategies for ACC.