Abstract 5187: Potent radiosensitization of adenoid cystic carcinoma in a patient derived xenograft model using the MDM2 inhibitor AMG 232
Authors: Javaid Amal , Swick Adam D. , Werner Lauryn , Prabakaran Prashanth , Hu Rong , Nickel Kwangok P. , Ong Irene , Sampene Emmanuel , Bruce Justine , Hartig Gregory , Wieland Aaron , Canon Jude , Harari Paul , Kimple Randall 
Published: July 2017

Abstract
Purpose: Adenoid cystic carcinoma (ACC) is a relatively rare cancer that typically arises in major or minor salivary gland tissues of the head and neck. There are currently no approved systemic agents for ACC and no established data supporting the delivery of chemoradiation for ACC patients. The scarcity of validated preclinical model systems has hampered research efforts. We report the successful establishment and propagation of an ACC patient derived xenograft (PDX), genomic evaluation of cancer associated mutations, and in vivo response to MDM2 inhibition combined with radiotherapy. Because TP53 mutations are seen in &lt;5% of ACCs, we investigated the role of a small molecule MDM2 inhibitor, AMG 232.
Methods: An ACC PDX was established and assessed for common cancer-associated mutations using the Illumina TruSeq Amplicon Cancer panel. Xenografts were treated with focal radiation with or without AMG 232. Focal radiation was delivered at 0, 2, 5, or 8 Gy x 8 fractions delivered twice weekly, with AMG 232 (50mg/kg) delivered daily by oral gavage. Tumor size was measured by caliper and comparisons between treatment groups made using a repeated measures ANOVA. A TCD50 was calculated by fitting log-transformed data to a dose-response curve and compared using the extra-sum-of-squares f test. Target inhibition and anti-cancer effect was confirmed via immuno-blotting of tumor lysates, and IHC staining or in situ hybridization of relevant targets within FFPE sections of tumors harvested 2 and 48 hrs post treatment.
Results: The histologic characteristics of the primary human tumor are maintained in subsequent murine passages of this ACC PDX. Mutational profiling determined that the PDX was wildtype for TP53. AMG 232 alone resulted in modest slowing of tumor growth. Radiation alone produced a tumor growth delay in a dose dependent manner but did not result in sustained local tumor control. Strikingly, the combination of AMG 232 with RT (including low dose radiation of 2 Gy) produced dramatic tumor shrinkage and potent tumor control three months after the end of treatment. Target inhibition of MDM2 was confirmed by western blot of tumor lysates and IHC of FFPE samples taken 2 hrs post treatment. Antiproliferative and apoptotic effects were confirmed by western blot of tumor lysates and IHC of FFPE samples taken at 48 hrs post treatment.
Conclusions: This study suggests that MDM2 inhibition may provide potent radiosensitization in TP53 WT ACC. While additional translational models are warranted, the powerful response profile observed suggests that phase I clinical trial evaluation of this combination is worthy for this challenging malignancy.
Citation Format: Amal Javaid, Adam D. Swick, Lauryn Werner, Prashanth Prabakaran, Rong Hu, Kwangok P. Nickel, Irene Ong, Emmanuel Sampene, Justine Bruce, Gregory Hartig, Aaron Wieland, Jude Canon, Paul Harari, Randall Kimple. Potent radiosensitization of adenoid cystic carcinoma in a patient derived xenograft model using the MDM2 inhibitor AMG 232 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5187. doi:10.1158/1538-7445.AM2017-5187