37 (PB027) - Establishment and characterization of HPV+ metastatic squamous cell anal carcinoma XPDX models in athymic nude mice

Abstract

Background: Squamous cell carcinoma of the anus (SCCA) is a rare malignancy comprising less than 3% of all gastrointestinal cancers in the United States. While over 90% of SCCA have been found human papilloma virus positive (HPV+), a majority of cases present locally and can be cured with definitive therapy. However, metastatic SCCA is less treatable and poorly understood in part due to the lack of relevant preclinical models. To this end we have established four HPV+ XenoSTART ethnically and gender diverse Patient-Derived Xenograft (XPDX) models of metastatic SCCA designated ST4808, ST5678, ST5872 and ST6058. These models were established in athymic nude mice and characterized for receptor expression, genomic alterations, and in vivo drug sensitivity. Methods: ST4808 was established from biopsy collected from a 51-year-old Hispanic male with recurrent anal cancer following initial resection. ST5678 was established from a liver biopsy collected from a 55-year-old Hispanic male with newly-diagnosed SCCA. ST5872 was established from a liver biopsy collected from a 70-year-old Hispanic female with recurrent SCCA following prior treatment with 5-FU, mitomycin and radiation. ST6058 was established from a lung biopsy collected from a 55-year-old Caucasian female with recurrent SCCA following treatment with 5-FU/mitomycin/ radiation, carboplatin/gemcitabine, and investigational therapies. The resulting models were passaged and characterized using immunohistochemistry and genomic analysis including WES and RNAseq. In vivo studies were performed testing various chemotherapy and targeted agents; study endpoints included tumor volume and time from treatment initiation with % T/C values and tumor regression reported at study completion; a %T/C of £20 versus control was considered sensitive. Tumor regression (%T/C < 0) versus Day 0 tumor volume was also reported. Results: Immunohistochemistry analysis of each model confirmed disease similar to corresponding patient’s cancer using archival clinical samples. WES/RNAseq analysis identified EZH2 and STK11 variants in ST4808, ERBB2 and PIK3CA mutations in ST5678, an FGFR3-TACC3 fusion in ST5872 and KDM6A and CYLD variants in ST6058. In vivo, ST4808 demonstrated sensitivity to platinum chemotherapy while ST5678 was resistant to tucatinib, neratinib and alpelisib but not platinum. ST5872 reported modest sensitivity to erdafitinib and ST6058 was resistant to tested therapies. Conclusion: We have established and characterized four models of HPV+ metastatic SCCA cancer and benchmarked chemotherapy and relevant targeted therapies in each model. These models are valuable tools for evaluating potential therapies for metastatic anal cancer. No conflict of interest.