Abstract 1010: Genomic analysis of recurrent ovarian cancer in patient-derived xenografts treated with platinum and taxane chemotherapy
Authors: Stover Elizabeth , Amin-Mansour Ali , Palakurthi Sangeetha , Dharma Sanam , Zeng Qing , Zhou Shan , Desai Palak , Garraway Levi , Matulonis Ursula , Liu Joyce 
Published: July 2017

Introduction: Many women with advanced ovarian cancer (OC) are initially sensitive to platinum and taxane chemotherapy, but subsequently develop recurrent disease which is often incurable. OC chemotherapy resistance mechanisms are incompletely understood. We used patient-derived xenografts (PDX) to model OC recurrence following chemotherapy and to analyze genomic evolution of recurrent tumors.

Approach: We leveraged PDX derived from human OC ascites that accurately represent high-grade serous OC. We used two PDX models: PDX-A derived from a chemotherapy-naive patient with WT BRCA1/2; PDX-B derived from a chemotherapy-resistant patient with a BRCA1 mutation. Using luciferase-labeled tumor cells, we generated intraperitoneal disease in multiple recipients. We treated cohorts of 5-10 animals with vehicle, carboplatin, paclitaxel, or carboplatin + paclitaxel (C/T) for 3 cycles followed by observation with bioluminescence imaging of tumor burden.

Results: While vehicle- and paclitaxel-treated animals exhibited rapid disease outgrowth, carboplatin- and C/T-treated animals showed disease regression, followed by recurrence after 90-300 days. Median survival was significantly increased in carboplatin- and C/T-treated animals. Recurrent tumors were histologically similar to vehicle-treated tumors. We performed whole-exome sequencing and whole-transcriptome sequencing on ascites cells from 4 animals in each treatment group. We used a decontamination algorithm to remove stromal mouse reads from our tumor samples, resulting in a highly pure (over 99%) human tumor sequence data. Mutations, insertions/deletions, and copy number alterations were identified and compared among treatment groups. Known TP53 mutations were present at 100% frequency across samples. Average mutation frequencies were similar across all groups. We identified several mutations and copy number variants present in the carboplatin or C/T recurrent tumors that were distinct from the vehicle groups, including putative alterations in chemoresistance pathways such as DNA repair (BRCA1/2), apoptosis (BCL2L1), drug transport (ABC transporters), and PI3K signaling (EEF2K). In model PDX-A, all four carboplatin and one C/T treated recurrent tumors exhibited a similar copy-number profile, suggestive of subclonal expansion, which included an increase in WT copies of PTEN relative to the vehicle tumors. Phylogenetic analysis and whole-transcriptome analysis are ongoing.

Conclusions: Our study models recurrent ovarian cancer in PDX and identifies potential features of in vivo chemotherapy resistance.

Citation Format: Elizabeth Stover, Ali Amin-Mansour, Sangeetha Palakurthi, Sanam Dharma, Qing Zeng, Shan Zhou, Palak Desai, Levi Garraway, Ursula Matulonis, Joyce Liu. Genomic analysis of recurrent ovarian cancer in patient-derived xenografts treated with platinum and taxane chemotherapy [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 1010. doi:10.1158/1538-7445.AM2017-1010