OP0024 Use of novel patient-derived xenografts and molecular subtyping to improve precision medicine in high-grade serous ovarian cancer

Abstract

<h3>Background</h3> Epithelial ovarian cancer (EOC) mortality rates have remained unchanged in 30years. The most common EOC subtype, high-grade serous ovarian carcinoma (HG-SOC), can be divided into four subgroups on the basis of molecular characteristics. The C5 subgroup is defined by <i>MYCN</i> pathway activation and carries a poor prognosis. The commonly used EOC cell lines are poor models of HG-SOC, whereas patient-derived xenografts (PDX) retain pathological and immunohistochemical features of primary tumour, providing a valuable preclinical resource for therapeutic exploration. <h3>Methods</h3> Fourteen "C5-like" HG-SOC PDX were generated from tumour tissue transplanted into NOD/SCIDIL2R<i>γ</i>^null mice. Three were from a consecutive cohort of HG-SOC PDX identified by qRT-PCR of the <i>MYCN</i> pathway and the rest from a separate cohort by gene expression analysis. Molecular analysis done included qRT-PCR for <i>MYCN, HMGA2</i>, <i>LIN28B,</i> and sequencing of DNA repair genes. In-vivo response to cisplatin (intraperitoneal on days 1, 8, and 18) is underway, because platinum response provides prognostic information. Tumour volume is measured twice weekly and mice with tumours larger than 0.7cm³ are euthanised. PDX are deemed sensitive if response is maintained for 100 or more days; resistant if they had stable disease or relapsed in less than 100days; and refractory if they progressed on treatment. Investigation of in vivo response to compounds targeting the <i>MYCN</i> pathway is underway and each response is considered in light of molecular phenotype. <h3>Findings</h3> Preliminary data revealed six "C5-like" PDX overexpressed <i>LIN28B</i> and eight overexpressed <i>MYCN</i>. Three overexpressed <i>CCNE1</i> (drug resistance marker) and three PDX harboured mutations in DNA repair genes (marker of platinum sensitivity). Two PDX were sensitive to cisplatin, two were resistant, four were refractory, and one showed mixed response. <h3>Interpretation</h3> This cohort of "C5-like" HG-SOC PDX depicts molecular complexity and treatment response heterogeneity. Use of these molecularly annotated PDX to demonstrate novel effective therapies targeting the <i>MYCN</i> pathway will inform clinical trial design.