Molecular correlates of platinum response in human high‐grade serous ovarian cancer patient‐derived xenografts

Abstract

Introduction Improvement in the ability to target underlying drivers and vulnerabilities of high-grade serous ovarian cancer (HG-SOC) requires the development of molecularly annotated pre-clinical models reflective of clinical responses. Methods We generated patient-derived xenografts (PDXs) from consecutive, chemotherapy-naïve, human HG-SOC by transplanting fresh human HG-SOC fragments into subcutaneous and intra-ovarian bursal sites of NOD/SCID IL2Rγnull recipient mice, completed molecular annotation and assessed platinum sensitivity. Results The success rate of xenografting was 83%. Of ten HG-SOC PDXs, all contained mutations in TP53, two were mutated for BRCA1, three for BRCA2, and in two, BRCA1 was methylated. In vivo cisplatin response, determined as platinum sensitive (progression-free interval ≥100 d, n=4), resistant (progression-free interval <100 d, n=3) or refractory (n=3), was largely consistent with patient outcome. Three of four platinum sensitive HG-SOC PDXs contained DNA repair gene mutations, and the fourth was methylated for BRCA1. In contrast, all three platinum refractory PDXs overexpressed dominant oncogenes (CCNE1, LIN28B and/or BCL2). Conclusions Because PDX platinum response reflected clinical outcome, these annotated PDXs will provide a unique model system for preclinical testing of novel therapies for HG-SOC.

Patient-Derived Ovarian Tumor Xenografts Recapitulate Human Clinicopathology and Genetic Alterations

“…19), including breast (30,31), colorectal (32,33), lung (34), pancreatic cancers (35,36), and glioblastoma (37,38). While we were preparing this manuscript, two papers were published on tumor grafts obtained from ovarian tumors, one focusing on a small series of high-grade serous type (13), whereas the other presenting a large tumor bank of ovarian cancer of different histotype (14).…”

“…Cancer cell lines are reproducible, easy to use, and useful for studying specific mechanisms, but their resemblance to the original tumor and thus their therapeutic predictive value is very limited (12). Two studies describing ovarian cancer patientderived xenografts have been recently published (13,14). However, in those studies little characterization was carried out in relation to the recently proposed origin and pathogenesis of ovarian cancer (i.e., type I or type II), that is now basis for novel target therapy.…”

AAV9 delivering a modified human Mullerian inhibiting substance as a gene therapy in patient-derived xenografts of ovarian cancer

“…The recent development of PDXs, in which small pieces of undigested primary tumors are serially passaged in immunocompromised mice, has ushered in a new era of precision medicine, where mice function as avatars to evaluate patient-specific therapies (22)(23)(24)(25)(26). Some of the limitations of PDXas are the serial passaging of the tumors, which can be lengthy and cause loss of clonal diversity, and replacement of human stroma and human vasculature (27,28).…”

MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors

“…50 In the case of ovarian cancer, tumors with Mcl-1 amplification have been found to be particularly resistant to conventional platinum-based chemotherapy. 51 The BH3-only protein Noxa is a potent and relatively selective neutralizer of Mcl-1. 34,52 Although the present study demonstrates that MLN4924 induces Noxa upregulation and Mcl-1 neutralization in AML, further studies are required to determine whether a similar mechanism will be observed in other hematological malignancies or solid tumors.…”