Patient-derived xenograft models capture genomic heterogeneity in endometrial cancer

Abstract

Background Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprises four molecular subtypes with differing etiology, prognoses, and responses to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. As pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models. Methods Here, we report whole exome or whole genome sequencing of 11 PDX models and their matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the copy number high/p53-mutant and mismatch-repair deficient molecular subtypes of EC. Results PDX models were successfully generated from grade 2/3 tumors, including three uterine carcinosarcomas. The models showed similar histomorphology to the primary tumors and represented all four molecular subtypes of EC, including five mismatch-repair deficient models. The different PDX lineages showed a wide range of inter-tumor and intra-tumor heterogeneity. However, for most PDX models, one arm recapitulated the molecular landscape of the primary tumor without major genomic drift. An in vivo response to talazoparib was detected in four copy number high models. Two models (carcinosarcomas) showed a response consistent with stable disease and two models (one copy number high serous EC and another carcinosarcoma) showed significant tumor growth inhibition, albeit one consistent with progressive disease; however, all lacked the HR deficiency genomic signature. Conclusions EC PDX models represent the four molecular subtypes of disease and can capture intra-tumor heterogeneity of the original primary tumor. PDXs of the copy number high molecular subtype showed sensitivity to PARPi; however, deeper and more durable responses will likely require combination of PARPi with other agents.

Validation of a Patient-Derived Xenograft Model for Cervical Cancer Based on Genomic and Phenotypic Characterization

“…On average, 90% of the genome had the same copy number in the primary and PDX tumors. Bonazzi et al performed whole-exome sequencing in endometrial cancers, including four common molecular subtypes [ 37 ]. They focused on mismatch repair-deficient (MMRd) and p53 mutant subtypes.…”

Genomic Validation of Endometrial Cancer Patient-Derived Xenograft Models as a Preclinical Tool

“…Extensively characterized PDX models could represent a unique tool for the design of novel strategies to test drug efficacy [ 26 ] and could be used in preclinical trials to enhance therapy predictive value and ensure an increment of the success rate in drug development and safety translation to the clinic. However, PDX models also have limitations.…”

Generation and Integrated Analysis of Advanced Patient‐Derived Orthoxenograft Models (PDOX) for the Rational Assessment of Targeted Therapies in Endometrial Cancer

“…To achieve this and to overcome all the aforementioned experimental limitations, we have expanded our knowledge on EC by generating direct orthotopic xenograft models from 15 EC patients. Although the generation of panels of >10 subcutaneous and/or subrenal EC PDX have been described in the recent years, [ 57 , 58 , 59 , 60 , 61 ] to the best of our knowledge, no other attempts to systematically implant and profile at a genome‐wide scale matched primary tumor and orthotopically inserted primary‐derived EC tissue in mice have been reported. Importantly, we provide abundant data demonstrating that implantation and engraftment of primary EC tissue in the mouse uterus can regenerate the human tumor in mice.…”