Of mice and men: pre-clinical models to identify therapy responsive patient subgroups

Abstract

© Gynecology and Pelvic Medicine. All rights reserved. Gynecol Pelvic Med 2020;3:13 | http://dx.doi.org/10.21037/gpm.2020.04.01 Ovarian cancer is the eighth leading cause of cancer related death among women, accounting for more than 150,000 deaths annually worldwide (1,2). High-grade serous ovarian cancer (HGSOC) is the most malignant form of ovarian cancer and accounts for approximately 70% of ovarian cancer diagnosis. Studies on cancer initiation, growth and metastasis have typically focused on genetic derangements in neoplastic cells; however, tumor growth cannot be exclusively explained by aberrations in cancer cells. Thus, it is of great interest to have a comprehensive understanding of how the tumor microenvironment (TME) promotes the neoplastic niche, and ultimately how to target the TME (including tumor stroma, extracellular matrix, and immune cells) to reduce disease recurrence and drug resistance. Historically, preclinical models focus on the genetic characteristics of the epithelial cells and have lacked in maintaining relevant TME components. In a recent study by Maniati et al. (3), the authors focused on characterizing the epithelial compartment and the TME of orthotropic syngeneic mouse tumor models to determine their analogy to patient tumors and to what extent these models can be utilized in preclinical studies that test TME targeting therapeutics. Six metastatic omental models of HGSOC were characterized. Two models, 30200 and 60577, were developed from genetically engineered mouse models (GEMMs) which had been engineered for Trp53, Brca and inactivation of the tumor suppressor function of Rb. Four additional models were developed from GEMMs with fallopian tube specific inducible inactivation of Brca2, Trp53, and Pten (models HGS1-4). RNA sequencing (RNAseq) analysis revealed nearly 1,300 differentially expressed genes [false discovery rate (FDR) <0.05] in the murine tumors compared to normal omental tissue. As expected, much of the tumor proliferation and survival pathways were significantly enriched (P<0.001). Copy number variation (CNV) frequently contributes to the alteration of oncogenic drivers or the deletion of tumor suppressors. HGSOC tumors have relatively more CNVs than many other tumor types, where patients have a medium fraction of 46% of their genome altered (4), compared to approximately 5–10% in various other cancer types (5). Typical preclinical models use immune-deficient HGSOC xenograft models with established cell lines. Much of the common cell lines used for in vivo modeling lack the CNV profiles that are commonly found in patient tumors further confirming a loss of genetic fidelity in historically used xenograft models. A study from Domcke et al. evaluating the genetic profile of 47 ovarian cell lines revealed profound differences in copy-number changes, mutations and mRNA expression of 12 of the most readily used Editorial Commentary