Next-Generation in vivo Modeling of Human Cancers

Abstract

Animal models of human cancers played a major role in our current understanding of tumor biology. In pre-clinical oncology, animal models empowered drug target and biomarker discovery and validation. In turn, this resulted in improved care for cancer patients. In the quest for understanding and treating a diverse spectrum of cancer types, technological breakthroughs in genetic engineering and single cell “omics” offer tremendous potential to enhance the informative value of pre-clinical models. Here, I review the state-of-the-art in modeling human cancers with focus on animal models for human malignant gliomas. The review highlights the use of glioma models in dissecting mechanisms of tumor initiation, in the retrospective identification of tumor cell-of-origin, in understanding tumor heterogeneity and in testing the potential of immuno-oncology. I build on the deep review of glioma models as a basis for a more general discussion of the potential ways in which transformative technologies may shape the next-generation of pre-clinical models. I argue that refining animal models along the proposed lines will benefit the success rate of translation for pre-clinical research in oncology.

Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities

“…Moreover, Ezh2 inhibition also affects macrophages response to inflammatory signaling ( Zhang et al, 2018 ). Hence, testing the hypothesis involving neoadjuvant-like Ezh2 inhibition followed by immunotherapy, such as therapeutic targeting of the CD47/SIRPA axis, should be extended to relevant autochthonous models with an intact innate immune system in which PRC2 loss causes inflammation ( Serresi et al, 2016 ; Gargiulo, 2018 ). The major outcome of this study is to demonstrate that orthotopic grafting of Kras G12D -driven NSCLC promotes homogeneous Ezh2 expression, whose inhibition in vivo unleashes an inflammatory response.…”

Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology

“…Current available platforms to examine the interactions between monocytes and glioma cells involve co-culture systems and organotypic systems, as well as small and large animal models. In addition to several genetically engineered mouse models (for review see [Gargiulo, 2018], large animal platforms involving pigs and dogs have been utilized. Spontaneously occurring low-and high-grade gliomas have been observed in dogs, but a systematic study of GAM in these tumors has not been performed [Bentley et al, 2017].…”

Considering the Experimental Use of Temozolomide in Glioblastoma Research

“…Furthermore, with the aim of bypassing any divergence induced by cell culture processes, patient-derived xenografts, also called 'Avatar models', have been developed. Patients' biopsies are directly transplanted into immunocompromised mice, thereby conserving intratumoural heterogeneity [171]. The grafts can be either heterotopic or orthotopic.…”