Patient-Derived Xenografts as a Model System for Radiation Research

Abstract

The cancer literature is filled with promising preclinical studies demonstrating impressive efficacy for new therapeutics, yet translation of these approaches into clinical successes has been rare, indicating that current methods used to predict efficacy are sub-optimal. The most likely reason for the limitation of these studies is the disconnect between preclinical models and cancers treated in the clinic. Specifically, most preclinical models are poor representations of human disease. Immortalized cancer cell lines that dominate the cancer literature may be, in a sense, “paper tigers” that have been selected by decades of culture to be artificially driven by highly targetable proteins. Thus, although effective in treating these cell lines either in vitro or as artificial tumors transplanted from culture into experimental animals as xenografts, the identified therapies will likely underperform in a clinical setting. This inherent limitation not only applies to drug testing, but also to experiments with radiation therapy. Indeed, traditional radiobiology methods rely on monolayer culture systems, with emphasis on colony formation and DNA damage assessment that may have limited clinical translation. As such, there has been keen interest in developing tumor explant systems in which patient tumors are directly transplanted into, and solely maintained in vivo, using immunocompromised mice. These so-called Patient-Derived Xenografts (PDX) represent a robust model system that has been garnering support in academia and industry as a superior preclinical approach to drug testing. Likewise, PDX models have the potential to improve radiation research. In this review, we describe how PDX models are currently being used for both drug and radiation testing and how they can be incorporated into a translational research program.

In vitro and in vivo assessment of direct effects of simulated solar and galactic cosmic radiation on human hematopoietic stem/progenitor cells

“…Despite the inherent technical limitations of using a xenogeneic transplant system (detailed in Supplementary Materials), 84,85 the immunocompromised mouse model enabled us to demonstrate, for the first time, that human HSC can be leukemogenically transformed by HZE ions typical of the space radiation environment, and that this process may be initiated by a single high-LET ion traversal. Furthermore, we establish that prior high-dose proton irradiation is radioprotective for T-ALL development in this scenario.…”

Pancreatic adenocarcinoma human organoids share structural and genetic features with primary tumors

“…Furthermore, PDX models have complex architecture and utilize heterogeneous patient tissue, but the clinical applicability is challenging due to prohibitive time requirements (up to 6 months to establish tumor growth), costs associated with in vivo systems, the large sample size required (~100 mm 3 ), and the influence of infiltrating murine stromal cells on the tumor (9,10). The latter factor may influence the recent observations that the more times a PDX tumor is passaged through mice, the more transcriptionally "mouse-like" it becomes (11). Due to the challenges related to existing systems, improved models of PDAC are essential.…”

Generation of Microtumors Using 3D Human Biogel Culture System and Patient-derived Glioblastoma Cells for Kinomic Profiling and Drug Response Testing

“…With the proband system, the PDX developed from a particular patient does not directly inform the clinician regarding that specific patient’s therapy, as with the tumor avatar system. Instead, a patient’s tumor is “matched” to a pre-existing, well-characterized (both molecularly and phenotypically) PDX 29 . Indeed, this model could serve as a “go-to” avatar or reside in a proband library as a comparative profile.…”