Patient-derived xenografts: a relevant preclinical model for drug development

Abstract

Identifying appropriate preclinical cancer models remains a major challenge in increasing the efficiency of drug development. A potential strategy to improve patient outcomes could be selecting the ‘right’ treatment in preclinical studies performed in patient-derived xenografts (PDXs) obtained by direct implants of surgically resected tumours in mice. These models maintain morphological similarities and recapitulate molecular profiling of the original tumours, thus representing a useful tool in evaluating anticancer drug response. In this review, we will present the state-of-art use of PDXs as a reliable strategy to predict clinical findings. The main advantages and limitations will also be discussed.

Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo

“…As anticipated, we found that cancer cells purified from BALB/c tumors expressed very high levels of cytokines, growth factors and members of the INFα/β and INFγ signaling pathways, hallmarks of an active interaction with the immune system. While PDX mice will continue to be invaluable resources for exploring therapeutic treatments that are independent of immune function, such as chemotherapies and cell cycle checkpoint inhibitors [33], therapies that engage the immune system to kill the tumor will require the development of ex vivo bioreactor type methodologies that will permit the incorporation of all immune components.…”

Personalized Cancer Therapy Prioritization Based on Driver Alteration Co-occurrence Patterns

“…Although thousands of genomic profiles of patient tumors are available, accurate information about pharmacological interventions and treatment outcome has not been systematically collected [23], or has not been disclosed yet [24]. Thus, to bypass these limitations, we compiled drug response data obtained in PDXs, since they preserve the overall molecular profile of the original tumor, and maintain its cellular and histological structure [32]. In particular, we based our study on 375 PDXs for which somatic mutations and copy number alterations have been characterized, together with their response to 62 treatments across six indications, using the 'one animal per model per treatment (1x1x1)' experimental design [28].…”

“…To some extent, PDXs preserve inter-and intra-tumoral heterogeneity, and mimic the clinical course of the disease and response to targeted therapy, at least in certain tumor types [29][30][31]. Indeed, a recent review reported a 91% (153 out of 167) correspondence between the clinical responses of patients and their cognate PDXs [32]. Although this data are more time-intensive and expensive to generate, it is still feasible to establish large in vivo screenings, covering a wide diversity of tumor types and drugs.…”

The role of mouse models in translational cancer research: present and future directions

“…7 Tumors are maintained by passaging fragments directly from mouse to mouse and then expanded for the evaluation of anticancer efficacy of treatments. Usually the time for engraftment is between 2 and 4 months and failure of engraftment should not be ascertained until at least 6 months and beyond.…”