Patient-derived xenografts for childhood solid tumors: a valuable tool to test new drugs and personalize treatments

Abstract

The use of preclinical models is essential in translational cancer research and especially important in pediatric cancer given the low incidence of each particular type of cancer. Cell line cultures have led to significant advances in cancer biology. However, cell lines have adapted to growth in artificial culture conditions, thereby undergoing genetic and phenotypic changes which may hinder the translational application. Tumor grafts developed in mice from patient tumor tissues, generally known as patient-derived xenografts (PDXs), are interesting alternative approaches to reproducing the biology of the original tumor. This review is focused on highlighting the interest of PDX models in pediatric cancer research and supporting strategies of personalized medicine. This review provides: (1) a description of the background of PDX in cancer, (2) the particular case of PDX in pediatric cancer, (3) how PDX can improve personalized medicine strategies, (4) new methods to increase engraftment, and, finally, (5) concluding remarks.

Orthotopic patient-derived xenografts of paediatric solid tumours

“…There are also international efforts to develop patient-derived xenografts (PDXs) for adult leukemias and solid tumors, including the EuroPDX consortium, the Public Repository of Xenografts, and the NCI Patient-Derived Models Repository 6–9 . Pediatric solid tumors are rare, relative to adult cancers, and access to tissue is a barrier to developing pediatric organoids or PDX models of solid tumors 10 .…”

Patient-Derived Orthotopic Xenograft Models of Pediatric Brain Tumors: In a Mature Phase or Still in Its Infancy?

“…Currently available pediatric brain tumor PDXs are established by xenografting fresh tissue, freshly isolated cell suspensions, or shortly cultured neurospheres in immunosuppressed rats (14), or immunodeficient mice (7,(15)(16)(17). Various immunocompromised mouse strains are available, with different rates of engraftment, lifespan, and sensitivity for chemotherapy or radiation (5,9,18). Not all strains have been fully characterized, and it is therefore essential to understand these differences when choosing the most appropriate animal model.…”

“…Aside from different responses to therapy, there are also significant differences in tumor engraftment between various strains. Generally, it is believed that the level of immunodeficiency correlates with the tumor take rate (8,9); as such, the more immunocompromised mouse strains, NOD/SCID/IL2γ-receptor null (NSG) and NOS/Rag/IL2γreceptor null (NRG), would be most suitable strains for the implantation of primary cancerous cells, stem cells or tissue (9,19,24). It has been reported that these models support more robust post-engraftment tumor growth compared to doublemutant mice (25, 26), whilst maintaining the characteristics of the original primary patient tumor (27).…”

“…One major limitation of the use of immunocompromised mice is that the interaction between the tumor and the immune microenvironment is partially or completely lost to ensure tumor engraftment is successful (5,9). Consequently, the current PDX models cannot be used to study the (tumor) immune microenvironment, or to test novel immunotherapeutic treatment strategies (9).…”

“…PDXs have been shown to have an increased reliability when reproducing the heterogeneity of the human disease, which may better reflect the therapy response in patients than GEMMs (5,6). In addition, we will focus on the models that have been established by xenografting fresh patient-derived material rather than established human cancer cell lines that have adapted to growth under artificial culture conditions, and are generally considered less relevant for clinical translation due to a more homogeneous, undifferentiated histology (7)(8)(9). Finally, we will only consider intracranial/orthotopic models, as these models retain the tumor-host microenvironment which may play a role in tumor response (10), and tumor growth (11).…”