Case study: patient-derived clear cell adenocarcinoma xenograft model longitudinally predicts treatment response

Abstract

There has been little progress in the use of patient-derived xenografts (PDX) to guide individual therapeutic strategies. In part, this can be attributed to the operational challenges of effecting successful engraftment and testing multiple candidate drugs in a clinically workable timeframe. It also remains unclear whether the ancestral tumor will evolve along similar evolutionary trajectories in its human and rodent hosts in response to similar selective pressures (i.e., drugs). Herein, we combine a metastatic clear cell adenocarcinoma PDX with a timely 3 mouse x 1 drug experimental design, followed by a co-clinical trial to longitudinally guide a patient’s care. Using this approach, we accurately predict response to first- and second-line therapies in so far as tumor response in mice correlated with the patient’s clinical response to first-line therapy (gemcitabine/nivolumab), development of resistance and response to second-line therapy (paclitaxel/neratinib) before these events were observed in the patient. Treatment resistance to first-line therapy in the PDX is coincident with biologically relevant changes in gene and gene set expression, including upregulation of phase I/II drug metabolism (CYP2C18, UGT2A, and ATP2A1) and DNA interstrand cross-link repair (i.e., XPA, FANCE, FANCG, and FANCL) genes. A total of 5.3% of our engrafted PDX collection is established within 2 weeks of implantation, suggesting our experimental designs can be broadened to other cancers. These findings could have significant implications for PDX-based avatars of aggressive human cancers.

Zebrafish Avatars towards Personalized Medicine—A Comparative Review between Avatar Models

“…To address this, "humanized-xenograft" models are being explored, consisting in the implantation of patient tumor cells together with human peripheral blood mononuclear cells or hematopoietic stem cells. This allows tumor-immune interactions and assessment of immune checkpoint inhibitors such as nivolumab [75,76].…”

“…Although still few, some fundamental studies in mice were performed in a prospective manner to guide clinical treatment decisions [76,[94][95][96][97]. In 2014, Stebbing et al [95] established 16 mPDXs from 29 patients with advanced sarcoma.…”

“…Consequently, most of these studies focus on metastatic stages to specify second lines of therapy, treatments after all other care has been exhausted, or if a therapy does not exist. An exception was the study of Vargas et al [76], which was able to predict response to first-line therapy (gemcitabine/nivolumab), development of resistance and response to second-line therapy (paclitaxel/neratinib) before these events were observed in the patient. The authors established a mPDX from a patient with metastatic clear cell adenocarcinoma of müllerian origin and developed a co-clinical experimental design to effectively guide patient treatment.…”

“…This prospective study for first line treatment was only feasible due to the possibility to harvest the tumor within 2 weeks of implantation (although only 5.3% implanted successfully). As pointed by the authors, this was only possible due to the availability of a large amount of tissue from the surgery and its intrinsic rapid proliferation, allowing the generation of multiple mPDXs [76].…”

Recent Approaches Encompassing the Phenotypic Cell Heterogeneity for Anticancer Drug Efficacy Evaluation

“…During a clinical study, it is not possible to reveal timing and mechanism of resistance. Here, PDXs are also of use allowing to predict both the development of resistance to the first-line therapy as well as the response to second-line therapy before this is observed in the donor patient, and to adjust further treatment accordingly [138]. Authors report correlation between clinical results and PDX models.…”