Characterization of drug responses of mini patient‐derived xenografts in mice for predicting cancer patient clinical therapeutic response

Abstract

BackgroundPatient-derived organoids and xenografts (PDXs) have emerged as powerful models in functional diagnostics with high predictive power for anticancer drug response. However, limitations such as engraftment failure and time-consuming for establishing and expanding PDX models followed by testing drug efficacy, and inability to subject to systemic drug administration for ex vivo organoid culture hinder realistic and fast decision-making in selecting the right therapeutics in the clinic. The present study aimed to develop an advanced PDX model, namely MiniPDX, for rapidly testing drug efficacy to strengthen its value in personalized cancer treatment.MethodsWe developed a rapid in vivo drug sensitivity assay, OncoVee® MiniPDX, for screening clinically relevant regimens for cancer. In this model, patient-derived tumor cells were arrayed within hollow fiber capsules, implanted subcutaneously into mice and cultured for 7 days. The cellular activity morphology and pharmacokinetics were systematically evaluated. MiniPDX performance (sensitivity, specificity, positive and negative predictive values) was examined using PDX as the reference. Drug responses were examined by tumor cell growth inhibition rate and tumor growth inhibition rate in PDX models and MiniPDX assays respectively. The results from MiniPDX were also used to evaluate its predictive power for clinical outcomes.ResultsMorphological and histopathological features of tumor cells within the MiniPDX capsules matched those both in PDX models and in original tumors. Drug responses in the PDX tumor graft assays correlated well with those in the corresponding MiniPDX assays using 26 PDX models generated from patients, including 14 gastric cancer, 10 lung cancer and 2 pancreatic cancer. The positive predictive value of MiniPDX was 92%, and the negative predictive value was 81% with a sensitivity of 80% and a specificity of 93%. Through expanding to clinical tumor samples, MiniPDX assay showed potential of wide clinical application.ConclusionsFast in vivo MiniPDX assay based on capsule implantation was developed-to assess drug responses of both PDX tumor grafts and clinical cancer specimens. The high correlation between drug responses of paired MiniPDX and PDX tumor graft assay, as well as translational data suggest that MiniPDX assay is an advanced tool for personalized cancer treatment.

Developing a Quantitative Ultrasound Image Feature Analysis Scheme to Assess Tumor Treatment Efficacy Using a Mouse Model

“…In order to identify the association between the image features and treatment efficacy, we computed the correlation coefficient of each feature with TSIR using the following equation 4 :where “r” is the Pearson correlation coefficient, “x” and “y” are one selected image feature and the TSIR, respectively. “n” is the case study size, which is 23 in this study.…”

“…The advantages and necessity of applying mouse models in the initial steps of developing new drugs and/or cancer treatment methods have been extensively investigated and discussed in previous studies 2,3 . As a result, a large number of mouse models bearing different types of simulated carcinoma tumors have been developed and used in cancer research field 4–6 .…”

Co-Clinical Imaging Resource Program (CIRP): Bridging the Translational Divide to Advance Precision Medicine

“…There is also an interesting variation of the in vivo PDX method, mini-PDX, where patient-derived tumor cells are seeded into hollow fiber capsules that are implanted subcutaneously into mice. The mini-PDX-bearing mice are treated with therapeutics of interest for 7 days and tumor cells in tubes are assessed for therapeutic effect ( 28 ). The authenticity of PDX models is crucial to the validity of the studies performed with them.…”

The Science and Engineering of Stem Cell–Derived Organoids-Examples from Hepatic, Biliary, and Pancreatic Tissues

“…PO studies were employed with OncoVee™-Mini PDX assay system, which bears hollow fibers. Primary tumors were digested purified, and loaded into these fiber-based capsules and transplanted in mice to form hPO in vivo (Zhang, Wang et al 2018). Analysis of tumor growth in response to drugs was similar to more complex patient-derived xenografts, suggesting this system could be widely used.…”