Using PDX for Preclinical Cancer Drug Discovery: The Evolving Field

Williams, Juliet

doi:10.3390/jcm7030041

Cited by 84 publications

(85 citation statements)

References 94 publications

(138 reference statements)

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“…(Bertotti et al, 2011). It may also be feasible to use one mouse per model per arm when there is a large number of mouse models, which compensate the loss of measurement accuracy on individual mice (Gao et al, 2015;Murphy et al, 2016;Townsend et al, 2016;Williams, 2018). Caution must be exercised to use this approach though, when the number of mouse models is small, or high measurement accuracy of individual mouse models is mandated, or response varies greatly among mice of same mouse models, as commonly observed for immunotherapeutic agents on syngeneic models.…”

Section: Mcts Can Explain Paradoxical Clinical Trial Resultsmentioning

confidence: 99%

The design, analysis and application of mouse clinical trials in oncology drug development

Guo

Jiang

Mao

et al. 2018

Preprint

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Mouse clinical trials (MCTs) are becoming widely used in pre-clinical oncology drug development. In this study, we provide some general guidelines on the design, analysis and application of MCTs. We first established empirical quantitative relationships between mouse number and measurement accuracy for both categorical and continuous efficacy endpoints, and showed that more mice are needed to achieve given accuracy for syngeneic models than for PDXs and CDXs. There is considerable disagreement between categorical methods on calling drug responses as objective response, indicating limitations of such approaches. We then introduced linear mixed models, or LMMs, to describe MCTs as clustered longitudinal studies, which explicitly model growth and drug response heterogeneities across mouse models and among mice within a mouse model. Several case studies were used to demonstrate the advantages of LMMs in discovering biomarkers and exploring a drug’s mechanism of action. We also introduced the additive frailty models to perform survival analysis on MCTs, which more accurately estimate hazard ratios by modeling the clustered population structures in MCTs. We performed computational simulations for LMMs and frailty models to generate statistical power curves, and showed that statistical power is close for designs with similar total number of mice at given drug efficacy. Finally, we explained how MCTs can explain discrepant results in clinical trials, hence, MCTs are more than preclinical versions of clinical trials but possess their unique values. Results in the report will make MCTs a better tool for oncology drug development.

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Section: Mcts Can Explain Paradoxical Clinical Trial Resultsmentioning

confidence: 99%

The design, analysis and application of mouse clinical trials in oncology drug development

Guo

Jiang

Mao

et al. 2018

Preprint

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“…Overall, our glioma PDOX cohort provides a useful platform for understanding tumor biology and preclinical treatment interventions at the individual patient level. Although the parallel use of PDOXs as patient avatars during treatment remains challenging due to the poor prognosis of GBM patients, PDOXs can play a key role in 'mouse clinical trials' 94 for personalized medicine regimens. Longitudinal models will further serve as a powerful tool for analysis of tumor evolution and resistance mechanisms upon general and targeted therapies.…”

Section: Discussionmentioning

confidence: 99%

Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Golebiewska

Hau

Oudin

et al. 2020

Preprint

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Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies.

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“…Therefore, we can anticipate patient's clinical outcome by referring to PDXs, and thus are useful for clinical translational research, drug screening, and biomarker discovery and validation. PDXs are in vivo models to test clinically guided hypotheses, capable of evaluating drug activity and novel drug combined strategies, and also to elucidate their predictive biomarkers [7,8].…”

Section: Introductionmentioning

confidence: 99%

Establishment and characterization of patient-derived xenografts as paraclinical models for head and neck cancer

et al. 2020

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Background: We investigated whether head and neck squamous cell carcinoma (HNSCC) patient-derived xenografts (PDXs) reaffirm patient responses to anti-cancer therapeutics. Methods: Tumors from HNSCC patients were transplanted into immunodeficient mice and propagated via subsequent implantation. We evaluated established PDXs by histology, genomic profiling, and in vivo anti-cancer efficacy testing to confirm them as the authentic in vivo platform. Results: From 62 HNSCCs, 15 (24%) PDXs were established. The primary cancer types were tongue (8), oropharynx (3), hypopharynx (1), ethmoid sinus cancer (1), supraglottic cancer (1), and parotid gland (1); six PDXs (40%) were established from biopsy specimens from advanced HNSCC. PDXs mostly retained donor characteristics and remained stable across passages. PIK3CA (H1047R), HRAS (G12D), and TP53 mutations (H193R, I195T, R248W, R273H, E298X) and EGFR, CCND1, MYC, and PIK3CA amplifications were identified. Using the acquisition method, biopsy showed a significantly higher engraftment rate when compared with that of surgical resection (100% [6/6] vs. 16.1% [9/56], P < 0.001). Specimens obtained from metastatic sites showed a significantly higher engraftment rate than did those from primary sites (100% [9/9] vs. 11.3% [6/53], P < 0.001). Three PDX models from HPV-positive tumors were established, as compared to 12 from HPV-negative (15.8% [3/19] and 27.9% [12/43] respectively, P = 0.311), suggesting that HPV positivity tends to show a low engraftment rate. Drug responses in PDX recapitulated the clinical responses of the matching patients with pan-HER inhibitors and pan-PI3K inhibitor.(Continued on next page)

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Using PDX for Preclinical Cancer Drug Discovery: The Evolving Field

Cited by 84 publications

References 94 publications

The design, analysis and application of mouse clinical trials in oncology drug development

The design, analysis and application of mouse clinical trials in oncology drug development

Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Establishment and characterization of patient-derived xenografts as paraclinical models for head and neck cancer

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