Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors

Izumchenko, Eugene; Paz, Keren; Ciznadija, Daniel; Sloma, Ido; Katz, Amanda; Vasquez-Dunddel, David; Ben-Zvi, Ido; Stebbing, Justin; McGuire, William P.; Harris, William Proctor; Maki, Robert G.; Gaya, Andrew; Bedi, Atul; Zacharoulis, Stergios; Ravi, Rajani; Wexler, Leonard H.; Hoque, Mohammad O.; Rodríguez‐Galindo, Carlos; Pass, Harvey I.; Peled, Nir; Davies, Angela M.; Morris, Ronnie; Hidalgo, Manuel; Sidransky, David

doi:10.1093/annonc/mdx416

Cited by 260 publications

(246 citation statements)

References 34 publications

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“…There is a need for preclinical models that faithfully represent this heterogeneity. Patient‐derived xenografts (PDXs) models are robust preclinical models to test targeted therapies because they conserve each patient's molecular heterogeneity and response to treatment . These models have emerged as an important translational research tool to identify new treatments and predictive biomarkers .…”

Section: Introductionmentioning

confidence: 99%

A large collection of integrated genomically characterized patient‐derived xenografts highlighting the heterogeneity of triple‐negative breast cancer

Coussy

Koning

Lavigne

et al. 2019

Intl Journal of Cancer

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Triple‐negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective targeted therapies remains a real challenge. Patient‐derived xenografts (PDX) are clinically relevant models that have emerged as important tools for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX (n = 61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of significantly mutated gene and somatic copy number alteration in PDX and the Cancer Genome Atlas TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes. TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research.

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Section: Introductionmentioning

confidence: 99%

A large collection of integrated genomically characterized patient‐derived xenografts highlighting the heterogeneity of triple‐negative breast cancer

Coussy

Koning

Lavigne

et al. 2019

Intl Journal of Cancer

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show abstract

Section: Introductionmentioning

confidence: 99%

“…Evidence has shown that PDXs retain the genome-wide exomic nucleotide variants, gene copy number alterations, and DNA methylation patterns of their corresponding tumors [1][2][3][4] irrespective of the number of passages, 1,3 although clonal selection during initial engraftment and passaging of PDXs has been observed. 4 PDX models also are increasingly used in the mechanistic characterization of resistance to targeted therapies, [9][10][11] the identification of novel Cancer November 1, 2019 biomarkers 12 and therapeutic targets, 13 and the characterization of intratumoral heterogeneity. 7,8 An analysis of the treatment responses of PDXs established from 92 patients with different solid tumors demonstrated a significant association between drug response in patients and the response in mice bearing the corresponding PDXs, indicating that PDXs can predict clinical treatment response.…”

Section: Introductionmentioning

confidence: 99%

Tumor characteristics associated with engraftment of patient‐derived non–small cell lung cancer xenografts in immunocompromised mice

Chen

Zhang

Wang

et al. 2019

Cancer

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BACKGROUND: Patient-derived xenograft (PDX) models increasingly are used in translational research. However, the engraftment rates of patient tumor samples in immunodeficient mice to PDX models vary greatly. METHODS: Tumor tissue samples from 308 patients with non-small cell lung cancer were implanted in immunodeficient mice. The patients were followed for 1.5 to approximately 6 years. The authors performed histological analysis of PDXs and some residual tumor tissues in mice with failed PDX growth at 1 year after implantation. Quantitative polymerase chain reaction and enzyme-linked immunoadsorbent assay were performed to measure the levels of Epstein-Barr virus genes and human immunoglobulin G in PDX samples. Patient characteristics were compared for PDX growth and overall survival as outcomes using Cox regression analyses. Disease staging was based on the 7th TNM staging system. RESULTS:The overall engraftment rate for PDXs from patients with non-small cell lung cancer was 34%. Squamous cell carcinomas had a higher engraftment rate (53%) compared with adenocarcinomas. Tumor samples from patients with stage II and stage III disease and from larger tumors were found to have relatively high engraftment rates. Patients whose tumors successfully engrafted had worse overall survival, particularly those individuals with adenocarcinoma, stage III or stage IV disease, and moderately differentiated tumors. Lymphoma formation was one of the factors associated with engraftment failure. Human CD8-positive and CD20-positive cells were detected in residual samples of tumor tissue that failed to generate a PDX at 1 year after implantation. Human immunoglobulin G was detected in the plasma of mice that did not have PDX growth at 14 months after implantation. CONCLUSIONS: The results of the current study indicate that the characteristics of cancer cells and the tumor immune microenvironment in primary tumors both can affect engraftment of a primary tumor sample. Cancer 2019;125:3738-3748.

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“…This observation is consistent with those of Izumchenko et al. that PDXs can more accurately replicate patient outcomes, supporting the capacity of these models to correctly guide treatment decisions that are most likely to be beneficial clinically …”

Section: Discussionmentioning

confidence: 99%

Optimization of a clofarabine‐based drug combination regimen for the preclinical evaluation of pediatric acute lymphoblastic leukemia

Xie

Span

Maarseveen

et al. 2019

Pediatric Blood & Cancer

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Background The aim of this study was to improve the predictive power of patient‐derived xenografts (PDXs, also known as mouse avatars) to more accurately reflect outcomes of clofarabine‐based treatment in pediatric acute lymphoblastic leukemia (ALL) patients. Procedure Pharmacokinetic (PK) studies were conducted using clofarabine at 3.5 to 15 mg/kg in mice. PDXs were established from relapsed/refractory ALL patients who exhibited good or poor responses to clofarabine. PDX engraftment and response to clofarabine (either as a single agent or in combinations) were assessed based on stringent objective response measures modeled after the clinical setting. Results In naïve immune‐deficient NSG mice, we determined that a clofarabine dose of 3.5 mg/kg resulted in systemic exposures equivalent to those achieved in pediatric ALL patients treated with clofarabine‐based regimens. This dose was markedly lower than the doses of clofarabine used in previously reported preclinical studies (typically 30‐60 mg/kg) and, when scheduled consistent with the clinical regimen (daily × 5), resulted in 34‐fold lower clofarabine exposures. Using a well‐tolerated clofarabine/etoposide/cyclophosphamide combination regimen, we then found that the responses of PDXs better reflected the clinical responses of the patients from whom the PDXs were derived. Conclusions This study has identified an in vivo clofarabine treatment regimen that reflects the clinical responses of relapsed/refractory pediatric ALL patients. This regimen could be used prospectively to identify patients who might benefit from clofarabine‐based treatment. Our findings are an important step toward individualizing prospective patient selection for the use of clofarabine in relapsed/refractory pediatric ALL patients and highlight the need for detailed PK evaluation in murine PDX models.

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Patient-derived xenografts effectively capture responses to oncology therapy in a heterogeneous cohort of patients with solid tumors

Abstract: Integration of PDX models as a preclinical platform for assessment of drug efficacy may allow a higher success-rate in critical end points of clinical benefit.

Cited by 260 publications

References 34 publications

A large collection of integrated genomically characterized patient‐derived xenografts highlighting the heterogeneity of triple‐negative breast cancer

A large collection of integrated genomically characterized patient‐derived xenografts highlighting the heterogeneity of triple‐negative breast cancer

Tumor characteristics associated with engraftment of patient‐derived non–small cell lung cancer xenografts in immunocompromised mice

Optimization of a clofarabine‐based drug combination regimen for the preclinical evaluation of pediatric acute lymphoblastic leukemia

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