Patient-derived xenografts: a promising resource for preclinical cancer research

Karamboulas, Christina; Ailles, Laurie

doi:10.1080/23723556.2018.1558684

Cited by 3 publications

(3 citation statements)

References 10 publications

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“…2b). In 29% of the PDX, we observed PDX-specific deep deletions in CDKN2A/CDKN2B, consistent with selection for loss of these tumor suppressor genes during the process of PDX engraftment 24 .…”

Section: Establishment and Characterization Of Utuc Pdx And Pdcsupporting

confidence: 70%

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Kim

Audenet

et al. 2020

Nat Commun

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Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of diseasespecific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.

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Section: Establishment and Characterization Of Utuc Pdx And Pdcsupporting

confidence: 70%

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Kim

Audenet

et al. 2020

Nat Commun

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“…Karamboulas et al established a large collection of PDX models of head and neck squamous cell carcinoma (HNSCC). They showed the efficacy of CDK4 and CDK6 inhibitors for HNSCC with CCND1 and CDKN2A genomic alterations [89,90]. For breast cancer, Grunewald et al evaluated the activity of a novel fibroblast growth factor receptor (FGFR) inhibitor, rogaratinib, using cancer cell lines and breast cancer PDX models [91].…”

Section: Application Of Pdx Models For Clinical Usementioning

confidence: 99%

Patient-Derived Xenograft Models of Breast Cancer and Their Application

Murayama

Gotoh

2019

Cells

107

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Recently, patient-derived xenograft (PDX) models of many types of tumors including breast cancer have emerged as a powerful tool for predicting drug efficacy and for understanding tumor characteristics. PDXs are established by the direct transfer of human tumors into highly immunodeficient mice and then maintained by passaging from mouse to mouse. The ability of PDX models to maintain the original features of patient tumors and to reflect drug sensitivity has greatly improved both basic and clinical study outcomes. However, current PDX models cannot completely predict drug efficacy because they do not recapitulate the tumor microenvironment of origin, a failure which puts emphasis on the necessity for the development of the next generation PDX models. In this article, we summarize the advantages and limitations of current PDX models and discuss the future directions of this field.

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“…We compared these predicted doses based on [ 64 Cu]Cu-DOTA-panitumumab F(ab') 2 to those estimated directly from the BOD of [ 177 Lu]Lu-DOTA-panitumumab F(ab') 2 to assess the feasibility of a PET theranostic strategy. The PDX mouse model of HNSCC used in this study is clinically relevant because these PDX recapitulate the properties of HNSCC tumours in patients (Karamboulas and Ailles, 2019 ). This strengthens our assessment of the feasibility of a PET theranostic strategy for patients with HNSCC.…”

Section: Introductionmentioning

confidence: 99%

Dose predictions for [177Lu]Lu-DOTA-panitumumab F(ab′)2 in NRG mice with HNSCC patient-derived tumour xenografts based on [64Cu]Cu-DOTA-panitumumab F(ab′)2 – implications for a PET theranostic strategy

Kondo

Cai

et al. 2021

EJNMMI radiopharm. chem.

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Background Epidermal growth factor receptors (EGFR) are overexpressed on many head and neck squamous cell carcinoma (HNSCC). Radioimmunotherapy (RIT) with F(ab')2 of the anti-EGFR monoclonal antibody panitumumab labeled with the β-particle emitter, 177Lu may be a promising treatment for HNSCC. Our aim was to assess the feasibility of a theranostic strategy that combines positron emission tomography (PET) with [64Cu]Cu-DOTA-panitumumab F(ab')2 to image HNSCC and predict the radiation equivalent doses to the tumour and normal organs from RIT with [177Lu]Lu-DOTA-panitumumab F(ab')2. Results Panitumumab F(ab')2 were conjugated to DOTA and complexed to 64Cu or 177Lu in high radiochemical purity (95.6 ± 2.1% and 96.7 ± 3.5%, respectively) and exhibited high affinity EGFR binding (Kd = 2.9 ± 0.7 × 10− 9 mol/L). Biodistribution (BOD) studies at 6, 24 or 48 h post-injection (p.i.) of [64Cu]Cu-DOTA-panitumumab F(ab')2 (5.5–14.0 MBq; 50 μg) or [177Lu]Lu-DOTA-panitumumab F(ab')2 (6.5 MBq; 50 μg) in NRG mice with s.c. HNSCC patient-derived xenografts (PDX) overall showed no significant differences in tumour uptake but modest differences in normal organ uptake were noted at certain time points. Tumours were imaged by microPET/CT with [64Cu]Cu-DOTA-panitumumab F(ab')2 or microSPECT/CT with [177Lu]Lu-DOTA-panitumumab F(ab')2 but not with irrelevant [177Lu]Lu-DOTA-trastuzumab F(ab')2. Tumour uptake at 24 h p.i. of [64Cu]Cu-DOTA-panitumumab F(ab')2 [14.9 ± 1.1% injected dose/gram (%ID/g) and [177Lu]Lu-DOTA-panitumumab F(ab')2 (18.0 ± 0.4%ID/g) were significantly higher (P < 0.05) than [177Lu]Lu-DOTA-trastuzumab F(ab')2 (2.6 ± 0.5%ID/g), demonstrating EGFR-mediated tumour uptake. There were no significant differences in the radiation equivalent doses in the tumour and most normal organs estimated for [177Lu]Lu-DOTA-panitumumab F(ab')2 based on the BOD of [64Cu]Cu-DOTA-panitumumab F(ab')2 compared to those estimated directly from the BOD of [177Lu]Lu-DOTA-panitumumab F(ab')2 except for the liver and whole body which were modestly underestimated by [64Cu]Cu-DOTA-panitumumab F(ab')2. Region-of-interest (ROI) analysis of microPET/CT images provided dose estimates for the tumour and liver that were not significantly different for the two radioimmunoconjugates. Human doses from administration of [177Lu]Lu-DOTA-panitumumab F(ab')2 predicted that a 2 cm diameter HNSCC tumour in a patient would receive 1.1–1.5 mSv/MBq and the whole body dose would be 0.15–0.22 mSv/MBq. Conclusion A PET theranostic strategy combining [64Cu]Cu-DOTA-panitumumab F(ab')2 to image HNSCC tumours and predict the equivalent radiation doses in the tumour and normal organs from RIT with [177Lu]Lu-DOTA-panitumumab F(ab')2 is feasible. RIT with [177Lu]Lu-DOTA-panitumumab F(ab')2 may be a promising approach to treatment of HNSCC due to frequent overexpression of EGFR.

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Patient-derived xenografts: a promising resource for preclinical cancer research

Cited by 3 publications

References 10 publications

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Patient-Derived Xenograft Models of Breast Cancer and Their Application

Dose predictions for [177Lu]Lu-DOTA-panitumumab F(ab′)2 in NRG mice with HNSCC patient-derived tumour xenografts based on [64Cu]Cu-DOTA-panitumumab F(ab′)2 – implications for a PET theranostic strategy

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