Patient-Derived Ovarian Tumor Xenografts Recapitulate Human Clinicopathology and Genetic Alterations

Ricci, Francesca; Bizzaro, Francesca; Cesca, Marta; Guffanti, Federica; Ganzinelli, Monica; Decio, Alessandra; Ghilardi, Carmen; Perego, Patrizia; Fruscio, Robert; Buda, Alessandro; Milani, Rodolfo; Ostano, Paola; Chiorino, Giovanna; Bani, Maria Rosa; Damia, Giovanna; Giavazzi, Raffaella

doi:10.1158/0008-5472.can-14-0274

Cited by 120 publications

(184 citation statements)

References 46 publications

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“…S2C). The comparable results on A2780-1A9 tumor growing ectopically in the subcutis or orthotopically in the ovary were consistent with our previous finding, showing that the histologic features (including vasculature) do not differ in the two sites (47).…”

Section: Maldi Msi Visualization Of Paclitaxel Shows More Homogeneoussupporting

confidence: 92%

Bevacizumab-Induced Inhibition of Angiogenesis Promotes a More Homogeneous Intratumoral Distribution of Paclitaxel, Improving the Antitumor Response

Cesca

Morosi

Berndt

et al. 2016

Molecular Cancer Therapeutics

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The antitumor activity of angiogenesis inhibitors is reinforced in combination with chemotherapy. It is debated whether this potentiation is related to a better drug delivery to the tumor due to the antiangiogenic effects on tumor vessel phenotype and functionality. We addressed this question by combining bevacizumab with paclitaxel on A2780-1A9 ovarian carcinoma and HT-29 colon carcinoma transplanted ectopically in the subcutis of nude mice and on A2780-1A9 and IGROV1 ovarian carcinoma transplanted orthotopically in the bursa of the mouse ovary. Paclitaxel concentrations together with its distribution by MALDI mass spectrometry imaging (MALDI MSI) were measured to determine the drug in different areas of the tumor, which was immunostained to depict vessel morphology and tumor proliferation. Bevacizumab modified the vessel bed, assessed by CD31 staining and dynamic contrast enhanced MRI (DCE-MRI), and potentiated the antitumor activity of paclitaxel in all the models. Although tumor paclitaxel concentrations were lower after bevacizumab, the drug distributed more homogeneously, particularly in vascularized, nonnecrotic areas, and was cleared more slowly than controls. This happened specifically in tumor tissue, as there was no change in paclitaxel pharmacokinetics or drug distribution in normal tissues. In addition, the drug concentration and distribution were not influenced by the site of tumor growth, as A2780-1A9 and IGROV1 growing in the ovary gave results similar to the tumor growing subcutaneously. We suggest that the changes in the tumor microenvironment architecture induced by bevacizumab, together with the better distribution of paclitaxel, may explain the significant antitumor potentiation by the combination. Mol Cancer Ther; 15(1); 125-35. Ó2015 AACR.

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Section: Maldi Msi Visualization Of Paclitaxel Shows More Homogeneoussupporting

confidence: 92%

Bevacizumab-Induced Inhibition of Angiogenesis Promotes a More Homogeneous Intratumoral Distribution of Paclitaxel, Improving the Antitumor Response

Cesca

Morosi

Berndt

et al. 2016

Molecular Cancer Therapeutics

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“…Eleven patient-derived epithelial ovarian cancer xenografts, eight serous, two endometrioid and one clear cell (EOC-PDX, Table 1), were obtained as described in detail [23]. EOC-PDX recovered from frozen stocks were used within 5-6 passages after establishment from patients and maintained by i.p.…”

Section: Human Ovarian Carcinoma Modelsmentioning

confidence: 99%

“…transplantation in nude mice as a 10 9 10 6 cell suspension [24]. These EOC-PDX models were molecularly, biologically and pharmacologically characterized [23]. Their response to DDP varies from low responsive to very responsive (Table 1).…”

Section: Human Ovarian Carcinoma Modelsmentioning

confidence: 99%

“…Ascites was harvested, EOC-PDX were obtained from ascites at paracentesis and established i.p. in nude mice, as described in [23] a Clinicopathological characteristics of the ovarian tumors from patients, at diagnosis centrifuged at 1200 rpm for 10 min and the volume of fluid and pellet (representative of tumor burden) recorded.…”

Section: Treatment Evaluationmentioning

confidence: 99%

“…We used our panel of EOC patient-derived xenografts (EOC-PDX), phenotypically, genotypically and pharmacologically characterized and shown to maintain the features of the patient's original tumor [23,24], to investigate the activity of Ced alone and in combination with chemotherapy and start to shed light on the unpredictable responses of the different tumors. We showed the response to Ced as single agent or combined with chemotherapy varies among EOC-PDX and the outcome of the combination was not associated to cisplatin (DDP) responsiveness.…”

Section: Introductionmentioning

confidence: 99%

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Cediranib combined with chemotherapy reduces tumor dissemination and prolongs the survival of mice bearing patient-derived ovarian cancer xenografts with different responsiveness to cisplatin

Decio

Cesca

Bizzaro

et al. 2015

Clin Exp Metastasis

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Cediranib is a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor that affects tumor angiogenesis and is under investigation in clinical studies on ovarian cancer. Using a panel of eleven patient-derived ovarian cancer xenografts (EOC-PDX) growing orthotopically in the peritoneal cavity of nude mice we investigated the effect of cediranib as monotherapy or in combination with chemotherapy on overall survival (primary endpoint, at euthanasia), and tumor dissemination and metastasis in the peritoneal cavity (secondary endpoint, interim analysis). The response of EOC-PDX to cediranib varied (increment of lifespan, ILS between 12 and 85 %) in the different EOC-PDX, independently from tumor responsiveness to cisplatin (DDP). Cediranib combined with DDP and in maintenance regimen prolonged the survival of mice bearing EOC-PDX with different responsiveness to DDP (ILS between 34 and 224 % with only DDP and between 135 and 337 % with DDP plus Cediranib); survival was extended with the addition of paclitaxel to chemotherapy (50-77 % complete remissions). Cediranib reduced ascites of advanced EOC-PDX, but had limited effect on tumor dissemination; only combined with chemotherapy, ascites and metastases were both reduced. The reduction of tumor dissemination was associated to the increase of overall survival. In conclusion, the response to cediranib differs in the various EOC-PDX, reproducing the heterogeneous response of cancer patients to angiogenesis inhibitors. Cediranib potentiated chemotherapy, significantly inhibiting tumor progression and dissemination to metastatic organs, even in tumors poorly responsive to DDP. EOC-PDX preclinical models with different responsiveness to Cediranib may help in identifying determinants of response to cediranib and mechanisms of adaptation to antiangiogenic treatments.

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Targeting HER2 in patient‐derived xenograft ovarian cancer models sensitizes tumors to chemotherapy

et al. 2018

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Ovarian cancer is the most lethal gynecologic malignancy. About 75% of ovarian cancer patients relapse and/or develop chemo‐resistant disease after initial response to standard‐of‐care treatment with platinum‐based therapies. HER2 amplifications and overexpression in ovarian cancer are reported to vary, and responses to HER2 inhibitors have been poor. Next generation sequencing technologies in conjunction with testing using patient‐derived xenografts (PDX) allow validation of personalized treatments. Using a whole‐genome mate‐pair next generation sequencing (MPseq) protocol, we identified several high grade serous ovarian cancers (HGS‐OC) with DNA alterations in genes encoding members of the ERBB2 pathway. The efficiency of anti‐HER2 therapy was tested in three different PDX lines with the identified alterations and high levels of HER2 protein expression. Treatment responses to pertuzumab or pertuzumab/trastuzumab were compared in each PDX line WITH standard carboplatin and paclitaxel combination treatment. In all three PDX models, HER2‐targeted therapy resulted in significant inhibition of tumor growth compared with untreated controls. However, the responses in each case were inferior to those to chemotherapy, even for chemo‐resistant lines. When chemotherapy and HER2‐targeted therapy were administered together, a significant regression of tumor was observed after 6 weeks of treatment compared with chemotherapy alone. Post‐treatment analysis of these tissues revealed that inhibition of the ERBB2 pathway occurred at the level of phosphorylation and expression of downstream targets. In conclusion, while targeting of presumably activated ERBB2 pathway alone in HGS‐OC results in a modest treatment benefit, a combination therapy including both chemotherapy drugs and HER2 inhibitors provides a far better response. Further studies are needed to address development of recurrence and sensitivity of recurrent disease to HER2‐targeted therapy.

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Patient-Derived Ovarian Tumor Xenografts Recapitulate Human Clinicopathology and Genetic Alterations

Cited by 120 publications

References 46 publications

Bevacizumab-Induced Inhibition of Angiogenesis Promotes a More Homogeneous Intratumoral Distribution of Paclitaxel, Improving the Antitumor Response

Bevacizumab-Induced Inhibition of Angiogenesis Promotes a More Homogeneous Intratumoral Distribution of Paclitaxel, Improving the Antitumor Response

Cediranib combined with chemotherapy reduces tumor dissemination and prolongs the survival of mice bearing patient-derived ovarian cancer xenografts with different responsiveness to cisplatin

Targeting HER2 in patient‐derived xenograft ovarian cancer models sensitizes tumors to chemotherapy

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