Mutation Status of KRAS, BRAF, PIK3CA and Expression Level of AREG and EREG Identify Responders to Cetuximab in a Large Panel of Patient Derived Colorectal Carcinoma Xenografts of All Four UICC Stages

Becker, Michael W.; Mayr, Tobias; Hinzmann, Bernd; Kretschmar, K.; Stecker, Katrin; Mantke, René; Pauli, R.; Pertschy, J.; Hertel, K.; Ridwelski, K.; Hellwig, Karsten; Pross, M.; Radke, Cornelia; Fichtner, Iduna; Hoffmann, Jens; Rosenthal, André; Viszeralchirurgie, Klinik für Allgemein-und; Magdeburg, Klinikum; Medizin, Molekulare

doi:10.4236/jct.2013.42083

Cited by 4 publications

(11 citation statements)

References 36 publications

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“…Previous and independent studies have demonstrated through use of a panel of tumor models established from cell lines that the status of KRAS, BRAF, PIK3CA, and PTEN did not significantly influence the response to aflibercept (44, data not shown). Similar findings have been reported for bevacizumab (45).…”

Section: Genomic Characterization Of Pdx Modelssupporting

confidence: 80%

Differential Antitumor Activity of Aflibercept and Bevacizumab in Patient-Derived Xenograft Models of Colorectal Cancer

Chiron

Bagley

Pollard

et al. 2014

Molecular Cancer Therapeutics

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The recombinant fusion protein aflibercept (ziv-aflibercept in the United States) binds VEGF-A, VEGF-B, and placental growth factor (PlGF). The monoclonal antibody bevacizumab binds VEGF-A. Recent studies hypothesized that dual targeting of VEGF/PlGF is more beneficial than targeting either ligand. We compared activity of aflibercept versus bevacizumab in 48 patient-derived xenograft (PDX) colorectal cancer models. Nude mice engrafted subcutaneously with PDX colorectal cancer tumors received biweekly aflibercept, bevacizumab, or vehicle injections. Differential activity between aflibercept and bevacizumab, determined by mouse (m), human (h), VEGF-A, and PlGF levels in untreated tumors, was measured. Aflibercept induced complete tumor stasis in 31 of 48 models and bevacizumab in 2 of 48. Based on statistical analysis, aflibercept was more active than bevacizumab in 39 of 48 models; in 9 of 39 of these models, bevacizumab was considered inactive. In 9 of 48 remaining models, aflibercept and bevacizumab had similar activity. Tumor levels of hVEGF-A (range 776-56,039 pg/mg total protein) were $16-to 1,777-fold greater than mVEGF-A (range 8-159 pg/mg total protein). Tumor levels of mPlGF (range 104-1,837 pg/mg total protein) were higher than hPlGF (range 0-543 pg/mg total protein) in 47 of 48 models. Tumor cells were the major source of VEGF; PlGF was primarily produced by tumor stroma. Because tumor levels of hVEGF-A were far greater than mVEGF-A, bevacizumab's inability to bind mVEGF-A is unlikely to explain higher and more consistent aflibercept activity. Neutralizing PlGF and VEGFR-1 activation may be a factor and should be investigated in future studies. In these colorectal cancer PDX models, aflibercept demonstrated greater antitumor activity than bevacizumab. Mol Cancer Ther; 13(6); 1636-44. Ó2014 AACR.

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Section: Genomic Characterization Of Pdx Modelssupporting

confidence: 80%

Differential Antitumor Activity of Aflibercept and Bevacizumab in Patient-Derived Xenograft Models of Colorectal Cancer

Chiron

Bagley

Pollard

et al. 2014

Molecular Cancer Therapeutics

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“…In addition, we validated the classifier's predictive power on two independent CRC xenograft cohorts and one independent human cohort. We generated RNAseq data on a previously reported collection from EPO ( n =60) 58 and downloaded the informative data from Novartis PDXs (NV, n =36) 12 , and from a human cohort of 68 patients KF ( n =68) 46 , all treated with cetuximab ( Fig. 10c ; Supplementary Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors

et al. 2017

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Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I–IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling >4,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab.

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“…This is in contrast to anti-EGFR-based antibody therapies, where the mutational status of KRAS and BRAF predicts responsiveness. 13,24 Indeed, the xenograft models used in our study that expressed either mutated KRAS or BRAF were refractory to cetuximab treatment. 24 We did not see a correlation between the effects of regorafenib and the mutational status of b-catenin and APC.…”

Section: Discussionmentioning

confidence: 97%

“…13,24 Indeed, the xenograft models used in our study that expressed either mutated KRAS or BRAF were refractory to cetuximab treatment. 24 We did not see a correlation between the effects of regorafenib and the mutational status of b-catenin and APC. However, there may be other genes worth considering and further research is required.…”

Section: Discussionmentioning

confidence: 97%

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Regorafenib (BAY 73‐4506): Antitumor and antimetastatic activities in preclinical models of colorectal cancer

Schmieder

Hoffmann

Becker

et al. 2014

Intl Journal of Cancer

112

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Regorafenib, a novel multikinase inhibitor, has recently demonstrated overall survival benefits in metastatic colorectal cancer (CRC) patients. Our study aimed to gain further insight into the molecular mechanisms of regorafenib and to assess its potential in combination therapy. Regorafenib was tested alone and in combination with irinotecan in patient-derived (PD) CRC models and a murine CRC liver metastasis model. Mechanism of action was investigated using in vitro functional assays, immunohistochemistry and correlation with CRC-related oncogenes. Regorafenib demonstrated significant inhibition of growth-factor-mediated vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR3 autophosphorylation, and intracellular VEGFR3 signaling in human umbilical vascular endothelial cells (HuVECs) and lymphatic endothelial cells (LECs), and also blocked migration of LECs. Furthermore, regorafenib inhibited proliferation in 19 of 25 human CRC cell lines and markedly slowed tumor growth in five of seven PD xenograft models. Combination of regorafenib with irinotecan significantly delayed tumor growth after extended treatment in four xenograft models. Reduced CD31 staining indicates that the antiangiogenic effects of regorafenib contribute to its antitumor activity. Finally, regorafenib significantly delayed disease progression in a murine CRC liver metastasis model by inhibiting the growth of established liver metastases and preventing the formation of new metastases in other organs. In addition, our results suggest that regorafenib displays antimetastatic activity, which may contribute to its efficacy in patients with metastatic CRC. Combination of regorafenib and irinotecan demonstrated an increased antitumor effect and could provide a future treatment option for CRC patients.What's new?Regorafenib is a multikinase inhibitor with antiangiogenic activity recently approved in the US and in Europe for the treatment of metastatic colorectal cancer in patients who failed previous therapies. Here, a research team led by Bayer Pharma AG, the discoverer of the drug, confirms inhibition of key mediators of angiogenesis and lymphangiogenesis (VEGFR2 and VEGFR3) as the potential antiangiogenic mechanism of action of the drug. Regorafenib further inhibited growth of established and prevented formation of new liver metastases, and in combination with the chemotherapeutic drug irinotecan led to significant tumor growth delay in four patient-derived colorectal cancer xenograft models. The authors speculate that combination treatments including regorafenib may provide novel therapeutic opportunities for patients with therapy-resistant colorectal cancer.

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Mutation Status of KRAS, BRAF, PIK3CA and Expression Level of AREG and EREG Identify Responders to Cetuximab in a Large Panel of Patient Derived Colorectal Carcinoma Xenografts of All Four UICC Stages

Cited by 4 publications

References 36 publications

Differential Antitumor Activity of Aflibercept and Bevacizumab in Patient-Derived Xenograft Models of Colorectal Cancer

Differential Antitumor Activity of Aflibercept and Bevacizumab in Patient-Derived Xenograft Models of Colorectal Cancer

Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors

Regorafenib (BAY 73‐4506): Antitumor and antimetastatic activities in preclinical models of colorectal cancer

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