Regorafenib Effects on Human Colon Carcinoma Xenografts Monitored by Dynamic Contrast-Enhanced Computed Tomography with Immunohistochemical Validation

Cyran, Clemens C.; Kazmierczak, Philipp M.; Hirner, Heidrun; Moser, Matthias; Ingrisch, Michael; Havla, Lukas; Michels, Alexandra; Eschbach, Ralf; Schwarz, Bettina; Reiser, Maximilian; Bruns, Christiane; Nikolaou, Konstantin

doi:10.1371/journal.pone.0076009

Cited by 26 publications

(25 citation statements)

References 29 publications

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“…These results are in accordance with several preclinical and clinical studies in the literature [28,36,37]. Intraindividual comparisons of early vascular CEUS and DCE-MRI perfusion parameters revealed only moderate, but significant correlations for WiAUC (CEUS) and PF (DCE-MRI).…”

Section: Discussionsupporting

confidence: 91%

“…Corresponding to CEUS measurements, a tissue region of interest was placed over the tumor periphery using semi-quantitative area under the curve (AUC) maps [28]. Tumor periphery was defined as the outer rim of the tumor (3 mm) as a representative region of viable tumor tissue which is less affected by elevated interstitial pressure and necrosis compared to the tumor center [29].…”

Section: Methodsmentioning

confidence: 99%

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Contrast-Enhanced Ultrasound with VEGFR2-Targeted Microbubbles for Monitoring Regorafenib Therapy Effects in Experimental Colorectal Adenocarcinomas in Rats with DCE-MRI and Immunohistochemical Validation

et al. 2017

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ObjectivesTo investigate contrast-enhanced ultrasound (CEUS) with VEGFR2-targeted microbubbles for monitoring therapy effects of regorafenib on experimental colon carcinomas in rats with correlation to dynamic contrast-enhanced MRI (DCE-MRI) and immunohistochemistry.Materials and MethodsHuman colorectal adenocarcinoma xenografts (HT-29) were implanted subcutaneously in n = 21 (n = 11 therapy group; n = 10 control group) female athymic nude rats (Hsd: RH-Foxn1rnu). Animals were imaged at baseline and after a one-week daily treatment with regorafenib or a placebo (10 mg/kg bodyweight), using CEUS with VEGFR2-targeted microbubbles and DCE-MRI. In CEUS tumor perfusion was assessed during an early vascular phase (wash-in area under the curve = WiAUC) and VEGFR2-specific binding during a late molecular phase (signal intensity after 8 (SI8min) and 10 minutes (SI10min)), using a conventional 15L8 linear transducer (transmit frequency 7 MHz, dynamic range 80 dB, depth 25 mm). In DCE-MRI functional parameters plasma flow (PF) and plasma volume (PV) were quantified. For validation purposes, CEUS parameters were correlated with DCE-MRI parameters and immunohistochemical VEGFR2, CD31, Ki-67 and TUNEL stainings.ResultsCEUS perfusion parameter WiAUC decreased significantly (116,989 ± 77,048 a.u. to 30,076 ± 27,095a.u.; p = 0.005) under therapy with no significant changes (133,932 ± 65,960 a.u. to 84,316 ± 74,144 a.u.; p = 0.093) in the control group. In the therapy group, the amount of bound microbubbles in the late phase was significantly lower in the therapy than in the control group on day 7 (SI8min: 283 ± 191 vs. 802 ± 460 a.u.; p = 0.006); SI10min: 226 ± 149 vs. 645 ± 461 a.u.; p = 0.009). PF and PV decreased significantly (PF: 147 ± 58 mL/100 mL/min to 71 ± 15 mL/100 mL/min; p = 0.003; PV: 13 ± 3% to 9 ± 4%; p = 0.040) in the therapy group. Immunohistochemistry revealed significantly fewer VEGFR2 (7.2 ± 1.8 vs. 17.8 ± 4.6; p < 0.001), CD31 (8.1 ± 3.0 vs. 20.8 ± 5.7; p < 0.001) and Ki-67 (318.7 ± 94.0 vs. 468.0 ± 133.8; p = 0.004) and significantly more TUNEL (672.7 ± 194.0 vs. 357.6 ± 192.0; p = 0.003) positive cells in the therapy group. CEUS parameters showed significant (p < 0.05) correlations to DCE-MRI parameters and immunohistochemistry.ConclusionsCEUS with VEGFR2-targeted microbubbles allowed for monitoring regorafenib functional and molecular therapy effects on experimental colorectal adenocarcinomas with a significant decline of CEUS and DCE-MRI perfusion parameters as well as a significant reduction of specifically bound microbubbles under therapy, consistent with a reduced expression of VEGFR2.

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Contrast-Enhanced Ultrasound with VEGFR2-Targeted Microbubbles for Monitoring Regorafenib Therapy Effects in Experimental Colorectal Adenocarcinomas in Rats with DCE-MRI and Immunohistochemical Validation

et al. 2017

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“…Regorafenib was approved by the FDA in 2012 for the second-line treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, with anti-VEGF therapy and, if KRAS wild type, with anti-EGFR therapy [83]. Clinical studies show that regorafenib significantly reduces tumor vascularity, delays tumor growth, and prevents metastasis in colon cancer models, supporting its use as an antiangiogenic treatment for CRC [111,112].…”

Section: Current and Emerging Multitargeting Antiangiogenic Agentsmentioning

confidence: 99%

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

2015

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Angiogenesis, or the formation of new capillary blood vessels, occurs primarily during human development and reproduction; however, aberrant regulation of angiogenesis is also a fundamental process found in several pathologic conditions, including cancer. As a process required for invasion and metastasis, tumor angiogenesis constitutes an important point of control of cancer progression. Although not yet completely understood, the complex process of tumor angiogenesis involves highly regulated orchestration of multiple signaling pathways. The proangiogenic signaling molecule vascular endothelial growth factor (VEGF) and its cognate receptor (VEGF receptor 2 [VEGFR‐2]) play a central role in angiogenesis and often are highly expressed in human cancers, and initial clinical efforts to develop antiangiogenic treatments focused largely on inhibiting VEGF/VEGFR signaling. Such approaches, however, often lead to transient responses and further disease progression because angiogenesis is regulated by multiple pathways that are able to compensate for each other when single pathways are inhibited. The platelet‐derived growth factor (PDGF) and PDGF receptor (PDGFR) and fibroblast growth factor (FGF) and FGF receptor (FGFR) pathways, for example, provide potential escape mechanisms from anti‐VEGF/VEGFR therapy that could facilitate resumption of tumor growth. Accordingly, more recent treatments have focused on inhibiting multiple signaling pathways simultaneously. This comprehensive review discusses the limitations of inhibiting VEGF signaling alone as an antiangiogenic strategy, the importance of other angiogenic pathways including PDGF/PDGFR and FGF/FGFR, and the novel current and emerging agents that target multiple angiogenic pathways for the treatment of advanced solid tumors. Implications for Practice: Significant advances in cancer treatment have been achieved with the development of antiangiogenic agents, the majority of which have focused on inhibition of the vascular endothelial growth factor (VEGF) pathway. VEGF targeting alone, however, has not proven to be as efficacious as originally hoped, and it is increasingly clear that there are many interconnected and compensatory pathways that can overcome VEGF‐targeted inhibition of angiogenesis. Maximizing the potential of antiangiogenic therapy is likely to require a broader therapeutic approach using a new generation of multitargeted antiangiogenic agents.

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“…In regards to regorafenib, as of March 2014 several articles with CRC cells have been reported [6,[35][36][37] but those with other types of malignant cells are still limited. In studies by Wilhelm et al in 2011 [6], several types of cancer cells including CRC, HCC, melanoma and gastrointestinal stromal tumor (GIST) as well as HUVECs, human aortic smooth muscle cells and NIH-3T3 cells were analyzed for regorafenib, where studies revealed that regorafenib inhibited angiogenic kinases such as VEGFR1, VEGFR2, VEGFR3, tyrosine kinase with immunoglobulin and epidermal growth factor homology domain-2, PDGFRB and fibroblast growth factor receptor 1 (FGFR1), as well as mutant oncogenic kinases of C-Kit, ret proto-oncogene (RET) and BRAF.…”

Section: Preclinical Development Of Regorafenibmentioning

confidence: 99%

“…Abou-Elkacem et al analyzed the inhibitory effects of regorafenib on tumor growth, angiogenesis and metastasis using orthotopic xenograft CRC models [36]. In addition, Cyran et al analyzed suppression of tumor vascularity for regorafenib using dynamic contrast-enhanced computed tomography effectively [37].…”

Section: Preclinical Development Of Regorafenibmentioning

confidence: 99%

The preclinical development of regorafenib for the treatment of colorectal cancer

Miura

Satoh

Kinouchi

et al. 2014

Expert Opinion on Drug Discovery

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In order to better predict the efficacy of kinase inhibitors and to utilize them more efficiently, our understanding of drug discovery, the approaches for kinase profiling, and technologies needed for their development are paramount. Indeed, the authors believe that the field should better explore the use of predictive biomarkers that might be able to better assess these therapeutics. Pharmaceutical scientists must also consider the cost effectiveness of the targeted agents developed as a number of the drugs developed are very expensive.

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Regorafenib Effects on Human Colon Carcinoma Xenografts Monitored by Dynamic Contrast-Enhanced Computed Tomography with Immunohistochemical Validation

Cited by 26 publications

References 29 publications

Contrast-Enhanced Ultrasound with VEGFR2-Targeted Microbubbles for Monitoring Regorafenib Therapy Effects in Experimental Colorectal Adenocarcinomas in Rats with DCE-MRI and Immunohistochemical Validation

Contrast-Enhanced Ultrasound with VEGFR2-Targeted Microbubbles for Monitoring Regorafenib Therapy Effects in Experimental Colorectal Adenocarcinomas in Rats with DCE-MRI and Immunohistochemical Validation

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

The preclinical development of regorafenib for the treatment of colorectal cancer

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