Combination therapy of gemcitabine or oral S-1 with the anti-VEGF monoclonal antibody bevacizumab for pancreatic neuroendocrine carcinoma

Kasuya, Kazuhiko; Nagakawa, Yuichi; Suzuki, Minako; Suzuki, Yoshiaki; Kyo, Bunso; Matsudo, Takaaki; Tsuchida, Akihiko; Aoki, Tatsuya

doi:10.3892/etm.2012.456

Cited by 13 publications

(8 citation statements)

References 17 publications

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“…Our findings coincide with those of others showing that while targeting PDGF-B with the selective aptamer AX102 reduced tumor vascularity, it did not decrease tumor size(23). By contrast, several studies have demonstrated the effectiveness of combining anti-angiogenic agents with chemotherapy in inhibiting tumor growth and inducing tumor regression(38, 39). Combining the chemotherapeutic agent, gemcitabine, with the anti-VEGF monoclonal antibody, bevacizumab, resulted in a strong antitumor effect in a model of pancreatic neuroendocrine carcinoma (38).…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, several studies have demonstrated the effectiveness of combining anti-angiogenic agents with chemotherapy in inhibiting tumor growth and inducing tumor regression(38, 39). Combining the chemotherapeutic agent, gemcitabine, with the anti-VEGF monoclonal antibody, bevacizumab, resulted in a strong antitumor effect in a model of pancreatic neuroendocrine carcinoma (38). We propose that blocking BMC differentiation into pericytes may potentially augment the activity and effect of cytotoxic chemotherapy when used in combination.…”

Section: Discussionmentioning

confidence: 99%

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Blocking SDF-1α/CXCR4 Downregulates PDGF-B and Inhibits Bone Marrow–Derived Pericyte Differentiation and Tumor Vascular Expansion in Ewing Tumors

Hamdan

Zhou

Kleinerman

2014

Molecular Cancer Therapeutics

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Bone marrow cells (BMCs) are critical to the expansion of the tumor vessel network that supports Ewing’s sarcoma growth. BMCs migrate to the tumor and differentiate into endothelial cells and pericytes. We recently demonstrated that stromal derived growth factor 1α (SDF-1α) regulates platelet derived growth factor B (PDGF-B) and that this pathway plays a critical role in BM-derived pericyte differentiation in vitro. We investigated the role of SDF-1α/PDGF-B in the tumor microenvironment in vivo in promoting BM-derived pericyte differentiation in Ewing’s tumors. The CXCR4 antagonist, AMD 3100, was used to disrupt the SDF-1α/CXCR4 axis in vivo in two xenograft Ewing’s tumor models. BMCs from green fluorescent protein (GFP+) transgenic mice were transplanted into lethally irradiated nude mice in order to track BMC migration to the tumor site. Following BMC engraftment, tumor-bearing mice received daily subcutaneous injections of either PBS or AMD 3100 for 3 weeks. Tumors were resected, and tumor sections were analyzed by immunohistochemistry. AMD 3100 inhibited BMC differentiation into desmin+ and NG2+ pericytes, affected the morphology of the tumor vasculature, decreased perfusion, and increased tumor cell apoptosis. We observed smaller vessels with tiny lumens and a decrease in the microvessel density. AMD 3100 also inhibited PDGF-B protein expression in vitro and in vivo. SDF-1α in the tumor microenvironment plays a critical role in promoting pericyte formation and Ewing’s sarcoma tumor neovascularization by regulating PDGF-B expression. Interfering with this pathway affects tumor vascular morphology and expansion.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Blocking SDF-1α/CXCR4 Downregulates PDGF-B and Inhibits Bone Marrow–Derived Pericyte Differentiation and Tumor Vascular Expansion in Ewing Tumors

Hamdan

Zhou

Kleinerman

2014

Molecular Cancer Therapeutics

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“…Thus, a therapeutic approach inhibiting this pathway appears to be promising. Therefore, the multikinase inhibitor sunitinib and the monoclonal antibody bevacizumab have both been evaluated in clinical trials including patients with advanced pNENs [ 41 , 42 ]. Sunitinib, which irreversibly blocks tyrosine kinases such as VEGFR 2 and 3 and platelet-derived growth factor receptor (PDGFR), showed a prolonged progression free survival compared to placebo [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Distinct Expression Patterns of VEGFR 1-3 in Gastroenteropancreatic Neuroendocrine Neoplasms: Supporting Clinical Relevance, but not a Prognostic Factor

Bösch

Altendorf-Hofmann

Jacob

et al. 2020

JCM

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Introduction: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are an increasing tumor entity. Since many patients are diagnosed at an advanced stage, treatment is still challenging and dependent on many tumor and patient specific factors. Therefore, the aim of the present study was to elucidate the expression rates and the prognostic value of vascular endothelial growth factor receptor (VEGFR) 1-3 in GEP-NENs. A potential association to immune checkpoint markers was further investigated. Material and Methods: The expression levels of VEGFR 1-3 were analyzed by immunohistochemistry and correlated with the expression of the checkpoint markers PD-1 and PD-L1. Furthermore, the tumor samples of 249 GEP-NEN patients were studied and correlated with overall survival rates and clinicopathological features. Kaplan–Meier analyses and the log rank test were used for survival analyses. Categorical variables were compared by the χ2 test. Results: The most common primary tumor site was the small intestine (50.6%), followed by the pancreas (25.7%). VEGFR 1 was highly expressed in 59%, VEGFR 2 in 6.4%, and VEGFR 3 in 61.8% of the analyzed samples. The expression of VEGFR 1-3 was not significantly associated with survival rates. Pancreatic NENs had the highest expression of VEGFR 1 and 3 in 80% of the cases. VEGFR 1-3 positivity correlated with the expression levels of immune checkpoint markers. Discussion: VEGFR 1-3 show a distinct expression pattern in different subgroups of neuroendocrine neoplasias indicating a conceivable target. Moreover, there was a substantial association between VEGFRs and immune checkpoint markers. Taken together, anti-VEGFR therapy represents a promising therapeutic approach in GEP-NEN patients and should be addressed in future studies.

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“…Traditional medical treatment of PNET includes cytotoxic streptozocin, doxorubicin, 5-fluorouracil [103], capecitabine and oxaliplatin [104], and gemcitabine [105,106] combined in several ways. Somatostatin analogs have long been evaluated and therefore used in the treatment of unresectable or metastatic neuroendocrine tumors of all origins, including PNETs.…”

Section: Systemic Medical Managementmentioning

confidence: 99%

Pancreatic neuroendocrine tumors

Karakaxas¹,

Gazouli²,

Liakakos³

et al. 2014

European Journal of Gastroenterology &Amp; Hepatology

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Pancreatic neuroendocrine tumors (PNETs) share a unique genetic identity, functional behavior, and clinical course. Compared with tumors of the exocrine pancreas, they are rare and show a different biologic behavior and prognosis. On the basis of data from recent studies, all PNETs, outside of small insulinomas, should be considered potentially malignant and treated accordingly. Untreated tumors have a high possibility to grow locally into adjacent structures or spread to distant organs. Although surgical excision irrespective of tumor functioning or nonfunctioning state remains the cornerstone of therapy, providing the best disease-free and survival rates to date, the understanding of the genetic nature of the disease yields new 'targets' to consider in drug development. The aim of this review is to summarize all recent advances of genetic research and new drug development in terms of PNETs, especially their genetic identity and subsequent alterations leading to the development of near or total malignant activity, and the new medical treatment strategies of this potentially curable disease on the basis of therapeutical agents acting, where possible, at the genetic level.

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Combination therapy of gemcitabine or oral S-1 with the anti-VEGF monoclonal antibody bevacizumab for pancreatic neuroendocrine carcinoma

Cited by 13 publications

References 17 publications

Blocking SDF-1α/CXCR4 Downregulates PDGF-B and Inhibits Bone Marrow–Derived Pericyte Differentiation and Tumor Vascular Expansion in Ewing Tumors

Blocking SDF-1α/CXCR4 Downregulates PDGF-B and Inhibits Bone Marrow–Derived Pericyte Differentiation and Tumor Vascular Expansion in Ewing Tumors

Distinct Expression Patterns of VEGFR 1-3 in Gastroenteropancreatic Neuroendocrine Neoplasms: Supporting Clinical Relevance, but not a Prognostic Factor

Pancreatic neuroendocrine tumors

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