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Journal ArticleDOI

Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors

01 Oct 2005-Cancer Cell (Cancer Cell)-Vol. 8, Iss: 4, pp 299-309
TL;DR: Function-blocking antibodies to VEGF receptors R1 and R2 were used to probe their roles in controlling angiogenesis in a mouse model of pancreatic islet carcinogenesis, finding phenotypic resistance to V EGFR2 blockade emerged.
About: This article is published in Cancer Cell.The article was published on 2005-10-01 and is currently open access. It has received 1541 citations till now. The article focuses on the topics: Angiogenesis & Fibroblast growth factor.
Citations
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Journal ArticleDOI
TL;DR: Most of the hallmarks of cancer are enabled and sustained to varying degrees through contributions from repertoires of stromal cell types and distinctive subcell types, which presents interesting new targets for anticancer therapy.

3,486 citations


Cites background from "Drug resistance by evasion of antia..."

  • ...…is likely multifactorial, based on preclinical studies in mouse models, which have revealed in some cases evasion of the signaling blockage (Casanovas et al., 2005), in others recruitment of additional or different subtypes of proangiogenic IICs or CAFs (Priceman et al., 2010; Shojaei et…...

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Journal ArticleDOI
TL;DR: Emerging data support a proposition that two modes of unconventional resistance underlieAngiogenesis inhibitors targeting the vascular endothelial growth factor signalling pathways are affording demonstrable therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers.
Abstract: In both preclinical and clinical settings, the benefits of angiogenesis inhibitors targeting the vascular endothelial growth factor signalling pathways are at best transitory and followed by restoration of tumour growth and progression. Emerging data support a proposition that two modes of unconventional resistance underlie such results.

2,670 citations

Journal ArticleDOI
TL;DR: It is reported that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis.

2,303 citations


Cites background or methods from "Drug resistance by evasion of antia..."

  • ...Therapeutic Trials RIP1-Tag2 mice were treated starting at 10 or 12 weeks of age as indicated, and immunocompromised RIP1-Tag2;Rag1-KO mice were used for longterm DC101 treatment to avoid immune reaction against the therapeutic antibody....

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  • ...Tumor-bearing immunocompromised RIP1-Tag2 mice treated with DC101 for a relatively brief period of 1 week had reduced tumor vasculature and volume compared to control age-matched untreated animals, as described previously (Figure 1A and data not shown; Casanovas et al., 2005)....

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  • ...This realization motivates clinical studies to confirm and potentially target this insidious consequence of antiangiogenic therapies. growth factor (FGF) ligands (Casanovas et al., 2005)....

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  • ...…were used: (1) 1 mg/mouse twice per week of anti-VEGFR2 blocking antibody (DC101) purified from a hybridoma culture (American Type Culture Collection) and its control purified rat IgG (Jackson ImmunoResearch) as described previously (Casanovas et al., 2005) administered intraperitoneally (i.p.)....

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  • ...Error bars indicate ± SD. VEGFR2 (DC101) in the RIP1-Tag2 model of pancreatic neuroendocrine cancer (PNET) (Casanovas et al., 2005), we sought to focus on the initial onset of malignant progression to invasive islet carcinoma....

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Journal ArticleDOI
TL;DR: There is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumour types, and clinical reagents that specifically target the FGFs or FGF receptors are being developed.
Abstract: Fibroblast growth factors (FGFs) and their receptors control a wide range of biological functions, regulating cellular proliferation, survival, migration and differentiation. Although targeting FGF signalling as a cancer therapeutic target has lagged behind that of other receptor tyrosine kinases, there is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumour types, and clinical reagents that specifically target the FGFs or FGF receptors are being developed. Although FGF signalling can drive tumorigenesis, in different contexts FGF signalling can mediate tumour protective functions; the identification of the mechanisms that underlie these differential effects will be important to understand how FGF signalling can be most appropriately therapeutically targeted.

2,211 citations


Cites background from "Drug resistance by evasion of antia..."

  • ...Finally there is substantial crosstalk between FGFR and vascular endothelial growth factor receptor (VEGFR) signalling in angiogenesis, and the FGFR system may mediate resistance to VEGFR targeting in some situation...

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Journal ArticleDOI
TL;DR: Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors.
Abstract: The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials.

2,192 citations


Additional excerpts

  • ...Constipation 12 (14) 12 (14) 0 16 (20) 15 (18) 1 (1)...

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  • ...Mucosal inflammation 13 (16) 12 (14) 1 (1) 6 (7) 6 (7) 0...

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  • ...Weight loss 13 (16) 12 (14) 1 (1) 9 (11) 9 (11) 0...

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References
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Journal ArticleDOI
TL;DR: The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.
Abstract: background Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy. methods Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. results The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progressionfree survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed. conclusions The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.

10,161 citations


"Drug resistance by evasion of antia..." refers background or result in this paper

  • ...…bevacizumab (Avastin), a humanized monoclonal antibody against VEGF-A, in combination with conventional chemotherapy, increased CANCER CELL : OCTOBER 2005 · VOL. 8 · COPYRIGHT © 2005 ELSEVIER overall survival by 5 months in colorectal cancer patients (Hurwitz et al., 2004), leading to FDA approval....

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  • ...To date, human clinical trials that selectively target VEGF or VEGFRs are merely delaying time to progression after a period of stable disease, thus CANCER CELL : OCTOBER 2005 affording a modest survival advantage (e.g., Hurwitz et al., 2004), much like that seen in this mouse model of cancer....

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  • ...This pattern of tumor stasis and then tumor growth is arguably analogous to the delayed time to progression seen in the clinical trials with bevacizumab (Avastin) as monotherapy (Yang et al., 2003) or in combination with chemotherapy (Hurwitz et al., 2004)....

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Journal ArticleDOI
TL;DR: Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions and is implicated in pathologicalAngiogenesis associated with tumors, intraocular neovascular disorders and other conditions.
Abstract: Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.

8,942 citations


"Drug resistance by evasion of antia..." refers background in this paper

  • ...A prominent proangiogenic signaling circuit involves the vascular endothelial growth factor (VEGF) family, and in particular VEGF-A (Ferrara et al., 2003)....

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  • ...A recent phase III clinical trial demonstrated that bevacizumab (Avastin), a humanized monoclonal antibody against VEGF-A, in combination with conventional chemotherapy, increased CANCER CELL : OCTOBER 2005 · VOL. 8 · COPYRIGHT © 2005 ELSEVIER overall survival by 5 months in colorectal cancer patients (Hurwitz et al., 2004), leading to FDA approval....

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  • ...Here, we use specific function-blocking monoclonal antibodies to two VEGF receptors to probe their role in mediating and sustaining angiogenesis and tumor growth in an endogenous mouse model of islet cell carcinogenesis, where the functional importance of VEGF signaling has been previously documented, via gene knockout of VEGF-A (Inoue et al., 2002) and pharmacological inhibition of VEGF receptors with small molecules (Bergers et al., 2000, 2003)....

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  • ...While the VEGF-A ligand is itself upregulated in the treated tumors (and hypoxic tumor cell lines), it is evidently in- CANCER CELL : OCTOBER 2005 Figure 6....

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  • ...Using mRNA prepared from these two FACS-purified cell populations, we evaluated the expression levels of the proangiogenic ligands and found that most were upregulated in the tumor cell population (VEGF-A, FGF1, FGF2, FGF7, FGF8, Ephrin-A1, and Angiopoietin-2) whereas a partially overlapping set was upregulated in the tumor endothelial cells (FGF1, FGF2, Ephrin-A1, and Angiopoietin-1 and -2) (Figure 5B)....

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Journal ArticleDOI
09 Aug 1996-Cell
TL;DR: The work from the authors' laboratories reviewed herein was supported by grants from the National Cancer Institute.

6,895 citations


"Drug resistance by evasion of antia..." refers background in this paper

  • ...…balance shifts in favor of angiogenesis inducers, an angiogenic switch activates the normally quiescent vasculature to develop new blood vessels (Hanahan and Folkman, 1996), often concomitant with enlargement (dilation and microhemorrhaging) of the preexisting vasculature (Ryschich et al.,…...

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Journal ArticleDOI
06 Mar 1992-Cell
TL;DR: The introduction of a mutation in RAG-1 into the germline of mice via gene targeting in embryonic stem cells is described and it is shown that this mutation either activates or catalyzes the V(D)J recombination reaction of immunoglobulin and T cell receptor genes.

2,821 citations


"Drug resistance by evasion of antia..." refers background in this paper

  • ...(Hanahan, 1985) and the Rag1 knockout (Mombaerts et al., 1992) have...

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  • ...The generation and characterization of the single transgenic RIP-Tag2 mice (Hanahan, 1985) and the Rag1 knockout (Mombaerts et al., 1992) have been previously reported....

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  • ...Mice lacking Rag1 are unable to perform V(D)J recombination of immunoglobulins and T cell receptor genes during immune cell maturation, and thus are completely deficient in adaptive immunity (Mombaerts et al., 1992)....

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Journal ArticleDOI
TL;DR: Bvacizumab can significantly prolong the time to progression of disease in patients with metastatic renal-cell cancer, and this trial was stopped after the interim analysis met the criteria for early stopping.
Abstract: Background Mutations in the tumor-suppressor gene VHL cause oversecretion of vascular endothelial growth factor by clear-cell renal carcinomas. We conducted a clinical trial to evaluate bevacizumab...

2,724 citations


"Drug resistance by evasion of antia..." refers result in this paper

  • ...This pattern of tumor stasis and then tumor growth is arguably analogous to the delayed time to progression seen in the clinical trials with bevacizumab (Avastin) as monotherapy (Yang et al., 2003) or in combination with chemotherapy (Hurwitz et al....

    [...]

  • ...This pattern of tumor stasis and then tumor growth is arguably analogous to the delayed time to progression seen in the clinical trials with bevacizumab (Avastin) as monotherapy (Yang et al., 2003) or in combination with chemotherapy (Hurwitz et al., 2004)....

    [...]