An overview of small-molecule inhibitors of VEGFR signaling

Ivy, S. Percy; Wick, Jeannette Y.; Kaufman, B.

doi:10.1038/nrclinonc.2009.130

Cited by 309 publications

(235 citation statements)

References 88 publications

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“…5C). Like VEGFR-1, VEGFR-2 is primarily located on the vascular endothelium, but its expression has also been verified on neuronal, hematopoietic and cancer cells including glioma cells (Knizetova et al, 2008;Ivy et al, 2009). Notably, expression of both, VEGF and VEGFR-2, becomes induced as a consequence of ionizing radiation and is markedly counteracted in response to treatment with CCI-779 (Fig.…”

Section: Discussionmentioning

confidence: 91%

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

et al. 2012

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An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.Oncogene advance online publication, Word Count:5,868 words Condensed title:Radiation-enhanced mTOR inhibition in glioblastomaWeiler et al. 2 AbstractA relevant mode of resistance to antiangiogenic and radiotherapy appears to be promotion of tumour cell motility and invasiveness in various cancer types, a process commonly referred to as 'evasive resistance' that may underlie progressive disease and complicates further treatment. Hence, a logical advancement in current oncology consists in optimizing antiangiogenic regimens by identifying suitable complementary strategies, ideally targeting cell motility. Here we report that clinically relevant radiation-enhanced inhibition of the mTOR complexes 1 and 2 exercises such a dual control of angiogenesis and invasiveness independent from PTEN/AKT activation in glioblastoma, a tumour entity that is paradigmatic for both excessive vascular proliferation and cell invasion. This is due to a concerted disrupture of the VEGF/VEGFR-2 signalling axis and likewise suppression of RGS4, which we identified to be a key driver of glioblastoma invasiveness. This combined antiangiogenic/antiinvasive approach might be a promising therapeutic option and warrants further clinical investigation in upfront glioblastoma therapy.Weiler et al.3

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Section: Discussionmentioning

confidence: 91%

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

et al. 2012

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“…Among VEGF receptors, VEGFR-2 is expressed in proliferating vascular endothelial cells of tumours as well as on circulating endothelial progenitor cells, and is related to multiple biological activities of VEGF, such as cell proliferation, migration and survival [3,4]. The EGFR is required for normal cellular proliferation, survival, adhesion, migration, and differentiation but a dysregulation of this pathway can lead to oncogenesis.…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

Bocci¹,

Fioravanti²,

Motta³

et al. 2011

Biochemical Pharmacology

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Aims. To demonstrate the antiproliferative and pro-apoptotic activity of the novel pyrazolopyrimidine derivative multiple tyrosine kinase inhibitor CLM3, alone and in combination with SN-38 (the active metabolite of irinotecan), on endothelial and tumour cells and to show its mechanism of action.Methods. Proliferation and apoptotic assays were performed on microvascular endothelial (HMVECd) and lung (A549) and thyroid cancer (8305C, TT) cell lines exposed to CLM3 and to the simultaneous combination with SN38 for 72h. Cell-based phospho-VEGFR-2, phospho-EGFR and phospho-RET inhibition assays were performed and ERK1/2 and Akt phosphorylation were quantified by ELISA kits. Conclusions.The pyrazolopyrimidine derivative CLM3 demonstrated a highly significant and promising antiproliferative and proapoptotic activity, alone and in combination with SN-38, for activated endothelial and cancer cell cells. These effects are mainly due to its inhibition of phosphorylation of VEGFR-2, EGFR and RET tyrosine kinases and their related signalling pathways.

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“…22 Similarly, VEGF signaling and monoclonal antibodies and small molecule inhibitors of VEGF or its receptors have been established as a proven approach to inhibit tumor growth. [23][24][25] In an attempt to elucidate the molecular mechanism underlying the possible tumor vessel promoting activity of stem/progenitor cells, many studies have recently demonstrated that VEGF signaling plays a critical role in the upregulation of a range of cellular functions of EPCs, such as cell migration, proliferation, survival and angiogenesis. 26 In sites of hypoxic tumor tissue, the recruited EPCs secrete abundant VEGF and promote an abnormal vascular network.…”

Section: Resultsmentioning

confidence: 99%