The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; A review

Eskens, Ferry A.L.M.; Verweij, Jaap

doi:10.1016/j.ejca.2006.09.015

Cited by 303 publications

(201 citation statements)

References 43 publications

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“…The first is whether any of the changes may be relevant to a particular toxicity commonly associated with the use of such drugs, such as hypertension, extreme fatigue, diarrhea, nausea, and hand-foot syndrome, among others (3,6,12). If so, one or more of the changes might be exploited as a predictive marker for such toxicities.…”

Section: Discussionmentioning

confidence: 99%

“…With respect to the former, the growing need to discover and validate surrogate biomarkers to help determine the optimal therapeutic dose, predict which patients are most likely to achieve clinical benefit, indicate emerging resistance, or foretell a particular toxic side effect are all well known (1,2). With respect to recurrent findings, toxicities such as hypertension and proteinuria are very common side effects of treatment with drugs that target VEGF or VEGF receptors (VEGFR), including VEGFR-2, whether antibodies or small-molecule receptor tyrosine kinase (RTK) inhibitors (RTKIs) (3). For RTKIs, another common feature is a triad of molecular changes involving circulating proteins, namely, increased levels of plasma VEGF and placental growth factor (PlGF), another member of the VEGF family that binds to VEGFR-1, along with reduced levels of soluble VEGFR-2 (sVEGFR-2) (4).…”

mentioning

confidence: 99%

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Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy

Ebos

Lee

Christensen

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

340

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Cancer patients treated with antiangiogenic multitargeted receptor tyrosine kinase (RTK) inhibitors show increased levels of plasma VEGF and placental growth factor and decreased levels of soluble VEGF receptor-2, thus implicating these overall changes as a possible class effect of such drugs and raising the possibility of their exploitation as surrogate biomarkers for pharmacodynamic drug activity/exposure and patient benefit. A postulated mechanism for these changes is that they are tumor-dependent, resulting from drug-induced decreases in vascular function, increases in tumor hypoxia, and changes in hypoxia-regulated genes. However, here we report that an identical pattern of change is observed in normal nontumor-bearing mice treated with SU11248/sunitinib, a small-molecule inhibitor of VEGF and PDGF RTKs. The changes were dose-dependent, plateaued after 4 days of consecutive treatment, reversed after discontinuation of therapy, and correlated with antitumor activity. Altered protein expression was found in a broad variety of tissues, and dose-dependent elevations were observed of several plasma proteins previously unassociated with this class of inhibitor, including G-CSF, SDF-1␣, SCF, and osteopontin. Our results suggest that observed sunitinib-induced molecular plasma changes, including those both directly and indirectly targeted by drug, represent a systemic tumor-independent response to therapy and may correlate with the most efficacious antitumor doses, potentially having utility for defining the optimal biologic dose range for this drug class but not as predictive markers of tumor response or clinical benefit. They may also be relevant to drug-associated toxicities, drug resistance, and observed rapid tumor (re)growth seen after cessation of therapy.angiogenesis ͉ optimal biological dosing ͉ SU11248 ͉ surrogate biomarkers

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy

Ebos

Lee

Christensen

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

340

250

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show abstract

“…Published functional analy ses (Jin et al, 2003;Tzima et al, 2005) used chemical inhibitors of tyrosine kinase activity that do not discriminate between these paralogues (Eskens and Verweij, 2006), thus, it is unclear to what extent VEGFR2 and 3 have unique effectors, and function additively or redundantly. VEGFR2 is required for shear mediated activation of PI3K and integrins, and for cell align ment.…”

Section: Vegfrs Display Functional Overlap and Dosage Sensitivitymentioning

confidence: 99%

Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex

Coon¹,

Baeyens²,

Han³

et al. 2015

J Gen Physiol

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“…Other rare but serious complications noted with antiangiogenic therapy include myocardial infarction, arterial stroke, reversible posterior leukoencepha-lopathy syndrome, and thrombotic thrombocytopenic purpura. 33,124,125 …”

Section: Toxicity Profilementioning

confidence: 99%

Antiangiogenic Strategies for Treatment of Malignant Gliomas

2009

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The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; A review

Cited by 303 publications

References 43 publications

Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy

Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy

Intramembrane binding of VE-cadherin to VEGFR2 and VEGFR3 assembles the endothelial mechanosensory complex

Antiangiogenic Strategies for Treatment of Malignant Gliomas

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