Anti-Vascular Endothelial Growth Factor Therapies and Cardiovascular Toxicity: What Are the Important Clinical Markers to Target?

Vaklavas, Christos; Lenihan, Daniel J.; Kurzrock, Razelle; Tsimberidou, Apostolia M.

doi:10.1634/theoncologist.2009-0252

Cited by 104 publications

(91 citation statements)

References 118 publications

(136 reference statements)

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“…In contrast, other VEGFR-or MET-targeted kinase inhibitors produced significant cell damage in various normal cell lines, including rat cardiomyocytes, when used at concentrations comparable with those used for TAS-115. During clinical development, VEGFR-targeted inhibitors were recognized to cause cardiovascular toxicity (32), possibly via reduction of nitric oxide function in endothelial cells (33) and due to capillary rarefaction based on VEGF/VEGFR signal inhibition (34). Other mechanisms by which multi-kinase inhibition can produce cardiotoxicity have been described (35).…”

Section: Discussionmentioning

confidence: 99%

The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has MarkedIn VivoAntitumor Properties and a Favorable Tolerability Profile

Fujita

Miyadera

Kato

et al. 2013

Molecular Cancer Therapeutics

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VEGF receptor (VEGFR) signaling plays a key role in tumor angiogenesis. Although some VEGFR signaltargeted drugs have been approved for clinical use, their utility is limited by associated toxicities or resistance to such therapy. To overcome these limitations, we developed TAS-115, a novel VEGFR and hepatocyte growth factor receptor (MET)-targeted kinase inhibitor with an improved safety profile. TAS-115 inhibited the kinase activity of both VEGFR2 and MET and their signal-dependent cell growth as strongly as other known VEGFR or MET inhibitors. On the other hand, kinase selectivity of TAS-115 was more specific than that of sunitinib and TAS-115 produced relatively weak inhibition of growth (GI 50 > 10 mmol/L) in VEGFR signal-or MET signalindependent cells. Furthermore, TAS-115 induced less damage in various normal cells than did other VEGFR inhibitors. These data suggest that TAS-115 is extremely selective and specific, at least in vitro. In in vivo studies, TAS-115 completely suppressed the progression of MET-inactivated tumor by blocking angiogenesis without toxicity when given every day for 6 weeks, even at a serum-saturating dose of TAS-115. The marked selectivity of TAS-115 for kinases and targeted cells was associated with improved tolerability and contributed to the ability to sustain treatment without dose reduction or a washout period. Furthermore, TAS-115 induced marked tumor shrinkage and prolonged survival in MET-amplified human cancer-bearing mice. These data suggest that TAS-115 is a unique VEGFR/MET-targeted inhibitor with improved antitumor efficacy and decreased toxicity. Mol Cancer Ther; 12(12); 2685-96. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has MarkedIn VivoAntitumor Properties and a Favorable Tolerability Profile

Fujita

Miyadera

Kato

et al. 2013

Molecular Cancer Therapeutics

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“…Comparing the toxicities associated with sunitinib with those associated with the selective anti-VEGF monoclonal antibody bevacizumab may be useful. For example, grade 3 to 4 left ventricular dysfunction has been observed to occur with greater frequency with sunitinib treatment than with either bevacizumab or sorafenib (0.3%, 1.4%, and 0.05% in phase I-III studies), suggesting a potential off-target effect (72). One potential explanation may be that the reduced left ventricular ejection fraction is a result of sunitinib-induced hypothyroidism (24).…”

Section: Discussionmentioning

confidence: 99%

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

Aparicio-Gallego

Blanco

Figueroa

et al. 2011

Molecular Cancer Therapeutics

102

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The introduction of targeted therapy represents a major advance in the treatment of tumor progression. Targeted agents are a novel therapeutic approach developed to disrupt different cellular signaling pathways. The tyrosine kinase inhibitor sunitinib specifically blocks multiple tyrosine kinase receptors that are involved in the progression of many tumors. Sunitinib is the current standard of care in first-line treatment of advanced renal cell carcinoma, and it is approved in imatinib-intolerant and imatinib-refractory gastrointestinal stromal tumors. However, it is increasingly evident that sunitinib may display collateral effects on other proteins beyond its main target receptors, eliciting undesirable and unexpected adverse events. A better understanding of the molecular mechanisms underlying these undesirable sunitinib-associated side effects will help physicians to maximize efficacy of sunitinib and minimize adverse events. Here, we focus on new insights into molecular mechanisms that may mediate sunitinib-associated adverse events. Mol Cancer Ther; 10(12); 2215-23. Ó2011 AACR.

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“…Normally, the heart is able to adapt to afterload stress through compensatory mechanisms, but the inhibition of PDGFR-b, determined by anti-angiogenic TKIs, inhibits cardiac adaptation to afterload stress. Hence, it causes heart failure ( Figure 2) [15][16][17][18][19][20][21][22][23]. Common side-effects are peripheral edema, an indicator of cardiac dysfunction, and symptoms like fatigue and dyspnea that could also be attributed to the disease itself or they could be associated with other conditions [9].…”

Section: Pathophysiological Mechanisms Of Cardiotoxicity Of Anti-angimentioning

confidence: 99%

Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting tyrosine kinase inhibitor-based therapy

Bronte

Novo

et al. 2014

Expert Opinion on Drug Safety

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Anti-Vascular Endothelial Growth Factor Therapies and Cardiovascular Toxicity: What Are the Important Clinical Markers to Target?

Cited by 104 publications

References 118 publications

The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has MarkedIn VivoAntitumor Properties and a Favorable Tolerability Profile

The Novel VEGF Receptor/MET–Targeted Kinase Inhibitor TAS-115 Has MarkedIn VivoAntitumor Properties and a Favorable Tolerability Profile

New Insights into Molecular Mechanisms of Sunitinib-Associated Side Effects

Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting tyrosine kinase inhibitor-based therapy

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