The reverse side of the victory: Flare up of symptoms after discontinuation of sunitinib or sorafenib in renal cell cancer patients. A report of three cases

Desar, Ingrid M.E.; Mulder, Sasja F.; Stillebroer, Alexander B.; Spronsen, Dick-Johan van; Mulders, Peter F.A.; Herpen, Carla M.L. van

doi:10.1080/02841860902974167

Cited by 54 publications

(38 citation statements)

References 7 publications

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“…However, during each sunitinib washout period or after sunitinib withdrawal, tumors showed rapid regrowth. Similar observations have been noted in clinical practice when using VEGFR-targeted kinase inhibitors (37,38). The mechanisms mediating "withdrawal flare" are not understood, but modulation of plasma levels of circulating proteins involved in VEGF signaling during VEGFR inhibitor treatment might lead to tumor progression.…”

Section: Discussionsupporting

confidence: 51%

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: Discussionsupporting

confidence: 51%

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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“…Indeed, comparably to our findings preclinical immunohistochemical analyses have demonstrated rapid revascularization after stopping the VEGFR-TKI AG-013736 (32). Moreover, regrowth of lymph node metastases and flare up of clinical symptoms have been reported during the sunitinib-free period or rapidly after discontinuation (33,34).…”

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confidence: 64%

VEGF-PET Imaging Is a Noninvasive Biomarker Showing Differential Changes in the Tumor during Sunitinib Treatment

et al. 2011

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“…Recent studies have demonstrated that antiangiogenesis agents could increase local invasion and distant metastasis during or after treatment (11,12,36,37). For example, VEGFR inhibitors, such as sorafenib and sunitinib, can result in upregulation of MET, leading to promotion of metastasis (19,32,38).…”

Section: Discussionmentioning

confidence: 99%

Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET

Xiang

Chen

Ren

et al. 2014

Clinical Cancer Research

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Purpose: MET signaling has been suggested a potential role in hepatocellular carcinoma (HCC) and associated with prometastasis during antiangiogenesis therapy. We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC. Antitumor effects of cabozantinib, a dual inhibitor of MET and VEGFR2, were examined in cultured HCC cells as well as in vivo models.Experimental Design: Total MET and phosphorylated MET (p-MET) were measured in 29 resected HCC specimens, and correlated with response to sorafenib as postoperative adjuvant therapy. In the second set of experiments using cultured HCC cells, and mouse xenograft and metastatic models, effects of cabozantinib were examined.Results: High level of p-MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy. In cultured HCC cells that expressed p-MET, cabozantinib inhibited the activity of MET and its downstream effectors, leading to G 1 -phase arrest. Cabozantinib inhibited tumor growth in p-METpositive and p-MET-negative HCC by decreasing angiogenesis, inhibiting proliferation, and promoting apoptosis, but it exhibited more profound efficacy in p-MET-positive HCC xenografts. Cabozantinib blocked the hepatocyte growth factor (HGF)-stimulated MET pathway and inhibited the migration and invasion of the HCC cells. Notably, cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model.Conclusions: Patients with HCC with high level of p-MET are associated with resistance to adjuvant sorafenib treatment. The dual blockade of VEGFR2 and MET by cabozantinib has significant antitumor activities in HCC, and the activation of MET in HCC may be a promising efficacy-predicting biomarker.

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The reverse side of the victory: Flare up of symptoms after discontinuation of sunitinib or sorafenib in renal cell cancer patients. A report of three cases

Cited by 54 publications

References 7 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

VEGF-PET Imaging Is a Noninvasive Biomarker Showing Differential Changes in the Tumor during Sunitinib Treatment

Cabozantinib Suppresses Tumor Growth and Metastasis in Hepatocellular Carcinoma by a Dual Blockade of VEGFR2 and MET

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