The novel kinase inhibitor ponatinib is an effective anti-angiogenic agent against neuroblastoma

Whittle, Sarah Burkhead; Patel, Kalyani R.; Zhang, Linna; Woodfield, Sarah E.; Du, Michael Yifei; Smith, Valeria; Zage, Peter E.

doi:10.1007/s10637-016-0387-y

Cited by 19 publications

(23 citation statements)

References 32 publications

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“…Recently, it has been suggested that the use of reduced doses of ponatinib (down to 15 mg/day instead of the usual dosage of 45 mg/day) might maintain therapeutic activity in most patients while decreasing the vascular adverse events (24,26). Although clinicians will have to tackle the side effects observed upon ponatinib administration, the results achieved through our study, as well as others (17,18), indicate that this drug has the potential to be employed in clinical trials aimed to evaluate benefits in high-risk NB patients.…”

Section: Discussionsupporting

confidence: 50%

“…Although we could not prove a significant activity of axitinib in our in vivo model, one previous study indicated that axitinib could partially impair the growth of human NB xenografts by inhibiting angiogenesis (16). Notably, independent investigations have very recently proposed ponatinib itself as a drug displaying antitumor efficacy against NB (17,18). Ponatinib proved to inhibit the FGFR1-activated signaling pathway and enhance the cytotoxic effects of doxorubicin on NB cells (18).…”

Section: Discussionmentioning

confidence: 62%

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A High-Content Screening of Anticancer Compounds Suggests the Multiple Tyrosine Kinase Inhibitor Ponatinib for Repurposing in Neuroblastoma Therapy

Sidarovich

Mariano

Aveic

et al. 2018

Molecular Cancer Therapeutics

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Novel druggable targets have been discovered in neuroblastoma (NB), paving the way for more effective treatments. However, children with high-risk NB still show high mortality rates prompting for a search of novel therapeutic options. Here, we aimed at repurposing FDA-approved drugs for NB treatment by performing a high-content screening of a 349 anticancer compounds library. In the primary screening, we employed three NB cell lines, grown as three-dimensional (3D) multicellular spheroids, which were treated with 10 μmol/L of the library compounds for 72 hours. The viability of 3D spheroids was evaluated using a high-content imaging approach, resulting in a primary hit list of 193 compounds. We selected 60 FDA-approved molecules and prioritized drugs with multi-target activity, discarding those already in use for NB treatment or enrolled in NB clinical trials. Hence, 20 drugs were further tested for their efficacy in inhibiting NB cell viability, both in two-dimensional and 3D models. Dose-response curves were then supplemented with the data on side effects, therapeutic index, and molecular targets, suggesting two multiple tyrosine kinase inhibitors, ponatinib and axitinib, as promising candidates for repositioning in NB. Indeed, both drugs showed induction of cell-cycle block and apoptosis, as well as inhibition of colony formation. However, only ponatinib consistently affected migration and inhibited invasion of NB cells. Finally, ponatinib also proved effective inhibition of tumor growth in orthotopic NB mice, providing the rationale for its repurposing in NB therapy. .

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Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 62%

A High-Content Screening of Anticancer Compounds Suggests the Multiple Tyrosine Kinase Inhibitor Ponatinib for Repurposing in Neuroblastoma Therapy

Sidarovich

Mariano

Aveic

et al. 2018

Molecular Cancer Therapeutics

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“…Pazopanib potently inhibits VEGF‐induced phosphorylation of VEGFR2 in HUVEC cells with IC 50 of 8 nM. Ponatinib inhibits multiple RTKs implicated in pathological angiogenesis such as PDGFRα, VEGFR‐2, FGFR1, and Src . It exhibited a significant antiangiogenic effect and was approved in 2012.…”

Section: Recent Advances In Small‐molecule Antiangiogenic Agentsmentioning

confidence: 99%

“…Ponatinib inhibits multiple RTKs implicated in pathological angiogenesis such as PDGFR , VEGFR-2, FGFR1, and Src. 156 It exhibited a significant antiangiogenic effect and was approved in 2012. Linifanib is a potent ATP-competitive inhibitor for VEGFR-2, Flt-1/3, and PDGFR .…”

Section: Multitarget Rtkis As Antiangiogenic Agentsmentioning

confidence: 99%

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

Shan

Wang

Zhang

2018

Medicinal Research Reviews

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Pathological angiogenesis plays a crucial role in malignant neoplasia. Vascular normalization has been confirmed as a promising strategy to promote chemotherapy efficacy. However, compensatory activation of alternative angiogenic receptor tyrosine kinases (RTKs) reduces vascular normalization and induces resistance. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat with single-target agents. Accordingly, it has been proposed that multiplex inhibition of RTKs could enhance treatment efficacy and overcome resistance on the basis of the vascular normalization concept. Meanwhile, it is feasible to develop multiplex inhibitors against VEGFR-2/Tie-2/EphB4 because of their highly conserved ATP-binding pockets. These inhibitors possess the properties of not only stabilizing the vascular normalization "time window" but also preventing the occurrence of resistance. This novel strategy has yielded promising results in the discovery of antiangiogenic agents. This review highlights the recent progress on the development of such angiogenesis inhibitors.

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“…The mechanisms of action of PON include the regulation of several intracellular signaling pathways, such as STAT3, PI3K/AKT, and ERK, which are all involved in supporting tumor cell proliferation and survival [ 7 ]. However, some studies have found an increased rate of resistance to PON in either pre-clinical or clinical settings [ 8 – 10 ], and a similar finding may therefore be possible in neuroblastoma, in which the efficacy of PON emerged from both in vitro and in vivo pre-clinical assessments [ 11 , 12 ]. In a previous high-throughput screening (HTS) study, among 349 compounds tested, PON gave the best results in impeding the growth of neuroblastoma cells [ 13 ].…”

Section: Introductionmentioning

confidence: 98%

Autophagic flux inhibition enhances cytotoxicity of the receptor tyrosine kinase inhibitor ponatinib

Corallo

Pastorino

Pantile

et al. 2020

J Exp Clin Cancer Res

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Background Despite reported advances, acquired resistance to tyrosine kinase inhibitors still represents a serious problem in successful cancer treatment. Among this class of drugs, ponatinib (PON) has been shown to have notable long-term efficacy, although its cytotoxicity might be hampered by autophagy. In this study, we examined the likelihood of PON resistance evolution in neuroblastoma and assessed the extent to which autophagy might provide survival advantages to tumor cells. Methods The effects of PON in inducing autophagy were determined both in vitro, using SK-N-BE(2), SH-SY5Y, and IMR-32 human neuroblastoma cell lines, and in vivo, using zebrafish and mouse models. Single and combined treatments with chloroquine (CQ)—a blocking agent of lysosomal metabolism and autophagic flux—and PON were conducted, and the effects on cell viability were determined using metabolic and immunohistochemical assays. The activation of the autophagic flux was analyzed through immunoblot and protein arrays, immunofluorescence, and transmission electron microscopy. Combination therapy with PON and CQ was tested in a clinically relevant neuroblastoma mouse model. Results Our results confirm that, in neuroblastoma cells and wild-type zebrafish embryos, PON induces the accumulation of autophagy vesicles—a sign of autophagy activation. Inhibition of autophagic flux by CQ restores the cytotoxic potential of PON, thus attributing to autophagy a cytoprotective nature. In mice, the use of CQ as adjuvant therapy significantly improves the anti-tumor effects obtained by PON, leading to ulterior reduction of tumor masses. Conclusions Together, these findings support the importance of autophagy monitoring in the treatment protocols that foresee PON administration, as this may predict drug resistance acquisition. The findings also establish the potential for combined use of CQ and PON, paving the way for their consideration in upcoming treatment protocols against neuroblastoma.

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The novel kinase inhibitor ponatinib is an effective anti-angiogenic agent against neuroblastoma

Cited by 19 publications

References 32 publications

A High-Content Screening of Anticancer Compounds Suggests the Multiple Tyrosine Kinase Inhibitor Ponatinib for Repurposing in Neuroblastoma Therapy

A High-Content Screening of Anticancer Compounds Suggests the Multiple Tyrosine Kinase Inhibitor Ponatinib for Repurposing in Neuroblastoma Therapy

New strategies in achieving antiangiogenic effect: Multiplex inhibitors suppressing compensatory activations of RTKs

Autophagic flux inhibition enhances cytotoxicity of the receptor tyrosine kinase inhibitor ponatinib

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