Receptor tyrosine kinase inhibitors: molecularly targeted drugs for veterinary cancer therapy

Bavčar, Špela; Argyle, David

doi:10.1111/j.1476-5829.2012.00342.x

Cited by 27 publications

(34 citation statements)

References 69 publications

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“…While tyrosine kinase inhibitors (TKIs) are routinely employed in human oncology with success, their use in veterinary medicine is limited. Two small molecule tyrosine kinase inhibitors, toceranib (TOC) phosphate (Palladia®; Zoetis, Madison, NJ) and masitinib (Masivet®, Kinavet®; AB Science, Paris, France) have been approved by the FDA for use in veterinary medicine for the treatment of recurrent, non-resectable intermediate and high grade canine cutaneous mast cell tumors (MCTs) [1]. The success of targeted therapies in both human and veterinary oncology, however, is largely tempered by the inevitable development of drug resistance.…”

Section: Introductionmentioning

confidence: 99%

Development of an in vitro model of acquired resistance to toceranib phosphate (Palladia®) in canine mast cell tumor

et al. 2014

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BackgroundMast cell tumors (MCTs) are the most common skin tumors in dogs and exhibit variable biologic behavior. Mutations in the c-kit proto-oncogene are associated with the tumorigenesis of MCTs, resulting in growth factor-independent and constitutive phosphorylation of the KIT receptor tyrosine kinase (RTK). Toceranib (TOC) phosphate (Palladia®) is a KIT RTK inhibitor that has biological activity against MCTs. Despite these benefits, patients ultimately develop resistance to TOC. Therefore, there is a need to identify distinguishing clinical and molecular features of resistance in this population.ResultsThe canine C2 mastocytoma cell line contains an activating mutation in c-kit. Three TOC-resistant C2 sublines (TR1, TR2, TR3) were established over seven months by growing cells in increasing concentrations of TOC. TOC inhibited KIT phosphorylation and cell proliferation in a dose-dependent manner in the treatment-naïve, parental C2 line (IC50 < 10 nM). In contrast, the three sublines were resistant to growth inhibition by TOC (IC50 > 1,000 nM) and phosphorylation of the KIT receptor was less inhibited compared to the TOC-sensitive C2 cells. Interestingly, sensitivity to three structurally distinct KIT RTK inhibitors was variable among the sublines, and all 3 sublines retained sensitivity to the cytotoxic agents vinblastine and lomustine. Sequencing of c-kit revealed secondary mutations in the juxtamembrane and tyrosine kinase domains of the resistant sublines. These included point mutations in TR1 (Q574R, M835T), TR2 (K724R), and TR3 (K580R, R584G, A620S). Additionally, chronic TOC exposure resulted in c-kit mRNA and KIT protein overexpression in the TOC-resistant sublines compared to the parental line. C2, TR1, TR2, and TR3 cells demonstrated minimal P-glycoprotein (P-gp) activity and no functional P-gp.ConclusionsThis study demonstrates the development of an in vitro model of acquired resistance to targeted therapy in canine MCTs harboring a c-kit-activating mutation. This model may be used to investigate the molecular basis of and strategies to overcome TOC resistance.

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Section: Introductionmentioning

confidence: 99%

Development of an in vitro model of acquired resistance to toceranib phosphate (Palladia®) in canine mast cell tumor

et al. 2014

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“…This therapy consists in a continuous administration of compounds inhibiting angiogenesis, and has immunomodulatory effects on the neoplasm inducing hypoxia, nutrient deprivation and tumour growth arrest (Lana and others 2007, London and others 2012, Mitchell and others 2012). Drugs used include, alkylanting agent (cyclophosphamide, chlorambucil, melfalan), nonsteroidal anti-inflammatory drugs (piroxicam, meloxicam, coxib) and/or tyrosine kinase inhibitor (TKI) such as TP (Lana and others 2007, Mutsaers 2009, Bavcar and Argyle 2012). …”

Section: Discussionmentioning

confidence: 99%

“…TP is an inhibitor of some tyrosine kinase receptors, such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, stem cell factor receptor (Kit), colony stimulating factor-1 receptor and FMS-like tyrosine kinase 3 (Flt-3 C) (Bavcar and Argyle 2012). A few cases of human angiosarcomas have reported durable disease stabilisation with TKIs due to an unknown mechanism or inhibition of VEGFR-2 receptor (Kiesel and others 2009, Yoo and others 2009, Tokuyama and others 2010).…”

Section: Discussionmentioning

confidence: 99%

Caudoventral abdominal lymphangiosarcoma in a cat treated with metronomic chemotherapy

Castro‐López¹,

Bermúdez²,

Martínez³

et al. 2013

Vet Record Case Reports

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A 10‐year‐old, male neutered domestic shorthair cat was referred for reddish discolouration of its abdominal skin with serosanguineous discharge. The affected skin was bruised, nodular and had fluid‐filled cavities. It was painful on palpation. A final diagnosis of lymphangiosarcoma was made by prospero‐related homeobox gene‐1 (PROX‐1) immunohistochemistry. Metronomic chemotherapy treatment was instaured with toceranib phosphate, chlorambucil and meloxicam. Partial remission was achieved at 18 days and stable disease was maintained for 36 days (survival time: 54 days). Afterward, the tumour began to regrow aggressively and the patient developed anorexia; owners elected for euthanasia. Total survival time achieved was 63 days. To the authors’ knowledge, this is the first case report of feline caudoventral abdominal lymphangiosarcoma treated with metronomic chemotherapy.

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“…Masitinib targets PDGFR‐α, PDGFR‐β, KIT, Lyn, and to a lesser degree, the FGFR3 and FAK pathways as well as VEGFR‐2, and is conditionally approved by the United States Food and Drug Administration and the European Medicines Agency for use against canine mast cell tumours. Studies evaluating its clinical efficacy against sarcomas are lacking, although one study demonstrated antiproliferative activity against canine oral fibrosarcoma in vitro …”

Section: Receptor Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

“…This is illustrated by a growing number of clinical and preclinical studies evaluating safety and efficacy of these TKIs as single therapy or in combination with traditional cytotoxic chemotherapeutic agents and/or cyclooxygenase (COX) inhibitors. 35,178,[184][185][186][187][188] Proposed mechanisms supporting their use in combination with other agents include chemosensitization as well as immunomodulation through suppression of regulatory T cells and restoration of T cell-mediated immune responses. 108,189 Toceranib is a multitargeted TKI targeting several RTKs, including VEGFR, PDGFR, KIT, CSF1R, and FLT3 and was developed as an orally bioavailable anti-angiogenic drug.…”

Section: Receptor Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

Borgatti

Dickerson

Lawrence

2019

Vet Comparative Oncology

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Sarcomas represent a group of genomically chaotic, highly heterogenous tumours of mesenchymal origin with variable mutational load. Conventional therapy with surgery and radiation therapy is effective for managing small, low‐grade sarcomas and remains the standard therapeutic approach. For advanced, high‐grade, recurrent, or metastatic sarcomas, systemic chemotherapy provides minimal benefit, therefore, there is a drive to develop novel approaches. The discovery of “Coley's toxins” in the 19th century, and their use to stimulate the immune system supported the application of unconventional therapies for the treatment of sarcomas. While promising, this initial work was abandoned and treatment paradigm and disease course of sarcomas was largely unchanged for several decades. Exciting new therapies are currently changing treatment algorithms for advanced carcinomas and melanomas, and similar approaches are being applied to advance the field of sarcoma research. Recent discoveries in subtype‐specific cancer biology and the identification of distinct molecular targets have led to the development of promising targeted strategies with remarkable potential to change the landscape of sarcoma therapy in dogs. The purpose of this review article is to describe the current standard of care and limitations as well as emerging approaches for sarcoma therapy that span many of the most active paradigms in oncologic research, including immunotherapies, checkpoint inhibitors, and drugs capable of cellular metabolic reprogramming.

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Receptor tyrosine kinase inhibitors: molecularly targeted drugs for veterinary cancer therapy

Cited by 27 publications

References 69 publications

Development of an in vitro model of acquired resistance to toceranib phosphate (Palladia®) in canine mast cell tumor

Development of an in vitro model of acquired resistance to toceranib phosphate (Palladia®) in canine mast cell tumor

Caudoventral abdominal lymphangiosarcoma in a cat treated with metronomic chemotherapy

Emerging therapeutic approaches for canine sarcomas: Pushing the boundaries beyond the conventional

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