Toceranib

Toceranib is an inhibitor which blocks various tyrosine kinases expressed on the cell surface. Receptor tyrosine kinases (RTKs) are excellent candidates for molecular targeted therapy, because they play key roles in controlling cell proliferation and survival and are frequently dysregulated in a variety of malignancies.

In vitro: Toceranib inhibited KIT phosphorylation and cell proliferation in a dose-dependent manner in the treatment-naïve, parental C2 line (IC50 < 10 nM). In addition, chronic TOC exposure resulted in c-kit mRNA and KIT protein overexpression in the TOC-resistant sublines [1].

In vivo: Fourteen dogs with advanced mast cell tumors (MCTs) were enrolled in a prevoius study, among which 11 dogs were evaluable for KIT target modulation. Of these, eight MCTs showed reduced levels of phosphorylated KIT relative to total KIT after treatment with Toceranib, compared with pretreatment biopsies. All four evaluable MCTs expressing ITD mutant c-kit showed modulation of KIT phosphorylation, as did four of seven tumors expressing non-ITD c-kit. [2].

Clinical trials: Currenlty no clinical data are available.

References:
[1] Halsey CH, Gustafson DL, Rose BJ, Wolf-Ringwall A, Burnett RC, Duval DL, Avery AC, Thamm DH.  Development of an in vitro model of acquired resistance to toceranib phosphate (Palladia®) in canine mast cell tumor. BMC Vet Res. 2014;10:105. doi: 10.1186/1746-6148-10-105.
[2] Pryer NK, Lee LB, Zadovaskaya R, Yu X, Sukbuntherng J, Cherrington JM, London CA.   Proof of target for SU11654: inhibition of KIT phosphorylation in canine mast cell tumors. Clin Cancer Res. 2003;9(15):5729-34.

Skin depigmentation associated with toceranib phosphate in a dog.[Pubmed:28164401]

Vet Dermatol. 2017 Aug;28(4):400-e95.

BACKGROUND: Drug-induced depigmentation is frequently observed in humans undergoing tyrosine kinase inhibitor therapy, whereas it is not reported in dogs. The skin depigmentation can occur after the first week of treatment and it is reversible within a few weeks after drug discontinuation. OBJECTIVES: To report the clinical and histopathological features of an episode of cutaneous adverse drug reaction associated with short term administration of Toceranib phosphate. CASE REPORT: An 11-year-old intact male Bernese mountain dog was presented for investigation of a subcutaneous mast cell tumour (MCT) including treatment options. The major abnormality on physical examination was a 7.5 x 10 cm subcutaneous mass located cranial to the left shoulder joint consistent with a MCT. Toceranib phosphate therapy was initiated. Fourteen days after initiating treatment, the dog presented with skin erosions near the lateral canthus of the left eye. Three weeks later there were multiple skin lesions characterized by alopecia and depigmentation involving left and right eyelids; leukotrichia of the periorbital areas and depigmentation of the nasal planum and all paw pads. Histopathological findings were nonspecific; they were supportive of vitiligo. Resolution of skin lesions was observed after stopping the Toceranib phosphate therapy. CONCLUSION AND CLINICAL IMPORTANCE: Based on the gross lesions, histopathological features before and after tyrosine kinase inhibitor therapy, and Naranjo score, this case was considered to be consistent with cutaneous adverse drug effects. To the best of the authors' knowledge, this is the first report describing the clinical and histopathological features of presumed drug-induced skin depigmentation in a dog receiving Toceranib phosphate.

A pilot study of toceranib/vinblastine therapy for canine transitional cell carcinoma.[Pubmed:27855679]

BMC Vet Res. 2016 Nov 17;12(1):257.

BACKGROUND: Effective therapies for transitional cell carcinoma (TCC) are limited, with objective response rates to most chemotherapeutic regimens below 20%. The purpose of this study was to investigate the biologic activity of combined Toceranib phosphate and vinblastine chemotherapy for treatment of TCC. A secondary objective was to compare the utility of Computed Tomography (CT) and abdominal ultrasound (AUS) in tumor response assessments. RESULTS: Dogs with TCC received vinblastine at 1.6 mg/m2 every 2 weeks and Toceranib at 2.5-2.75 mg/kg on Monday/Wednesday/Friday. Tumor monitoring was achieved through CT and AUS. Five patients completed the 16-week study. Based on AUS assessments, 3 dogs experienced biologic response to therapy including partial responses (PR, n = 2) and stable disease (SD, n = 1). Based on CT, 5 dogs experienced a biologic response (n = 2 PR, n = 3 SD). Both imaging modalities (ultrasound and CT) were found to provide repeatable measurements between operators, however agreement between operator measurements was greater when CT images were used to assess tumor size. CONCLUSIONS: The combination of Toceranib and vinblastine did not result in improved response rates. While agreement in tumor volume assessments between both AUS and CT were excellent between operators, this did not extend to assessment of tumor response. The higher rate of concordance between operators when assessing response to treatment with CT suggests that CT should be considered for future clinical trials involving canine bladder TCC to improve the accuracy and repeatability of tumor measurement. The data suggest that response to therapy as assessed by AUS or CT do not predict duration of clinical response.

Successful treatment of a metastatic, gastrointestinal stromal tumour in a dog with toceranib phosphate (Palladia).[Pubmed:28199021]

J Small Anim Pract. 2017 Jul;58(7):416-418.

A ten-year-old, female-entire English springer spaniel presented with a large intra-abdominal mass but no other clinical signs. Gastrointestinal stromal tumour of the caecum with widespread abdominal metastasis was confirmed. Treatment with Toceranib phosphate resulted in complete response, despite the absence of exon-8 or exon-11 c-kit mutation. There was no clinical evidence of tumour recurrence nine months after diagnosis.

Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors.[Pubmed:12091352]

Blood. 2002 Jul 15;100(2):585-93.

Mutations in the proto-oncogene c-kit, including point mutations, deletions, or duplications in the negative regulatory juxtamembrane (JM) domain or point mutations in the catalytic domain, have been observed in human and canine cancers and often result in constitutive activation of Kit in the absence of ligand binding. To identify a receptor tyrosine kinase (RTK) inhibitor capable of blocking the function of mutant Kit, we evaluated 3 indolinones (SU11652, SU11654, and SU11655) that act as competitive inhibitors of adenosine triphosphate binding to several members of the split kinase family of RTKs, including VEGFR, FGFR, PDGFR, and Kit. Mast cell lines expressing either wild-type (WT) Kit, a point mutation in the JM domain, a tandem duplication in the JM domain, or a point mutation in the catalytic domain were used for these studies. All 3 indolinones inhibited phosphorylation of WT Kit in the presence of stem cell factor at concentrations as low as 0.01 microM. Autophosphorylation of both JM mutants was inhibited at 0.01 to 0.1 microM, resulting in cell cycle arrest within 24 hours, whereas autophosphorylation of the catalytic domain mutant was inhibited at 0.25 to 0.5 microM, resulting in cell death within 24 hours. poly(ADP-ribose) polymerase (PARP) cleavage was noted in all Kit mutant lines after indolinone treatment. In summary, SU11652, SU11654, and SU11655 are effective RTK inhibitors capable of disrupting the function of all forms of mutant Kit. Because the concentrations of drug necessary for receptor inhibition are readily achievable and nontoxic in vivo, these compounds may be useful in the treatment of spontaneous cancers expressing Kit mutations.

Toceranib phosphate (SU11654 phosphate) is an orally active receptor tyrosine kinase (RTK) inhibitor, and it potently inhibits PDGFR, VEGFR, and Kit with Kis of 5 and 6 nM for PDGFRβ and Flk-1/KDR, respectively. Toceranib phosphate (SU11654 phosphate) has antitumor and antiangiogenic activity, and used in the treatment of canine mast cell tumors.

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