toceranib-phosphate and Urinary-Bladder-Neoplasms

Urothelial carcinoma (UC) accounts for > 90% of canine tumors occurring in the urinary bladder. Toceranib phosphate (TOC) is a multi-target receptor tyrosine kinase (RTK) inhibitor that exhibits activity against members of the split kinase family of RTKs. The purpose of this study was to evaluate primary UC tumors and UC cell lines for the expression and activation of VEGFR2, PDGFRα, PDGFRβ, and KIT to assess whether dysregulation of these RTKs may contribute to the observed biological activity of TOC.. Transcript for VEGFR2, PDGFRα, PDGFRβ, and KIT was detected in all UC tissue samples and UC cell lines. The Proteome Profiler™ Human Phospho-RTK Array Kit (R & D Systems) provided a platform to assess phosphorylation of 42 different RTKs in primary UC tumors and UC cell lines. Evidence of PDGFRα and PDGFRβ phosphorylation was present in only 11% or 33% of UC tumors, respectively, and 25% of UC cell lines. Treatment of UC cell lines with TOC had no significant impact on cell proliferation, including UC cell lines with evidence of PDGFRβ phosphorylation.. Phosphorylation of several key RTKs targeted by TOC is present in a small subset of primary UC tumors and UC cell lines, suggesting that these RTKs do not exist in a state of continuous activation. These data suggest that activation of RTKs targeted by TOC is present in a small subset of UC tumors and UC cell lines and that treatment with TOC at physiologically relevant concentrations has no direct anti-proliferative effect on UC cells.

Topics: Animals; Carcinoma, Transitional Cell; Cell Line, Tumor; Cell Proliferation; Dog Diseases; Dogs; Female; Indoles; Male; Pyrroles; Receptor Protein-Tyrosine Kinases; Urinary Bladder Neoplasms

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.. 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.. 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.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Dog Diseases; Dogs; Female; Indoles; Male; Pilot Projects; Pyrroles; Reproducibility of Results; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography; Urinary Bladder Neoplasms; Vinblastine