title: Postsurgical adjuvant or metastatic renal cell carcinoma therapy models reveal potent antitumor activity of metronomic oral topotecan with pazopanib.
abstract: Renal cell carcinoma (RCC), normally considered an intrinsically chemotherapy-resistant cancer, is currently treated with targeted biologic therapies, including antiangiogenic tyrosine kinase inhibitors (TKIs), such as pazopanib. The efficacy of these agents is limited by both intrinsic and acquired resistance. Death is almost always due to advanced metastatic disease, a treatment circumstance seldom modeled in preclinical (mouse) drug testing. Similarly, therapy results using postsurgical adjuvant therapy models of microscopic disease have not been reported. Using in vivo selection and transfection of established human RCC cell lines (786-0 and SN12-PM6), we derived clonal luciferase-expressing variants capable of spontaneous metastasis from an orthotopic primary tumor to organs typical of clinical RCC, including bone, lungs, and brain. The bioluminescence and consistent metastatic spread of von Hippel-Lindau-wild type SN12-PM6-1 cells allowed for the establishment of perioperative therapy models of RCC. We report that the combination of daily low-dose metronomic topotecan with pazopanib has highly potent antiprimary tumor as well as both postsurgical adjuvant and metastatic therapy efficacy despite lack of an antimetastatic effect of pazopanib monotherapy. The combination therapy resulted in sustained metastatic tumor cell dormancy, but tumor progression occurred upon treatment cessation. We also obtained evidence for a direct effect of pazopanib on RCC cells, resulting in increased intracellular concentration of topotecan. Our results suggest that this type of treatment combination should be considered for clinical evaluation in early- or late-stage metastatic disease, even for tumors seemingly intrinsically "resistant" to antiangiogenic TKIs or chemotherapy.
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada.
authors: Christopher
authors: C
authors: Jedeszko
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada.
authors: Marta
authors: M
authors: Paez-Ribes
authors: Divisione di Farmacologia, Dipartimento di Medicina Clinica e Sperimentale, University of Pisa, Pisa 56126, Italy.
authors: Teresa
authors: T
authors: Di Desidero
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada.
authors: Shan
authors: S
authors: Man
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada.
authors: Christina R
authors: CR
authors: Lee
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada.
authors: Ping
authors: P
authors: Xu
authors: Sunnybrook Odette Cancer Centre, Toronto, Ontario M4N 3M5, Canada.
authors: Georg A
authors: GA
authors: Bjarnason
authors: Divisione di Farmacologia, Dipartimento di Medicina Clinica e Sperimentale, University of Pisa, Pisa 56126, Italy.
authors: Guido
authors: G
authors: Bocci
authors: Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 2J7, Canada. robert.kerbel@sri.utoronto.ca.
authors: Robert S
authors: RS
authors: Kerbel
mesh_terms: D059250:Administration, Metronomic; D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000601:surgery*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007191:Indazoles; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000601:surgery; D020714:Maximum Tolerated Dose; D009362:Neoplasm Metastasis; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D016019:Survival Analysis; D019772:Topotecan / Q000008:administration & dosage / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; D019772:Topotecan; C516667:pazopanib