title: Targeting folate receptors to treat invasive urinary bladder cancer.
abstract: Folate receptors (FR) may be of use for targeted delivery of cytotoxic drugs in invasive urothelial carcinoma (iUC), for which improved therapy is needed. FR expression and function in iUC were explored and the antitumor activity and toxicity of a folate-targeted vinblastine conjugate were evaluated in dogs with naturally occurring iUC, an excellent model for human iUC. FR immunohistochemistry was carried out on iUC and normal human and dog bladder tissues together with nuclear scintigraphy in dogs to monitor iUC folate uptake. Dose escalation of a folate-targeted vinblastine compound, EC0905, was conducted in dogs with biopsy-confirmed, FR-positive iUC. FRs were detected by immunohistochemistry (PU17) in most primary iUC and many nodal and lung metastases from dogs, and scintigraphy confirmed folate uptake in both primary and metastatic lesions. The maximum tolerated dose of EC0905 in dogs was 0.25 mg/kg IV weekly, with neutropenia at higher doses. Tumor responses included partial remission (≥ 50% reduction in tumor volume) in five dogs and stable disease (<50% change in tumor volume) in four dogs. Immunoreactivity to PU17 was similar in humans (78% of primary iUC, 80% of nodal metastases). Less immunoreactivity to mab343 (22% of cases) occurred. FR-β was noted in 21% of human iUC cases. Our findings suggest folate-targeted therapy holds considerable promise for treating iUC, where FR-β may be important in addition to FR-α.
authors.affiliation: Department of Veterinary Clinical Sciences, Purdue University, Indianapolis, Indiana 47907, USA.
authors.forename: Deepika
authors.initials: D
authors.lastname: Dhawan
authors.forename: José A
authors.initials: JA
authors.lastname: Ramos-Vara
authors.forename: James F
authors.initials: JF
authors.lastname: Naughton
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.forename: Philip S
authors.initials: PS
authors.lastname: Low
authors.forename: Ryan
authors.initials: R
authors.lastname: Rothenbuhler
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Leamon
authors.forename: Nikki
authors.initials: N
authors.lastname: Parker
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Klein
authors.forename: Iontcho R
authors.initials: IR
authors.lastname: Vlahov
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Reddy
authors.forename: Michael
authors.initials: M
authors.lastname: Koch
authors.forename: Linda
authors.initials: L
authors.lastname: Murphy
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: Fourez
authors.forename: Jane C
authors.initials: JC
authors.lastname: Stewart
authors.forename: Deborah W
authors.initials: DW
authors.lastname: Knapp
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D058973:Folate Receptors, GPI-Anchored / Q000037:antagonists & inhibitors*; D005492:Folic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010865:Pilot Projects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D014747:Vinblastine / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; C579135:EC0905; D058973:Folate Receptors, GPI-Anchored; D014747:Vinblastine; D005492:Folic Acid