Abstract LB-5: Folate-targeted therapy for invasive urinary bladder cancer
Authors: Deepika Dhawan, José Ramos-Vara, James Naughton, Liang Cheng, Phillip Low, Ryan Rothenbuhler, Christopher Leamon, Nikki Parker, Patrick Klein, Iontcho Vlahov, Lindsey Fourez, Linda Murphy, Deborah W. Knapp
Journal: Cancer Research (2012)

Abstract Introduction: Invasive transitional cell carcinoma of the urinary bladder (InvTCC) kills &amp;gt;14,000 people yearly in the US. Folate receptors (FRs, especially FRα) are being targeted for imaging and therapy across multiple cancer types. This work was performed to define FR expression and uptake in InvTCC, with comparison to normal bladder; and to determine the antitumor activity and toxicity of folate-targeted vinblastine in dogs with naturally-occurring InvTCC where the cancer closely mimics human InvTCC. Canine InvTCC metastasizes frequently, and only 35% of dogs have remission with chemotherapy. Methods: Immunohistochemistry (IHC, mab343, PU17, FRβmab) was performed in InvTCC, bladder tissues adjacent to InvTCC in humans, and in bladder from normal dogs. Folate uptake was determined ex vivo by folate binding assay, and in vivo in dogs with InvTCC by nuclear scintigraphy (99mTc based FR targeted imaging agent). A dose escalation study of folate-targeted vinblastine (EC0905, IV weekly) was performed in dogs with biopsy-confirmed, FR-positive, measurable InvTCC. Toxicity (VCOG criteria) was assessed by CBCs, serum chemistry profiles, urinalyses, physical exams, and dog owner observations. The MTD was defined as the highest dose at which 0 of 6 dogs had grade 4 toxicity and ≤1 of 6 dogs had grade 3 toxicity. Tumor response was assessed by ultrasonography (with detailed bladder mapping) and radiography. Results: FR expression (IHC, PU17) was noted in the majority of canine samples including 56 of 74 (76%) primary tumors, 7 of 12 (58%) nodal metastases, and 10 of 21 (48%) lung metastases, as well as in normal urothelium. Typically, &amp;gt;50% of tumor cells were positive. FR expression was cytoplasmic in 18, membrane in 6, and in both sites in 32 InvTCC cases. Scintigraphy (n= 12 dogs) revealed folate uptake in primary and metastatic lesions. The MTD of EC0905 in dogs was 0.25 mg/kg IV weekly. At doses above the MTD, gastrointestinal upset and myelosuppression occurred. No urologic toxicity was noted. Tumor responses included partial remission (≥50% reduction in tumor volume) in 5 dogs and stable disease (&amp;lt;50% change in tumor volume) in 5 dogs. In human InvTCC, IHC results with PU17 were similar to those in dogs with 29 of 36 (78%) primary tumors, 12 of 15 (80%) nodal metastases, and 5 of 5 tissues adjacent to InvTCC being positive. Immunoreactivity to mab343 was less frequent (22% of primary tumors, 33% of nodal metastases). FRβ was expressed in 3 of 14 (21%) InvTCC cases. Ex vivo folate binding to human and canine InvTCC was detected, although binding varied from case to case and did not always correlate with IHC. Conclusions: Folate-targeted therapy holds promise for the treatment of InvTCC. FR expression was detected in human and canine InvTCC, and folate-targeted vinblastine had excellent antitumor activity against canine InvTCC where the cancer closely mimics human InvTCC. In addition to FRα, FRβ may be important in InvTCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-5. doi:1538-7445.AM2012-LB-5