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.