Oncotarget | Phase I/II clinical trial of the targeted chemotherapeutic drug, folate-tubulysin, in dogs with naturally-occurring invasive urothelial carcinoma


The cover for issue 97 of Oncotarget features Figure 4, "Representative examples of FR expression detected on canine kidney," by Szigetvari, et al.

Experimental Design: A 3+3 dose escalation study of EC0531 was performed in dogs with iUC expressing high levels of FRs.

Unlike human neutrophils, canine neutrophils were found to express FRs, which contributes to the neutropenia at higher doses of EC0531 in dogs.

It is likely that humans will tolerate higher, potentially more effective doses of folate-tubulysin without myelotoxicity because of the absence of FRs on human neutrophils.

Dr. Deborah W. Knapp from the Department of Veterinary Clinical Sciences, at Purdue University, in West Lafayette, IN, USA as well as Purdue University Center for Cancer Research, in West Lafayette, IN, USA said "Targeted chemotherapy allows the selective delivery of a cytotoxic payload to tumor cells while limiting the exposure and toxicity to normal tissues."

"Targeted chemotherapy allows the selective delivery of a cytotoxic payload to tumor cells while limiting the exposure and toxicity to normal tissues."

- Dr. Deborah W. Knapp, Department of Veterinary Clinical Sciences, at Purdue University and Purdue University Center for Cancer Research

Several human cancer types, such as ovarian carcinoma, renal carcinoma, non-small cell lung cancer, colorectal cancer, and metastatic brain cancer, have 10- to 100-fold higher expression of FRs relative to normal tissues.

Figure 4:

Figure 4: Representative examples of FR expression detected on canine kidney (A), canine bone marrow sections (B, C), canine peripheral blood smears (D, E, F), and canine iUC (G, H, I). FR expression was detected by immunohistochemistry in panels (A–C) and (G–H), and by immunocytochemistry in panels (D–F). (A) Canine kidney used as a positive control. Immunoreactivity is detected on the apical surface of the proximal renal tubular epithelium. Image taken at 40× magnification. Scale bar = 50 μm. (B) Canine bone marrow section used as negative control. Note the absence of immunoreactivity in granulocytes (black arrowheads) and megakaryocytes (white "M"). (C) Paired bone marrow sample showing FR expression by early myeloid precursor cells (white arrowheads) and granulocytes (black arrowhead). Erythroid precursors (red asterisk) do not display immunoreactivity. (D) Canine peripheral blood smear negative control. (E) Paired specimen showing marked cytoplasmic and membranous immunoreactivity in granulocytes. (F) Absence of FR immunoreactivity on lymphocytes (black asterisk) contrary to positive immunoreactivity on granulocytes (black arrowheads). Images B to F were taken at 100× magnification. Scale bars = 10 μm. (G) Canine iUC, urinary bladder. Strong labeling of neoplastic cells for FR is observed. Scale bar = 200 μm. (H and I) Pulmonary metastases of canine iUC. Note the uneven labeling for FR. Scale bar = 75 μm. All images were collected with an Eclipse E400 microscope equipped with a Plan Fluor 40×/0.75 and a Nikon Plan Fluor 100×/1.30 oil objectives. Images were acquired with a DS-Fi2 camera controlled with the Digital Sight DS-L3 controller and the NIS-Elements F (4.60.00 version) software. Figures were prepared using the GIMP (version 2.8.22 version) image processing software.

Several conjugates of folate and cytotoxic drugs or folate and immune-modulating drugs have been developed in an attempt to exploit this disparity in FR expression.

Furthermore, growth inhibition was observed in 33% of cell lines tested in a standardized cancer cell line panel, the U.S. National Cancer Institute 60 tumor cell lines for anticancer drug screen.

Yet, conjugation of tubulysin, specifically tubulysin B, to folate creates a drug tolerated at doses 20 times higher than doses of unconjugated tubulysin, and a drug which has induced complete regression of cancer in mouse xenograft models.

The goal of the study reported here was to determine the safety and antitumor activity of a folate-tubulysin B drug conjugate in a canine spontaneous cancer model that incorporates factors which would affect drug response in humans such as tumor heterogeneity, metastatic behavior, immune system interactions, and innate and acquired drug resistance.

The Knapp research team concluded, in their Oncotarget Research Paper, "The naturally-occurring pet dog model of iUC incorporates the same clinical issues that affect cancer treatment in humans including tumor heterogeneity, aggressive cancer behavior, multiple drug resistance mechanisms, and limited tolerance for drug toxicity."

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DOI - https://doi.org/10.18632/oncotarget.26455

Full text - https://www.oncotarget.com/article/26455/text/

Correspondence to - Deborah W. Knapp - [email protected]

Keywords - animal model, bladder cancer, canine, clinical trial, targeted chemotherapy

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