01545-A: Pilot Study to Assess Folate Receptor Expression in Canine High-Grade Multicentric Lymphoma

Project Summary

Multicentric lymphoma is a common cancer in pet dogs. Although multicentric lymphoma can typically be controlled for several months or longer with chemotherapy, it is ultimately lethal in most dogs. This research project was important in demonstrating that half (5 of 10) of dogs with multicentric lymphoma in a pilot study had marked uptake of folate in their cancer detected via nuclear scintigraphy. Folate is a vitamin widely present in food and multivitamin supplements. Dr. Phil Low (collaborator on this project) in the Department of Chemistry at Purdue University has discovered that certain cancer cells take up much more folate than normal cells, and this typically occurs in cancer cells through overexpression of folate receptors (FR's). The finding of marked folate uptake in half of the dogs with lymphoma in this study is extremely important as there is a series of new targeted cancer treatment drugs being developed to exploit the uptake of folate by cancer cells. Briefly, cancer killing drugs are conjugated to folate, and then the conjugates are selectively taken up by cancer cells that overexpress FR's. Since FR's are expressed in few normal cells in the body, this treatment strategy minimizes exposure and harm to normal cells. This study provided good preliminary evidence for the potential role of FR-targeted therapy in dogs with lymphoma. One of 5 dogs had complete remission, and 2 of 5 dogs had stable disease of their cancer. Admittedly, we would prefer to have seen more remissions and longer-duration responses, but this initial assessment is encouraging. It is likely that newer emerging folate-conjugate cancer drugs will be considerably more active than the drug we tested in the pilot study. The drug we tested was a vinblastine conjugate, and it is recognized that there are drugs other than vinblastine that are much more active in canine lymphoma. We are eager to evaluate the newer folate conjugates in future studies of dogs with lymphoma. There was a second important finding in our study. Not all lymphomas in dogs take up excessive amounts of folate. This was not surprising because this is true across most cancer types studied to date. Thus, a selection process is needed to identity the patients with extensive folate uptake, as these are the patients who will most likely benefit from FR-targeted therapy. The results of this study show that the selection of dogs that may benefit from FR-targeted therapy should be based on scintigraphy, i.e. nuclear scans to detect folate uptake in the cancer, and not on immunohistochemistry (IHC). Our findings were unexpected in that IHC did NOT detect FR's, in dogs with positive nuclear scintigraphy scans. We have not observed this phenomenon previously; in dogs with other cancer types, positive nuclear scan results usually correlate with positive IHC results. We suspect that in canine lymphoma, the FR's are slightly different in their structure which prevents them from being detected by standard IHC antibodies used in dogs. In summary, the results of this pilot study clearly warrant future studies of FR expression and FR-targeted chemotherapy in canine lymphomas. Scintigraphy should be used to select patients for FR-targeted treatment trials, pending further characterization of FR's in canine lymphoma and optimization of methods to detect the FR's in tissue biopsies. The conjugation of folate with more active drugs against canine lymphomas, such as doxorubicin, is expected to lead to improved response rates, remission durations, and survival times in dogs with FR-expressing lymphomas.

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