01152: Liposomal BisphosphonateTherapy for Malignant Histiocytosis
Grant Status: Closed
The studies supported by CHF 01152 (Liposomal BisphosphonateTherapy for Malignant Histiocytosis) were designed to investigate the potential for liposomal bisphosphonates to be used as novel drugs for treating malignant histiocytosis (MH) in dogs. Bisphoshonates are a type of chemotherapy drug that has been used in the past primarily to inhibit the growth of tumor metastases in bone, as the bisphosphonate drugs rapidly bind to bone tissues and kill a type of cell in bone known as an osteoclast. But earlier experiments in mice have shown that when bisphosphonates, in particular a bisphosphonate known as clodronate) are placed into small liposomes before being injected, they no longer go to the bone, but instead are taken up by a type of white blood cell known as a macrophage. Malignant histiocytosis is a tumor of macrophages, so we hypothesized that liposomal clodronate (LC) would kill MH cells, both in vitro and in vivo. In the first aim of the grant, we determined the best way to prepare liposomes for targeting them to MH cells for killing in vitro. We also compared the efficiency of different liposomes for inducing MH killing and found that clodronate, which is relatively inexpensive to purchase and use in LCs was nearly as effective as the best bisphosphonate drug available. Due to cost considerations, we used LC for the remainder of the studies. In the second aim of the grant, we found that certain bisphosphonate drugs appeared to induce much greater killing of MH cells if they were combined with certain chemotherapy drugs. We identified 2 combinations that appeared to be particularly effective at killing MH cells in vitro, including clodronate plus vincristine, and zoledronate plus doxorubicin. These findings are important because they suggest that these 2 drug combinations could be used as a novel treatment approach for dogs with MH. The doxorubicin and zoledronate combination approach has been used previously safely in dogs with bone cancer and we believe that additional studies of this 2-drug combination are warranted in dogs with MH. The final aim of the grant was to conduct a pilot study to evaluate the potential safety and effectiveness of LC for treatment of dogs with MH. In the initial portion of this Aim, we treated 5 dogs with MH. We found that treatment by repeated weekly i.v. infusion of LC was well-tolerated by dogs with MH, and in one dog induced significant tumor regression (see Manuscript 1). Thus, it appears that LC can be given safely to dogs with MH, and that the drug has activity against the tumor in vivo. Therefore, a second clinical trial is now underway investigating the effectiveness of LC treatment for a larger number of dogs with MH. At this point, 20 dogs have been treated. The response rate observed to date has been approximately 40%, which is roughly equivalent to that induced by treatment with lomustine, which is considered the most effective drug for treating MH in dogs. Based on these data, a new CHF-funded study has been initiated, in which the effectiveness of LC administered together with lomustine will be compared.
Hafeman, S. D., Varland, D., & Dow, S. W. (2012). Bisphosphonates significantly increase the activity of doxorubicin or vincristine against canine malignant histiocytosis cells. Veterinary and Comparative Oncology, 10(1), 44–56. https://doi.org/10.1111/j.1476-5829.2011.00274.x
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