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eBAT – A New Drug in Our Arsenal Against Hemangiosarcoma

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This is an edited, updated version of an article published in The Alpenhorn (The Official Publication of the Bernese Mountain Dog Club of America), Winter issue of 2018, pp. 82-85. Copyright for the article belongs to the Animal Care and Cancer Research of the University of Minnesota. It can be distributed and reproduced for individual use and for non-profit purposes.
Studying Cancer in Dogs as a Path Towards a World Where We No Longer Fear Cancer - A New Strategy Raises Hope for Hemangiosarcoma

By Antonella Borgatti, Andrea M. Fahrenkrug, and Jaime F. Modiano
Animal Cancer Care and Research Program, University of Minnesota

In part 1 of this series we reviewed the characteristics of canine hemangiosarcoma. For this installment, we will describe how a promising new drug, called eBAT might overcome some of the major challenges faced when treating this disease.

The Current Standard of Care for Hemangiosarcoma

Hemangiosarcoma in dogs develops insidiously without any obvious signs of pain or discomfort, and it is generally diagnosed late in the course of the disease. Furthermore, the cells that give rise to hemangiosarcoma seem to disseminate to different organs in the body early during the development of the disease, and they are resistant to conventional cancer therapies. Together, these characteristics make the treatment of hemangiosarcoma extremely challenging.

The major goals of treatment for hemangiosarcoma are to slow down or delay the spread of the disease and to prevent life-threatening bleeding episodes. The only approach currently known to be effective in managing hemangiosarcoma combines surgery to remove accessible tumors with chemotherapy to kill or disable any tumor cells that are inaccessible, or that are not eliminated by surgery. This is the current best practice for hemangiosarcoma treatment, and it has not changed much for about 40 years. No other therapy introduced since then has been shown to be effective in more than a few anecdotal cases.

eBAT: A New Type of Cancer Drug

Through our efforts to develop more effective treatments for hemangiosarcoma, we discovered hemangiosarcoma tumors display two proteins on their cell surface that could serve as targets for therapy. These two proteins are the epidermal growth factor receptor (EGFR), which is normally present on cells of the skin and internal organs such as liver, kidney, and gut, and the urokinase-type plasminogen activator receptor (uPAR), which is normally present on certain white blood cells, cells of the female reproductive tract, and cells that line blood vessels. EGFR and uPAR are usually not expressed at the same time by normal cells; the observation that both of these proteins were present on hemangiosarcoma cells led us to test the hypothesis that these tumors would be sensitive to a targeted therapy that attacked both simultaneously. (Figure 1)

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Our approach was to use the proteins as baits to deliver a lethal toxin. eBAT, which stands for EGF-bispecific angiotoxin, is a drug invented, developed, and tested at the University of Minnesota. This drug consists of two proteins which simultaneously target EGFR and uPAR linked to a lethal bacterial toxin. The design of eBAT is responsible for its high specificity because the toxin component is only delivered to cells that display EGFR and uPAR on their surface. But eBAT has another unique property, in that it also disrupts the environment surrounding the tumor making it inhospitable for the cancer cells.

eBAT Has Proved to be Exceptionally Safe and to Improve Survival Rates of Dogs with Hemangiosarcoma

We initially verified that eBAT was able to kill cells responsible for the formation and growth of hemangiosarcoma . Next, we demonstrated that eBAT was effective in treating laboratory animals with cancer, but these experiments produced an even more remarkable result: while other drugs targeting EGFR have life-threatening toxicities, eBAT did not appear to cause any severe side effects. These experiments cleared the way for us to evaluate the safety and efficacy of eBAT in dogs with hemangiosarcoma.

In SRCBST-1 (sarcoma bispecific toxin trial-1), the first clinical trial using eBAT, we added eBAT to the standard of care for dogs with hemangiosarcoma of the spleen. In order to participate dogs had to undergo surgery to remove the spleen and there could not be any evidence of metastasis. Ten days after their surgery the dogs received three doses of eBAT over the course of one week. Two weeks after the last dose of eBAT the dogs were given a standard course of doxorubicin chemotherapy, consisting of five treatments spaced three weeks apart.

The dogs were monitored for side effects from the beginning of treatment until their death. Dogs whose tumors returned either during the course of treatment or after treatment ended were allowed to receive other therapies. To establish if eBAT improved patient outcomes, we compared the duration of remission (which is the time from diagnosis until the cancer was again detectable) and the overall survival time of dogs receiving eBAT with that of dogs treated with surgery and chemotherapy but without eBAT.

The study was designed to treat 30 dogs; the comparison group included 28 dogs. After the 23rd dog completed treatment we determined that adding more dogs to the trial would not affect the results in a meaningful way. The study results showed that eBAT had predictable and manageable side effects: four dogs had a drop in blood pressure during eBAT treatment that required medical attention. Two dogs had changes in liver blood tests, although these returned to normal within a few days without treatment. We concluded that eBAT could be administered safely to dogs with hemangiosarcoma, although its use requires precautions to prevent or manage a potential drop in blood pressure. It is especially worth noting that, as we saw in the laboratory experiments, eBAT did not cause any of the severe side effects typically associated with other drugs that target EGFR, suggesting that its simultaneous targeting of uPAR greatly reduces the risk for toxicity.

The most encouraging result was that 16 of the 23 dogs receiving eBAT in addition to surgery and chemotherapy were alive six months after their diagnosis. This represents more than 70% of the dogs in the experimental group, compared with only 38% of the dogs in the control group. Even more striking, six of the 23 dogs treated with eBAT were alive 15 months after their diagnosis, compared with only two of the 28 dogs in the control group.

Availability of eBAT and Next Steps

The success of eBAT is extremely encouraging. However, much work remains to be done. A second trial in which twenty-six more dogs were treated using eBAT has been completed, and additional clinical trials to define the most effective dose and timing for drug administration, identify other tumor types where eBAT can improve survival, and to test its potential to prevent hemangiosarcoma in dogs at risk are planned.

At present, eBAT is available to treat dogs with hemangiosarcoma exclusively through a compassionate care study at the University of Minnesota. The drug has been licensed to a company which is working to complete the regulatory approval and make eBAT more widely available.

Our results give us hope and inspiration. The efforts to optimize eBAT are guided by our relentless focus on improving survival and reducing the impact of hemangiosarcoma and other terminal malignancies on our patients’ quality of life, helping us to achieve a world where we no longer fear cancer.

 

 

About the Authors: Dr. Borgatti is Associate Professor of Oncology at the University of Minnesota Veterinary Medical Center. She graduated CUM LAUDE from the University of Torino, Italy (1996). After three years in general practice, she received a scholarship to pursue specialized training in oncology at North Carolina State University where she subsequently remained as a Research Associate, Oncology Intern, and Clinical Instructor in Oncology. She completed a Residency in Comparative Oncology at Purdue University where she also received a Master of Sciences Degree in 2006. Dr. Borgatti became a Diplomate of the American College of Veterinary Internal Medicine (Oncology) in 2006 and a Diplomate of the European College of Veterinary Internal Medicine in 2007. She worked at a specialty referral hospital in North Carolina for two years before joining the faculty at the University of Minnesota in 2008. She is also a Member of the Masonic Cancer Center at the University of Minnesota and Director of the Oncology residency program.

Dr. Modiano graduated from the Veterinary Medical Scientist Training Program (VMD/PhD) at the University of Pennsylvania in 1991. He completed a residency in Veterinary Clinical Pathology at Colorado State University in 1993 and a post-doc at the National Jewish Medical Center in 1995. He was on the faculties of Texas A&M University and the University of Colorado before joining the College of Veterinary Medicine and the Masonic Cancer Center of the University of Minnesota in 2007 as the Alvin and June Perlman Endowed Chair of Animal Oncology and Director of the Animal Cancer Care and Research Program.

Ms. Fahrenkrug is a former Senior Development Officer at the University of Minnesota College of Veterinary Medicine. She is a graduate of Saint Cloud State University and completed her master’s degree at Hamline University in 2005.  Ms. Fahrenkrug worked in the medical device industry before joining the University of Minnesota in 2008.