Development of New Lymphoma Treatment Strategy with a Selective Inhibitor of Nuclear Export

By Daisuke Ito, D.V.M., Ph.D., Department of Veterinary Clinical Sciences and Masonic Cancer Center

According to the Leukemia & Lymphoma Society, approximately 65,000 people were newly diagnosed with non-Hodgkin lymphoma (NHL) in the U.S. in 2010, and an estimated 20,000 patients died from the disease. This unacceptably high death rate persists even after the introduction of rituximab, one of the most successful cancer treatments in recent decades, highlighting the critical need to develop better treatments for NHL.

NHL also occurs in dogs. It is one of the most common tumors seen in dogs, and as is true in humans, cures for this disease are elusive. To circumvent this problem, we have worked diligently to establish new therapeutic strategies for lymphoma. However, we strongly believe that success will require a multi-pronged approach, and recently collaborated with scientists and oncologists at Karyopharm Therapeutics, Inc. in Natick, Massachusetts, to introduce their newly developed
selective inhibitors of nuclear export (SINE), to clinical trials for NHL.

Our trials take advantage of the similarities between human and canine NHL. The disease has similar biology and clinical behavior in both species; in many or most cases, the diseases have identical histology and comparable response to therapy.

Dogs and humans also have similar physiology and genome organization, and are largely exposed to the same environment. Yet, the more rapid progression of disease in dogs provides opportunities to answer questions in a shorter time frame than comparable trials in humans. Thus, therapy trials in dogs with NHL not only benefit dogs by helping to develop new potential treatments, but also can be translated to clinical trials in human patients with NHL.

The Karyopharm platform (KPT-SINE) inhibits the function of CRM1, a protein that exports nearly all known tumor suppressor proteins from the cell nucleus to the cytoplasm. Inhibition of CRM1 by KPT-SINE causes retention of multiple tumor suppressor proteins in the nucleus, resulting in the selective death of tumor cells—while normal cells undergo transient, but reversible proliferation arrest. This makes KPT-SINE unique among drugs in current use or undergoing trials for lymphoma treatment, which carries as an additional benefit the potential to be used as a single agent or in combination with other therapies.

This collaboration between Karyopharm and the Animal Cancer Care and Research program has a basic laboratory component and a planned clinical trial. The basic project will be led by Dr. Daisuke Ito, who will study the specific mechanisms of action that promote selective killing of canine lymphoma cells by KPT-SINE. The multi-site clinical trial will be conducted at the University of Minnesota and at The Ohio State University. We anticipate that this clinical trial will open for enrollment in 2011. As we enhance the options that exist to successfully treat dogs with NHL, we can translate these findings to human patients with the same disease and move forward in our mission to improve the health and well-being of animals and their human companions.