'Click' chemistry may help treat dogs with bone cancer

Researchers from California and Denmark were given the Nobel Prize in Chemistry in September for creating "click" chemistry, a method for connecting molecules like LEGOs, which could be a more effective way to transfer drugs to cancer tumors.

In a new study, a scientist from the University of Missouri has successfully demonstrated for the first time how click chemistry may be used to more effectively deliver medications to treat tumors in large dogs with bone cancer. Previously, this method had only been successful in small mice.

"If you want to attack a tumor using the immune system, an antibody is an extremely specific way to deliver a drug or radioactive payload to the tumor, but the problem with antibodies is they are huge molecules that circulate in the bloodstream for days or even weeks," said Jeffrey Bryan, an associate professor in the MU College of Veterinary Medicine and author on the study.

"If you put a drug or radioactive molecule onto the antibody, you leave radioactivity circulating in the bloodstream for a long time, which can spread to and negatively impact organs, bone marrow, and the liver while not getting as much dose to the specific tumor as you were hoping for."

The goal with click chemistry is to maximize the delivery of therapeutic drugs specifically to the cancer tumor to increase effectiveness while minimizing the circulation of those drugs throughout the bloodstream and causing dangerous side effects.

From mice to man's best friend

Many chemists believed for many years that although click chemistry has been successful in mice, the strategy would not be effective in large dogs or people due to the possibility that the size of the body would prevent the two sides of the therapy-delivering molecules from finding each other and 'clicking' together.

The first-ever successful "proof-of-concept" study at the MU College of Veterinary Medicine was carried out by Bryan in partnership with Brian Zeglis, an associate professor at Hunter College in New York who specializes in click chemistry. Five dogs with bone cancer weighing more than 100 pounds each got dosages of radiopharmaceuticals delivered exactly to the tumors via click chemistry.

"It is a huge step forward for the field to show that this worked in a human-sized body," Bryan said. "Going forward, this may pave the way for click chemistry to help humans with cancer in the future."

Bryan has been researching veterinary and comparative oncology for nearly two decades. He said some dogs with one known bone tumor have additional bone tumors hiding in their body's skeleton. An additional benefit of studies involving imaging scans and click chemistry is the ability to discover if additional cancer tumors are located in a dog's skeleton and impact its health.

"Osteosarcoma, a common form of bone cancer, impacts both dogs and people, and it causes severe pain, limping, swelling in the limbs, and treating the bone tumors with various radiation therapy and immune therapy approaches to take away the pain is something I am passionate about here at MU," Bryan said. "Everything we learn about treating these dogs can be translated to help humans down the road."

A leader in treating cancer - for people and pets

Clinical trials for cancer are conducted at the MU College of Veterinary Medicine, which received more than $14 million in federal research money from the National Institutes of Health last year. Participants and their pets come from California, Florida, New York, and other states to participate.

"It is heartwarming to be a part of it because the patients' families realize it is not just about better outcomes for their specific dog, but they are also contributing to better outcomes for other dogs in the future and hopefully better health outcomes for people as we translate these advances from the dogs to the human side," Bryan said.

While this was a successful 'proof-of-concept' imaging study involving click chemistry, Bryan's long-term goal is to develop a therapy using radiopharmaceuticals, potentially involving an antibody-targeting molecule, to treat dogs with bone cancer that may not be well enough for other treatments that involve surgery.

"This research is also an example of precision medicine, a key part of MU's NextGen Precision Health initiative, because we are using the molecules associated with the specific tumor to deliver the therapeutic dose of treatment," Bryan said. "We collaborate with the MU Research Reactor, the Molecular Imaging and Theranostics Center, and Washington University in St. Louis, so it is a team effort."

Bryan worked with ELIAS Animal Health in 2020 to develop a precision medicine strategy--a vaccination derived from a dog's own tumor--to target and eradicate cancer cells in dogs with osteosarcoma.

The Food and Drug Administration granted ELIAS Animal Health's parent company, TVAX Biomedical, a unique fast-track designation to study the ELIAS immunotherapy strategy to treat glioblastoma multiforme, a malignant brain tumor in humans, as a result of the treatment's efficacy in dogs.

"The last dog that participated in that study just died a few weeks ago, five years out from their original diagnosis of bone cancer, and the dog never relapsed with its cancer, so the dog was able to live the rest of its life cancer-free due to the immunotherapy," Bryan said. "Our overall goal is to come up with different tools in our toolbox to effectively help treat dogs with cancer, and one day even people, too."