The biology of humans and dogs are similar in many ways, including in the development of cancer. Each year, approximately 6 million cancer diagnoses are made in dogs across the United States. The clinical and genetic similarities of dog cancer and human cancer have allowed researchers in the field of comparative genomics to use information from studies of dog cancer to better understand human cancers, including sarcomas, which are a group of cancers that form in the bones and soft tissues such as muscle, cartilage, and fat.
Dogs are particularly prone to developing sarcomas, and they develop these cancers spontaneously over the course of their lives (unlike laboratory mice used in research, where the tumors are typically induced experimentally). Types of sarcomas that are rare in humans, such as osteosarcoma and angiosarcoma, are actually common in dogs, offering an opportunity to accelerate the development of new therapeutics. By studying cancer in dogs, researchers at UMass Cancer Center are working to improve the outcomes and extend the lives of both human patients and pet dogs with cancer.
Blood biopsy techniques in dogs for improved diagnosis and treatment of sarcoma
Elinor Karlsson, PhD, an associate professor at UMass Chan Medical School, is working to accelerate sarcoma research by partnering with oncologists and immunologists to figure out how pet dogs can help us make advances in cancer care. Much of her research is focused on blood biopsies — an exciting new technology that can sequence tumor DNA from a blood sample. In close collaboration with the Cummings School of Veterinary Medicine at Tufts University and the Broad Institute, Dr. Karlsson’s research team is answering important questions about this brand-new technology. Because the performance of this test depends on the amount of tumor DNA in a blood sample, they are testing whether taking the dogs’ blood samples at a particular time of day, or from a particular site, might give a larger amount of tumor DNA and therefore more accurate results.
Dr. Karlsson and her team hopes that this blood biopsy technology will allow them to monitor the response to cancer treatment, and detect relapse, much earlier than is currently possible. The clinical progression of cancer typically happens much more quickly in dogs than in humans, which makes dogs a good model to test the technology’s ability to detect relapse and to figure out within a year whether the technology works, and how it needs to be refined. Dr. Karlsson’s team is now collecting samples from dogs with different types of sarcoma, at times when the dogs are receiving treatment, in remission, and at relapse, and using tumor DNA sequencing to monitor how the cancer changes over time and in response to treatment.
It is well-known that one of the most important factors for successful genomic studies is large sample sizes. To that end, Dr. Karlsson is using mail-in blood biopsies to reach dog owners across the United States. In a pilot project testing this approach, a small number of dog owners will receive a specially designed blood tube to bring to their veterinarian for collection of a blood sample from their dogs. These blood samples will then be mailed in for measurement and sequencing of any tumor DNA found in the bloodstream of each dog. If this mail-in approach is found to be effective, Dr. Karlsson believes she can grow the research exponentially. She will soon be launching a portal at the Darwin’s Ark website where any dog owner who has a pet dog with cancer can sign up and be evaluated for inclusion in the project.
Immunotherapeutic approaches for metastatic osteosarcoma in dogs
Cheryl London, DVM, PhD, a professor at Tufts University, is also using liquid biopsy in collaboration with Dr. Karlsson to monitor the response to immunotherapeutic treatment (a type of treatment approach that harnesses the immune system to fight cancer) in dogs with metastatic osteosarcoma. Osteosarcoma, in which tumors typically develop in bones of the arms, legs, or pelvis, is the most common type of sarcoma. Cases of osteosarcoma are known as metastatic osteosarcoma when the tumors originate not in the bone itself but in other parts of the body and subsequently spread to the bone. Approximately 30% of human cancer patients succumb to metastasis, primarily to the lungs.
Despite decades of work on metastatic osteosarcoma, it remains a major challenge to treat. There have been increasing efforts to use immunotherapeutic approaches, particularly using checkpoint inhibition (which blocks proteins that prevent the immune system from attacking cancer cells), without success. In concert with researchers at Colorado State University, Dr. London has identified key targets for therapeutic modulation of the tumor’s immune microenvironment. Clinical trials to examine these targets are ongoing in dogs with osteosarcoma metastatic to the lungs. Recently, Dr. London found that a combination of anti-cancer immunotherapeutic drugs aimed at multiple targets — the kinase inhibitor toceranib (modulates regulatory T cells and myeloid-derived suppressor cells), high-dose losartan (inhibits the migration of CCR2/monocytes), and ladarixin (inhibits the C-X-C chemokine receptor 1/2 and blocks interleukin-8 signaling) — exhibits substantial biologic activity, with both complete and partial responses to therapy. In other studies that are underway, Dr. London is looking at key correlates of response to treatment, using a NanoString nCounter® analysis of immune cells (specifically, peripheral blood mononuclear cells) from treated dogs and new tools for comparative oncology in dogs, such as the nCounter Canine Immuno-Oncology Panel.
Exploring new therapeutic targets in dogs with osteosarcoma
Heather Gardner, DVM, PhD, an assistant research professor at Tufts University, is studying the molecular and genetic features of osteosarcoma in dogs, as a model to better understand the biology of osteosarcoma across species. She is working to define the genomic landscape of primary and metastatic osteosarcoma in dogs, with the goal of characterizing recurrent gene mutations that can be targeted to improve outcomes in both human patients and dogs with cancer. Through these efforts, she has identified several novel gene mutations in dogs with osteosarcoma, including mutations in the gene SETD2 and large deletions in DMD, the gene that encodes dystrophin (a protein critical for normal functioning of muscles). Dr. Gardner is currently exploring how loss of SETD2 and DMD in dogs with osteosarcoma alters cell signaling pathways and the progression of metastatic disease, and how they can be leveraged as a therapeutic vulnerability. She hopes that these studies will help provide insights that facilitate development of new therapeutic strategies for the benefit of both pet dogs and human patients with cancer.
