Studies We Support
Bone cancer affects many of the large breeds including the Doberman Pinscher, Golden Retriever, Great Dane, Greyhound, Labrador, Leonburger, and Rottweiler. In humans advanced stage breast cancer and prostate cancer metastasize to bone cancer. Finding a cure is a win-win for both humans and our canine companions.
Several of the studies we have supported include the following:
Adoptive Cell Therapy using Genetically Engineered Natural Killer Cells for Osteosarcoma
(Bruce Walcheck, PhD, University of Minnesota)
"Our research team has cloned canine Fc receptors and expressed these in engineered natural killer cells to enable their attachment to and killing of antibody-coated tumor cells. This approach allows for universal tumor antigen targeting by natural killer cells using available anti-tumor therapeutic antibodies. Funding from GREYlong will be used for next steps in testing the engineered cells to treat osteosarcoma."
Osteosarcoma Vaccine Study (Dr. Nicola Mason, University of Pennsylvania). The goal is to stimulate the dog's immune system to target Osteosarcoma cells that have survived chemo therapy by injecting a vaccine composed of a genetically modified Listeria bacterium. Listeria expresses a tumor marker known as Her2/neu. They are testing to determine if the bacteria will stimulate the patient's immune system to kill the bacteria and also kill cells that express Her2/neu, which is shown on 40% of OS tumors in canines and humans.
The vaccinated group (post amputation and with chemo therapy) had a survival rate of 956 days versus the control group’s survival rate of 423 days. So while this is not a cure for canine osteosarcoma, it certainly is a step forward in giving our companions quality of life for an extended period of time. Currently, the vaccine is being tested at over 20 different sites within the United States.
Niche Conditioning for Metastasis in Canine Osteosarcoma (Dr. Hiro Tomiyasu, University of Minnesota). The goal of this project is to determine how bone tumors communicate with tissues at distant sites in order create favorable conditions for tumor cells to colonize and survive, thereby giving rise to metastasis. Recent work suggests that the tumors send out “scout parties” in the form of small cell fragments called exosomes. These exosomes deliver biologically active molecules that make distant sites welcoming for wayward tumor cells. This project is designed to find markers in the exosomes that will allow us to predict where and when the disease will spread, as well as to identify targets we can use to delay or prevent this spread.
We have found that the process of loading osteosarcoma exosomes is “active”. In other words, in each tumor there is a selection process that determines molecules that are loaded into or excluded from the exosomes. This results in unique packages, which are associated with the potential of the cells to disseminate to the lungs or other sites. We also have shown that exosomes modify the behavior of normal cells in lab cultures. This suggests that exosomes are also likely to modify the behavior of cells in the body, allowing metastasis to occur.
A next critical step in this project is to identify specific candidate molecules that prevent or favor metastasis.
Genomics: Germline and Somatic Genetic Determinants of Osteosarcoma Outcome (David Largaespade with Logan Spector, Subbaya Subramanian, and Dr. Jaime Modiano, University of Minnesota). This study compares genetic and epigenetic alterations in the germline and in somatic cells of humans, dogs and mice with osteosarcoma to identify events that are responsible for the spectrum of clinical behaviors observed in OS. Their goal is to discover genetic markers that predict risk for OS to make early screening and targeted therapies feasible. They believe the interspecies approach affords a broader view to understanding OS.
Immunotherapy for Osteosarcoma (OSAL) (Dr. Vicki Wilke and Emily Lipsitz, University of Minnesota). This study will evaluate the safety and efficacy of non-pathogenic Salmonella organisms carrying an immune cytokine (IL-2) to mount specific anti-tumor responses in dogs with spontaneous osteosarcoma. This trial has current support from the Children's Cancer Research Fund and the Animal Cancer Care and Research Program of the University of Minnesota.
Osteosarcoma (OSA) Genetic Study (Dr. Guillermo Couto, Ohio State University). OSA is the death in retired racing Greyhounds, yet it is very uncommon in AKC Greyhounds. This provides a unique opportunity to evaluate genes involved in the development and progression of OSA in the breed. In collaboration with Dr. Alvarez's lab in Nationwide Children's Hospital they are currently evaluating samples from retired racers and AKC dogs with and without OSA, in order to identify genes involved in the development of this deadly disease. In addition, because racing Greyhounds are tattooed and their pedigrees easily obtained on line, they are evaluating pedigrees in dogs with and without OSA for statistical comparison. In addition, in collaboration with Dr. Breen's (NCSU) and Lindbladh-Toh's (The Broad Institute) labs they are evaluating OSA genes in Greyhounds and other breeds, and evaluating their role in response to treatment and prognosis. Finally, they are evaluating novel treatment protocols for both Greyhounds and dogs of other breeds with OSA.
Evaluation of Cyclopamine as a Therapy for Bone Cancer (Dr. Heather Wilson, Texas A&M). Cancer arises from a single mutated cell possessing the power to replicate and form a tumor. There are many theories as to the cause and progression of this process. One theory states that a cell with stem cell capabilities divides to produce new tumor-initiating cells and daughter cells. Identifying pathways that can increase sensitivity to therapeutic intervention is paramount to finding a cure for bone cancer. Cyclopamine, a chemical found in the corn lily plant, inhibits the pathway responsible for normal embryo development and directing the regeneration of tissues. This study will research Cyclopamine's effectiveness at inhibiting tumor-initiating cells in canine osteosarcoma cell lines. The goal is to provide a new targeted therapy for pets with osteosarcoma. The final report issued stated that the research team discovered that at high does cyclopamine inhibits an important signaling stem-cell pathway used by tumor-initiating cells. Based on these findings, researchers believe that adding cyclopamine during and after traditional chemotherapy may help inhibit the growth and spread of bone cancer in dogs. They plan to pursue further research in this regard.
Examining Drug Targets for Treating Bone Cancer (Dr. Joseph J. Wakshlag, Cornell University). Preliminary evidence in humans suggests that blocking a traditional pathway of inflammation, known as the lipoxygenase (LOX) pathway, can inhibit the growth of certain cancer cells. This study examines the role the LOX pathway plays in canine osteosarcoma development and whether inhibiting it can kill bone cancer cells. The findings may lead to a new drug therapy for osteosarcoma.
MicroRNA Expression Profiling of Canine Osteosarcoma (Dr. W.C. Kisseberth, Ohio State University). Using the assumption that cancer is fundamentally a genetic disease, by studying the MicroRNA expressions, investigators hope to identify new molecular targets for therapy, which will lead to better treatment of this disease.
Canine hemangiosarcoma is an incurable tumor of cells that line blood vessels. This type of sarcoma is difficult to treat because of its aggressive behavior and rapid progression after diagnosis.
Although dogs of any age and breed are susceptible to hemangiosarcoma, it occurs more commonly in dogs beyond middle age, and in breeds such as Golden Retrievers, German Shepherd Dogs, Portuguese Water Dogs, and Skye Terriers, among others. Hemangiosarcoma develops slowly and is essentially painless; so clinical signs are usually not evident until the advanced stages when the tumors are resistant to most treatments. Fewer than fifty percent of dogs treated with surgery and intensive chemotherapy survive more than six months.
Targeted Therapy for Canine Hemangiosarcoma ( SRCBST) Dr. Modiano, Ms. Borgatti, and Dr. Vallera, University of Minnesota have developed a treatment approach for sarcomas using a genetically-engineered bacterial toxin linked to two specific proteins that target it to the tumor environment. This treatment has advanced to two clinical trials (SRCBST-1 and SRCBST-2).
The question being asked is whether this approach can be extended to treat other sarcomas based on the pattern of expression of the receptors that act as “baits” for the ligands. Genomic engineering is being used to eliminate each receptor from tumor cells and from non-malignant cells in the supporting microenvironment to examine if this reduces or eliminates the drug’s efficacy, and if it has the potential to increase toxicity.
The results from this project will serve as a guide to develop companion biomarkers for patient selection, which will allow us to identify those patients who will benefit most from this therapy.
With regard to the SRCBST study, we have reason to believe this drug will be useful for virtually every type of soft tissue sarcoma, and possibly bone sarcomas. Their immediate next step is to determine factors that are necessary for a successful response in laboratory animals (mice) with aggressive fibro sarcoma, which has been found to metastasize to bone cancer.
Lymphoma is one of the most common and fatal cancers in dogs. Most dogs treated with chemo go into remission, but the cancer develops drug resistance and recurs.
Several of the studies we have supported include:
Determining the Correct Dosing for Anthracycline drug to Treat Canine Lymphoma (Dr. Alfred Legendre, University of Tennessee. AD198 is a new antrhacycline drug used in chemotherapy. This study will determine the best dose for dogs with lymphoma, and researchers will study how well AD 198 affects cancer cells so that an alternative treatment option can be available to owners and veterinarians.
Potential Drug Therapy for Treatment of Lymphoma (Dr. Laura Garrett, University of Illinois) using a novel compound called PAC-1 that has been shown to induce apoptosis (a normal process in which cells undergo programmed death.)
Immunotherapy and Genetic Studies
Several of the studies we have supported include:
CD47 Blockade to Enhance Adaptive Anti-tumor Immune Responses (Veterinary Student Katie Anderson, University of Minnesota, Dr. Jaime Modiano, and Dr. Matthew Mescher). The advantage of an immunological approach, to treat patients that have metastatic cancer, is that it uses the patient's own cells. This makes it easier to reach tumors that are inaccessible for conventional treatments, with fewer side effects. The success of this approach is tied to overcoming barriers that tumors build to evade the immune response. The objective of this study is to develop an approach whereby the patient's immune cells learn to recognize cancer cells at the primary site and eliminate renegade cancer cells before they spread to distant sites and establish metastases.
Effect of Tumor Microenvironment on Canine Myeloid Cells (Veterinary Student Scholar Jacob Wasserman, Ohio State University. Although chemotherapy has been the primary treatment of choice in human and veterinary oncology, chemotherapy is relatively untargeted and has numerous side effects. Stimulating the immune system to target tumor cells offers a potentially more effective and less toxic alternative to chemotherapy alone, and such cancer immunotherapy is being explored in canine and human cancer patients. In cancer, it is thought that myeloid cells, a type of cell derived from marrow, significantly contribute to the immunosuppression seen in cancer patients. This study was chosen to honor the memory of the Loeser's pet therapy dog, Brooke.
Studies we have supported include the following:
Investigating the Biology of Canine Met Mutations (Dr. Cheryl London, DVM, Ohio State University. Research has shown that mutations in a gene called Met contribute to the development of numerous types of cancer in humans and mice. This study is searching for genetic markers that will help better target cancer treatments and have identified two similar mutations in dogs, which have a high chance of developing cancer. The researchers are encouraged by their preliminary results with this inhibitor in several clinical cases of dogs diagnosed with osteosarcoma.
RNAi Delivery Vectors Target to Canine Tumors (Dr. D. Argyle, University of Edinburgh). This study ended in 2008. It identified a molecular target in cancer that is a near universal marker of malignancy. The study utilized RNA interference technology to develop a therapeutic strategy for cancers. They showed that the direct injection of these molecules may have an effect, albeit, not sustainable, in the cessation of cancer.