Research Grants

Morris Animal Foundation awards grant to identify genetic risk factors for anal furunculosis in German shepherd dogs and Leonbergers

Principal Investigators: Dr. Brian Catchpole, Professor of Companion Animal Immunology, Royal Veterinary College (RVC) and Dr. Lucy Davison, MRC Clinician Scientist Fellow and Professor of Veterinary Clinical Genetics, RVC

Abstract:
Morris Animal Foundation has awarded a grant to researchers at the Royal Veterinary College (RVC), United Kingdom, to study a painful disease common in German shepherd dogs and Leonbergers. The grant is funded by the American German Shepherd Dog Charitable Foundation through Morris Animal Foundation’s Donor-Inspired Study program. Anal furunculosis is a common disease in German shepherd dogs and also is seen in Leonbergers. The problem has been recognized for decades, but the genetic underpinnings of anal furunculosis remain elusive. In the study, the team will sequence the whole genome from banked DNA samples of 10 German shepherd dogs and three Leonbergers with the disease, and five German shepherd dogs and two Leonbergers without the disease.

02606: The Genetic Background of Lumbosacral Transitional Vertebrae in Dogs

Principal Investigator: Hannes Lohi, PhD, The Folkhälsan Institute of Genetics
Total Grant Amount: $59,320.00; Grant Period: 4/1/2019 – 3/31/2020

Abstract:
Dogs of medium and large size or breed can suffer from a condition called lumbosacral transitional vertebrae (LTV), which means that the dog has a malformed vertebra in the caudal end of the spinal cord. Different types of LTV exist and radiographic screening is used to determine the form of LTV in dogs. The disorder can be seen right after birth and it is hereditary. However, it is not known how the disease is inherited, or what genes may contribute to this abnormal development of the spinal vertebrae. LTV is common in German Shepherd Dogs and the disorder predisposes the dogs to cauda equina syndrome. Affected dogs may become increasingly painful or may develop paralysis of the hind legs. There is a need to clarify the genetic background of LTV. The investigators plan to use genetic analyses to identify and confirm genetic risk factors that bring about LTV in dogs. The researchers will both search for regions in the dog genome that associate with the disease and will also investigate the possible contribution of known LTV candidate genes discovered in other species.

02510: Identification of Novel Synthetic Lethal Partners to Optimize PI3K Targeted Therapies in Canine Hemangiosarcoma

Principal Investigator: Cheryl A. London, DVM PhD, Tufts Medical Center
Total Grant Amount: $168,857; Grant Period: 3/1/2018 – 2/28/2021

Abstract:
Hemangiosarcoma (HSA) is a cancer of the cells lining the blood vessels that is very aggressive and has nearly always spread by the time it is diagnosed. HSA accounts for 5-7% of all cancers in dogs resulting in approximately 25,000-50,000 new cases per year. The treatment of choice is surgical removal followed by chemotherapy administration. Unfortunately, despite aggressive therapy, the majority of dogs diagnosed succumb to their disease within 6-8 months. Virtually no improvements in outcome for affected dogs have occurred in the past 30 years despite multiple clinical trials and research efforts. More recently a new therapy has been developed targeting two receptors on HSA cells. However, the majority of dogs still died, by 10-12 months after treatment. The molecular pathway known as the PI3K/AKT/mTOR pathway has previously been implicated in the pathogenesis of many forms of cancer including HSA. Indeed, inhibitors of PI3K/AKT/mTOR pathway have some activity against HSA cell lines in the laboratory. The investigators have generated data showing that a subset of canine HSA tumors possess genetic mutations in PI3K that are known to activate the pathway in cancer cells. In this study, they will fully characterize the expression and function of PI3K in canine HSA tumor cell lines and tumor samples. This information will then be leveraged to identify new ways to block the PI3K/AKT/mTOR pathway using a combination of small molecule inhibitors that are most effective at killing tumor cells. These data will then be used to design future clinical trials in dogs with HSA.

D18CA-017: Finding Ways to Block Hemangiosarcoma Tumor Growth

Principal Investigator: University of Minnesota
Total Grant Amount: $177,316; Grand Period: 10/1/2017 – 10/1/2019

Abstract:
Hemangiosarcoma is an aggressive disease that is rapidly fatal in dogs. Studies suggest that hemangiosarcomas rely on cholesterol and lipids to fuel tumor growth. Researchers will further investigate how cholesterol and lipids promote cancer growth, and delve deeper into understanding the cell signaling pathways activated by these metabolites. The team also will use existing drugs to interrupt these processes to kill tumor cells. Findings will be used to optimize drug and chemotherapy combinations to provide better treatment options for patients. The development of new and less toxic approaches to treat canine hemangiosarcoma is an important step in improving survival rates for dogs diagnosed with this deadly cancer.

D18CA-310: Using Advanced Imaging to Diagnose and Monitor Spinal Cord Disease

Principal Investigator: Cornell University
Total Grant Amount: $66,565; Grand Period: 9/1/2017 – 9/1/2019

Abstract:
Canine degenerative myelopathy (CDM) is a neurodegenerative disorder that affects the spinal cord of dogs. The condition is progressive, has no treatment, and often results in euthanasia within six to nine months of diagnosis. Conventional MRI can’t detect the lesions caused by CDM which makes the disease challenging to diagnose and monitor. An advanced MRI technique called diffusion tensor imaging has been successful at detecting microscopic lesions in diseased spinal cords in humans, and researchers will see if this technique also is capable of detecting spinal cord lesions caused by degenerative myelopathy in dogs. In addition to providing a much-needed diagnostic tool, this technique will provide a way to monitor lesions for future studies assessing new drug therapies for dogs with this devastating disease.

02338: The Genetics of Bloat in German Shepherd Dogs: The Roles of Immune System Genes and the Gut Microbiome

Principal Investigator: Dr. Michael Alan Harkey, PhD, Fred Hutchinson Cancer Research Center
Total Grant Amount: $152,270; Grant Period: 6/1/2017 – 11/30/2019 – UPDATE

Abstract:
While Gastric Dilatation Volvulus (GDV or bloat) is a serious problem for many large canine breeds, little is known about the causes of this deadly disease. The most significant factors may be genetic, since certain breeds are more susceptible than others, and strong familial predispositions are seen within breeds. The investigators have recently shown a significant association of three immune genes with bloat in Great Danes. For each of the three genes, one allele (variant) is found at unusually high frequency in dogs that have been treated for bloat, and the presence of any one of these “risk” alleles triples the chance that the dog will experience bloat at some time in its life. The research team also showed that the bacterial population living in the gut (the gut microbiome) is altered in dogs with bloat, and in dogs that carry these “risk” alleles, which may predispose these dogs to bloat. It is not known if other breeds show this same association of genetics and microbiome with bloat. The team will investigate whether bloat in German Shepherd Dogs is associated with the same risk alleles and the same microbiome profiles as were seen in Great Danes. The results of this work could lead to genetic tests for at-risk dogs, as well as dietary and probiotic therapies to prevent bloat.

Testing Strategies to Treat Drug-Resistant Hemangiosarcomas

Erin B. Dickerson, PhD, University of Minnesota, D14CA-047

RESULTS: Researchers identify a chemotherapy resistance mechanism in hemangiosarcoma tumor cells Hemangiosarcoma is a common and deadly tumor of dogs. Growing in areas with a rich blood supply, such as the spleen or heart, many dogs die suddenly, secondary to massive blood loss when tumors rupture. Hemangiosarcomas also are quick to spread to other areas of the body, so even when tumors are discovered early, the tumors have already spread. Prognosis for this cancer hasn’t improved in nearly two decades, and new treatment options are desperately needed.

Morris Animal Foundation-funded researchers at the University of Minnesota felt that by gaining a better understanding of the underlying biology of this aggressive tumor, they could discover new ways of improving long term prognosis in dogs with hemangiosarcoma. Their targets were cells important in tumor growth, spread and drug responses.

The research team successfully identified a drug-resistant cell population within hemangiosarcoma tumors that may be an important player in chemotherapy resistance. The cells identified are extremely efficient at isolating cancer drugs in compartments called lysosomes. By trapping the drug within lysosomes, cancer cells were able to prevent the chemotherapy from reaching its target, effectively neutralizing the drug. This new information helps explain why some hemangiosarcoma tumors become chemotherapy resistant.

The Minnesota team also found that hemangiosarcoma cells with a high surface expression of a protein called colony-stimulating factor 1 receptor (CSF-1R) were the culprits in this process. The lysosomes in the cells with higher expression of CSF-1R were trapping the chemotherapy drug, preventing it from reaching its target, the nucleus of the cancer cells, in sufficient quantities to be effective. The team started searching for a drug that could prevent the accumulation of chemotherapy in the lysosomes, and found that the common beta blocker propranolol was effective in competing with the doxorubicin for lysosomal space. The researchers speculate that if the doxorubicin can’t be taken into the lysosome (essentially because propranolol got there first), it will be free to reach its target. The next research step is to further investigate propranolol and other beta blockers to see if they will work in combination with chemotherapy drugs, and then move to testing this new treatment approach in dogs with hemangiosarcoma.

This study identified a key mechanism in chemotherapy resistance in hemangiosarcoma tumors. Understanding how cancer cells hijack and block drugs from reaching their targets will help researchers develop more effective treatments for this difficult-to-treat cancer in dogs.

02257: Identification of Genetic Risk Factors for Canine Epilepsy

Principal Investigator: Dr. Gary S. Johnson, DVM PhD; University of Missouri, Columbia Total Grant Amount: $84,121.00; Grant Period: 5/1/2016 – 10/31/2017

Abstract:
Epilepsy is one of the most common neurologic diseases of dogs and a top concern of dog breeders. Despite strong evidence that genetics is important in determining the risk of idiopathic epilepsy, numerous gene mapping studies have failed to identify a locus that accounts for that risk in either dogs or humans. Seizures occur when excessive activity goes beyond the normal threshold for brain function, many factors contribute to that level of activity, and therefore, mutations in numerous genes may collectively contribute to increased activity until that threshold is exceeded, resulting in epilepsy. Any one of these mutations may be present in non-epileptic dogs, but because it only partially alters activity, it would not produce seizures. Therefore, traditional gene mapping studies might overlook that mutation. Using a novel whole genome sequencing approach the investigators hope to identify DNA variations in epileptic dogs that could affect the function of genes such as ion channels and neurotransmitter receptors that have been shown to alter the seizure threshold in humans or rodents. The frequency of such variations in populations of epileptic and non-epileptic dogs will be directly compared rather than the indirect markers used in traditional mapping studies. The increased power provided by looking for specific gene candidate variations rather than linked markers will aid the identification of epilepsy risk factors, perhaps leading to development of DNA tests to enable breeders to select against such risk factors.

Musculoskeletal Conditions and Disease Research Program Area

02275: Disease Risks Associated with Spay and Neuter: A Breed-Specific, Gender-Specific Perspective

Principal Investigator: Dr. Benjamin L Hart, DVM, PhD; University of California, Davis
Total Grant Amount: $61,784.00; Grant Period: 9/1/2016 – 8/31/2017

Project Abstract:
This study extends the investigator’s recently completed AKC Canine Health Foundation-funded project studying 12 dog breeds to identify major differences in the degree to which spay or neuter may be related to an increase in joint disorders (hip dysplasia; cranial cruciate ligament tear) and/or cancers (lymphoma; hemangiosarcoma; and mast cell tumor). The original breeds studied were: Labrador Retriever, Golden Retriever, German Shepherd Dog, Rottweiler, Boxer, Bulldog, Doberman Pinscher, Dachshund, Corgi (both breeds), Chihuahua, Yorkshire Terrier and Shih Tzu. Findings did not associate an increase in disease association in the small breeds with spaying or neutering, while in larger breeds disease risk was dependent upon gender, and whether the spay or neuter procedure was performed before or after one year of age (Hart, B.L., L.A. Hart, A.P. Thigpen and N. H. Willits. 2014. Long-term health effects of neutering dogs: Comparison of Labrador Retrievers and Golden Retrievers. PLoS ONE 9(7): 10.1371/journal.pone.0102241).

In this second phase, the following breeds have been added to the study: Great Dane, Australian Shepherd, Bernese Mountain Dog, Cocker Spaniel, Border Collie, Beagle, St. Bernard, Irish Wolfhound, Jack Russell Terrier, Pug, Maltese, Pomeranian, Miniature Schnauzer, Boston Terrier, Australian Cattle Dog, Shetland Sheepdog, English Springer Spaniel, Cavalier King Charles Spaniel, and West Highland White Terrier. Upon completion of the study, the major publisher, Wiley, has agreed to place the total data set of all 31 breeds on an open access website as a resource for breeders, dogs owners, researchers and veterinarians.

D17CA-059 Curbing tumor growth and chemotherapy resistance in canine hemangiosarcoma (Morris Animal Foundation)

Principal Investigator: Erin B Dickerson, PhD, University of Minnesota
Total Study Cost: $172,431; Grant period: 10/1/2016 – 9/30/2018

Project Abstract:
Hemangiosarcoma is an aggressive and almost uniformly fatal cancer of dogs. Researchers uncovered evidence that a common cellular signaling pathway is associated with aggressive hemangiosarcoma tumor growth and chemotherapy resistance. Signaling pathways are coordinated chemical activities in a cell that collectively control one or more cell functions. Abnormal activation of signals often trigger or facilitate the development of diseases, including cancer. Researchers will investigate how signaling pathways contribute to hemangiosarcoma growth, and if existing drugs can interrupt the process to reduce tumor growth and chemotherapy resistance. Finding a new approach to treat canine hemangiosarcoma is a vital step in improving survival rates in dogs with this aggressive cancer.

02275: Disease Risks Associated with Spay and Neuter

Principal Investigator: Dr. Benjamin L Hart, DVM, PhD; University of California, Davis
Total Grant Amount: $61,784.00; Grant Period: 9/1/2016 – 8/31/2017

02204: Using Enhanced Imaging to Evaluate Tumor Margins for Canine Mammary Cancer and Soft Tissue Sarcoma

Grant Amount: $46,358
Dr. Laura E. Selmic, BVetMed, University of Illinois

January 1, 2016 – December 31, 2017

Abstract:
Surgery is the primary treatment for many common tumors affecting dogs including mammary tumors and soft tissue sarcomas (STS). For these tumors, the best chance of cure is offered if the surgeon can fully remove both visible and microscopic traces of the tumor. Unfortunately, to do this, surgeons must rely on indirect and crude methods to assess the extent of the tumor during surgery. The success of the procedure will not be known until several days later, following sample assessment by the pathologist. After surgery, decisions regarding the necessity of further treatment and the patient’s prognosis are often determined from the pathology results. For malignant tumors, if the disease is minimally or incompletely removed, further surgery or radiation therapy is often required. Additional treatments such as these can result in further risk and discomfort for the patient as well as present emotional and financial costs for owners. Optical coherence tomography (OCT) is an emerging diagnostic imaging tool that uses light waves to generate real-time, high-resolution images of tissue at a microscopic level. These images can be used to evaluate for residual disease at the time of surgery giving immediate feedback to the surgeon. This study will focus on validating this technology for the imaging of surgical margins of two important canine cancers – mammary tumors and STS. If successful, this technology can be used to assess for residual cancer during surgery to benefit patients by guiding accurate treatment recommendations and attempting to reduce the need for additional treatments or surgery, and thus advancing the standard of care for canine patients.

02235-A: Medical Surveillance of Dogs Deployed to the World Trade Center and the Pentagon on 9/11/01 (Still Funded)

Principal Investigator: Dr. Cynthia M. Otto, DVM PhD; University of Pennsylvania
Total Grant Amount: $11,340.00; Grant Period: 12/1/2015 – 11/30/2016

Project Abstract:
As the investigators wrap up the 14th year of the 9/11 Medical Surveillance Study, they continue to follow 2 surviving deployed dogs and 1 surviving control dog, each of them now 16 years of age. The initial study group consisted of 95 deployed and 55 non-deployed Search and Rescue dogs. Findings to date indicate that overall these dogs have demonstrated good longevity and quality of life. This final phase of the study will monitor the remaining dogs, placing emphasis on health issues occurring in later years of life and necropsy evaluations at time of death. This vital information will allow for a comprehensive understanding of the impact of the deployment and a life spent working Search and Rescue on long-term canine health.

The rate of cancer in deceased deployed dogs to date is not different than in deceased control dogs. Of note, within the deployed dogs, the median age at death was significantly lower for dogs with cancer than the non-cancer group; however, this was not the case with the control group. As the final three dogs approach the end of their natural lives, the investigators will further define any effects of the 9/11 deployment in the full cohort of study dogs. As they analyze the data, a full picture of causes of death and types and incidences of cancer, and long-term impacts of the 9/11 deployment may become clear. The ability to see this study through to completion and publish the long term findings will provide critical information to canine health that may affect future tactics employed in Search and Rescue missions.

The AKC CHF is proud to have funded Dr. Otto through all the years of this important work on behalf of Search and Rescue dogs from its inception in 2001.

02217: A Novel Mechanism to Regulate the Growth of Canine Hemangiosarcoma (Still Funded)

Principal Investigator: Dr. Erin B. Dickerson, PhD; University of Minnesota
Total Grant Amount: $86,206.00; Grant Period: 1/1/2016 – 12/31/2017

Project Abstract:
Hemangiosarcoma is an extremely aggressive cancer that is rapidly fatal in dogs. While the lifetime risk is alarmingly high for some breeds such as Golden Retrievers and German Shepherd Dogs, the disease does not discriminate, and it can strike any dog at any time. Despite considerable efforts by veterinarians and scientists to find effective treatments, the outcome for dogs with hemangiosarcoma has changed very little over the past few decades. Recent evidence provides essential clues into how these tumors grow and progress, generating new ideas for treatment approaches. Such new evidence suggests that hemangiosarcoma cells rely on the metabolism of lipids or fatty acids to supply energy for tissue invasion or continued tumor growth. To obtain these lipids, hemangiosarcomas may take over the metabolic machinery of neighboring cells, forcing them to produce nutrients for the tumor cells to help them proliferate and grow. This study will verify that tumor cells rely on lipid metabolism for growth, and determine if tumor cells alter the metabolism of fat cells to obtain cellular nutrients and accelerate tumor cell lipid metabolism. Identifying and exploiting a novel mechanism that may disrupt this process by inhibiting the interactions between tumor cells and cells in the tumor environment will speed clinical investigations, and ultimately lead to improved outcomes for dogs with this devastating disease.