Funded Research

AKC Canine Health Foundation, Inc.
8051 Arco Corporate Drive, Suite 300 • Raleigh, NC 27617
888-682-9696 • www.akcchf.org


RESEARCH PROGRESS REPORT SUMMARY


Grant 02519: Prevalence of Bartonella spp. Infection in Dogs with Cardiac and Splenic Hemangiosarcomas within and between Geographic Locations
Principal Investigator: Edward Breitschwerdt, DVM & Matthew Breen, PhD
Research Institution: North Carolina State University Office of Sponsored Programs
Grant Amount: $219,026.00
Start Date: 2/1/2018 End Date: 1/31/2020
Progress Report: Mid-Year 1
Report Due: 7/31/2018 Report Received: 8/2/2018
(The content of this report is not confidential and may be used in communications with your organization.)


Original Project Description:
Splenic masses comprise ~50% of all canine splenic disease. Despite advances in imaging and pathologic definition, the etiology and medical relevance of splenic lesions in dogs are often ambiguous. While some splenic tumors are benign, approximately two-thirds are highly malignant and carry a poor prognosis. Hemangiosarcoma (HSA) accounts for the majority of canine malignant splenic tumors and occurs in many large dog breeds, including mixed breeds. A less common site of HSA localization is the heart (cardiac HSA). Risk factors for both cardiac and splenic HSA remain unclear, confounding development of preventative strategies. The investigators recently reported a high prevalence of species of the bacterial genus Bartonella in dogs with HSA from North Carolina, suggesting a potential role in the initiation and/or progression of this cancer. Bartonella species exist worldwide and are transmitted by blood-sucking arthropods (e.g. ticks, fleas) and their presence in splenic tissue could potentially be explained by the fact that the spleen is primarily responsible for removal of blood-borne parasites from the systemic circulation. The investigators will perform a comprehensive examination of the potential association between Bartonella infection and HSA by comparing the prevalence of Bartonella DNA in tumor and blood samples from both splenic and cardiac HSA cases, and also within and between distant geographical locations in the US. Ultimately, demonstration of a robust association between Bartonella infection and the development of HSA may lead to new opportunities for improved diagnosis, treatment and prevention of this devastating cancer.

Publications: Due to the early stage of testing, we have no publication.

Presentations: Due to the early stage of testing, we have made no presentations.

Report to Grant Sponsor from Investigator:
We are on track to accomplish all of our aims for this study. We were able to obtain the initial set of samples on April 26, 2018 so we had a short delay in starting the study. We have now received all samples, categorized and prepped them for further testing. We will be publishing additional research from our AKC-CHF study #02287, which will define the criteria for serodiagnosis of Bartonellosis in dogs by Western Blotting (WB). That work has required additional time and research effort to validate WB testing. Once completed, we will process the serum samples from this for WB by December 2018. We have been in touch with the pathologists in the three geographically different regions of the United States so that they can define inclusion criteria and start locating the retrospective samples that they will submit to us in January of 2019 to test.

AKC Canine Health Foundation, Inc.
8051 Arco Corporate Drive, Suite 300 • Raleigh, NC 27617
888-682-9696 • www.akcchf.org


RESEARCH PROGRESS REPORT SUMMARY


Grant 02217: A Novel Mechanism to Regulate the Growth of Canine Hemangiosarcoma
Principal Investigator: Erin Dickerson, PhD
Research Institution: University of Minnesota
Grant Amount: $86,206.00
Start Date: 1/1/2016 End Date: 6/30/2018
Progress Report: FINAL
Report Due: 6/30/2018 Report Received: 7/16/2018
(The content of this report is not confidential and may be used in communications with your organization.)


Original Project Description:
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.

Publications:
We have not yet published any of our findings. We anticipate that the following data will be part of a paper that is currently in preparation, and we plan to submit this paper in 2018:
1) Immunohistochemistry of -AR and tyrosine hydroxylase expression in primary hemangiosarcomas.
2) Expression of -ARs and the catecholamine enzymes in hemangiosarcoma cell lines.
3) Expression norepinephrine and dopamine in hemangiosarcoma cell lines.
4) Treatment of hemangiosarcoma and angiosarcoma cell lines with doxorubicin leads to an increase in TH expression, as well as an increase in the synthesis of dopamine and norepinephrine.

We also anticipate the publication of a second paper in 2019 describing the majority of the findings described in this report.

Presentations:
I attended a Keystone Conference on tumor metabolism in cancer cells in Whistler Canada in March 2017. A PhD student in my lab (Derek Korpela, DVM) also attended this meeting, and he presented some of the work described here. Dr. Korpela and I also attended the annual Veterinary Cancer Society meeting, held in Portland, OR, October 2017. Both abstracts were chosen for oral presentation. I presented some of this work as a State of the Art presentation at the conference; Dr. Korpela presented some of his work showing the metabolic impact of propranolol and its enantiomers on hemangiosarcoma cell metabolism. Funding support by the AKC Canine Health Foundation was acknowledged for all presentations.

Report to Grant Sponsor from Investigator:
Hemangiosarcoma is an incurable cancer that is almost uniformly fatal. The tumors often grow quickly and spread rapidly, with half of all dogs dying within six months of diagnosis, even with treatment. Because the prognosis has not changed over several decades, a better understanding of the disease is needed to develop new treatment approaches. We have found that hemangiosarcoma cells appear to rely on the metabolism of lipids to supply some of the energy and essential building blocks needed for tumor growth. We also found that propranolol, a common drug used to treat heart disease in both dogs and people, limits the uptake of lipids into cells and blocks the cell’s ability to process these compounds. Cancer cells have been shown to impose a self-serving metabolic program on normal cells by forcing normal cells to supply nutrients, such as sugars and lipids, to the tumor. Recent studies have shown that cells like adipocytes (fat cells) can be remodeled by tumor cells to help create a niche favoring tumor growth. Because propranolol can block the use of lipids by tumor cells, propranolol may be able to reverse the cancer-imposed metabolic reprogramming on adipocytes or other normal cells, limiting tumor growth. For this study, we sought to: 1) characterize the lipid metabolic program(s) in hemangiosarcoma cells and determine if the use of lipids by these cells could be blocked by propranolol; 2) determine if hemangiosarcoma cells alter the metabolic program(s) of adipocytes; and 3) whether these changes in adipocytes enhanced the tumor cell growth programs and the invasive nature of hemangiosarcomas. We found that propranolol inhibited key metabolic processes in hemangiosarcoma cells, including the uptake and processing of lipids. We also found that hemangiosarcoma cells reprogrammed normal adipocytes in a way that may force the adipocytes to produce nutrients for hemangiosarcoma cells to help them proliferate and grow. Parallel studies supported this idea by showing that adipocytes accelerated metabolic growth programs in hemangiosarcoma cells and enhanced programs favoring more aggressive disease. Future studies will be directed toward further assessing the metabolic programs of hemangiosarcomas and determining whether drugs like propranolol can be used to prevent the manipulation of adipocytes by tumor cells and reduce tumor growth and invasion.

Genetic Testing for PLN-Associated Variant Genes

After years of research supported by hundreds of Wheatens and their owners and breeders, Dr. Meryl Littman and Dr. Paula Henthorn at the University of Pennsylvania School of Veterinary Medicine (Penn Vet) identified mutations associated with PLN in two genes. A cheek swab test to determine an individual dog’s DNA status was introduced in May 2012. Read More ➤

Statement on Genetic Testing for PLN-Associated Variant Genes

Responsible Soft Coated Wheaten Terrier breeders and stud dog owners breed for type, temperament, soundness and health. The recent introduction of the test for PLN-associated variant genes gives us an additional tool to use in the health assessment of breeding stock. Using this test should give Wheaten breeders the ability to reduce the incidence of dogs with these variant genes slowly and carefully while still maintaining genetic diversity.

The Soft Coated Wheaten Terrier Club of America, Inc., and the SCWTCA Endowment, Inc., endorse testing for PLN-associated variant genes by breeders and stud dog owners as one tool in the assessment of breeding stock.

We strongly encourage all owners to become familiar with the test and to understand the meaning of the results and their use in breeding. Resources are available in the health section of the SCWTCA website at www.scwtca.org/health. SCWTCA neither requires nor prohibits any form of breeding beyond what is currently in the Code of Ethics.

All Wheaten owners should remember that screening for health goes beyond performing this test. Members of SCWTCA are reminded of the requirements of the Code of Ethics in regard to other testing and breeding requirements.

Launch of the Soft Coated Wheaten Terrier Database

After a number of years of development, the SCWTCA Endowment, Inc., is excited to announce the launch the Soft Coated Wheaten Terrier Database at http://www.scwtdb.org.

This database was originally developed by the Berner-Garde Foundation 30 years ago and is in use by several other breeds in addition to Wheatens. Starting with San Jeffries’ database of 46,000 dogs, a team of volunteer data operators has added dogs so we are debuting with records on nearly 60,000 Wheatens from around the world.

In furtherance of the Endowment’s mission, we believe the detailed collection of health and pedigree information in the database will help to identify, track, and reduce the incidence of health problems in the SCWT. Wheaten owners, breeders, and researchers can be used it to assist with decisions about the care and welfare of their dogs to make breeding decisions. We expect veterinarians and veterinary researchers working with Wheatens will find it a valuable data source.

The integrity of the information in the database is vital to its purpose. Much of the data comes from voluntary submissions from owners, which is verified before being published. Publicly available information, such as records from kennel clubs and OFA is also included as verified.

The best way to appreciate the potential of the Database is to use it! It is accessible to all at www.scwtdb.org once you’ve read and accepted the policies. Start by looking up your own dogs and seeing what the Database can do: from producing pedigrees to searching for dogs meeting specific criteria. (While the Database is easy to use, you’ll also find a link to a User’s Guide on the home page.) This will show you how you can help by submitting information on your own dogs to make the Database more robust. There are forms for sending information to add; and you can upload photos of your dog, both formal show shots and informal candids.

Despite the care our operators take, errors are, of course, inevitable. If you find a problem, please report it at comments@scwtdb.org.