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American Kennel Club, Canine Health Foundation

AKC CHF Canine Health Conference 2011

Recently, Julie Jackson and Joye Neff attended the 8th AKC CHF National Parent Club Canine Health Conference in St. Louis, MO for the BMDCA, and were joined by Pat Long, who attended on her own. The weekend was absolutely fantastic and we were privileged to hear the top "rock star" researchers discuss their new discoveries with an emphasis on cancer research developments in genetics, immunotherapy, drug treatments and nutrition. It was an honor to be invited to this event and we want to share the information that we gathered during the time we were there. I will be posting to the BMDCA Board Directors and the various Berner lists, summaries of the speakers' presentations over the next several weeks so you can see what is happening with the research dollars that we send to the AKC CHF. The first summary I am sending is the presentation by Dr. Matthew Breen, since we have just raised money to support his histiocytic sarcoma research grant. I'm sure you will be very happy to hear about the cytogenetic test they have developed that allows them to predict the duration of first remission of dogs diagnosed with lymphoma, when treated with doxorubicin based chemotherapy. There are great strides being made by the researchers and I know you will enjoy reading about what is happening.

Joye Neff and Maine's Xephyr Alpinebear, CGC - "Breeze" - BG #72657
and "Will" (German Shorthair Pointer)
Berner Fundraiser
Mt. Lebanon, Pittsburgh, PA

Comparative Cytogenetics of Cancer.
Just How Human Are Our Dogs?
Matthew Breen, PhD, CBiol, FSB
North Carolina State University, College of Veterinary Medicine,
Professor of Genomics

Summary by Joye Neff

Dr. Matthew Breen completed his PhD in cytogenetics in 1990 and then spent two years as a Post Doc in Molecular Genetics at the UK Medical Research Council’s Human Genetics Unit in Edinburgh, where he developed new techniques as part of the human genome project. Dr. Breen then spent four years working for the research arm of the Australian Thoroughbred industry, returning to the UK in 1996 where his laboratory developed molecular cytogenetics reagents, resources and techniques for application to canine genome mapping, comparative cytogenetics and cancer studies. In 2002 Dr. Breen relocated his laboratory to NCSU’s College of Veterinary Medicine as part of its Genomics initiative. Since then his research interests have continued to focus on the genomics, genome mapping and the comparative aspects of canine cancer. He is leader of the Clinical Genomics Core of the Center for Comparative Medicine and Translational Research and co-Director of the Clinical Studies Core. Dr. Breen currently has a number of active grants from the AKC-CHF that are focused on the molecular cytogenetic evaluation of canine tumors.

There are currently 80 million dogs residing in 40 million households. Cancer is the leading cause of death in dogs and the presentation is similar to humans; they share the same environment and the causes are probably comparable. Humans have 1.53 million cancers per year; dogs have 4.2 million per year (10 fold higher incidence than humans.) The most common cancers in dogs are (1) lymphoma (20 times higher than humans), (2) mast cell tumors, (3) osteosarcoma, (4) melanoma, (5) leukemia, and (6) soft tissue. All of the genes in dogs are likely also in humans, but arranged differently. Researchers can use the dog genome to identify cancer genes hidden in the human genome. They can use the genes in dogs to narrow down the number of regions to look for genes in humans.

The application of genomics to canine biomedical research has resulted in significant advances as we strive to enhance the health and welfare of our companions. Over the past several years we have recruited tumor tissues and blood samples from hundreds of dogs presenting with a variety of cancers, as well as their family members. During the same period we generated a series of sophisticated molecular cytogenetic reagents and resources that complete the genomics ‘toolbox’. Collectively these tools provide a robust means to interrogate tumor specimens for organizational changes to the genome, which lead to identification of genome regions and gene associated with cancer. We have demonstrated the presence of numerous cytogenetic signatures associated with canine cancer subtypes and are using these to offer a more sophisticated means of tumor diagnosis. In addition we have begun to define genomic lesions that correlate with prognosis. For example, in our CHF and MAF funded work with canine lymphoma we have developed a cytogenetic test that allows us to predict the duration of first remission of dogs diagnosed with lymphoma, when treated with doxorubicin based chemotherapy. This test has been licensed to a global company and will be launched in 2012. Some of the revenues from this test will flow back to the CHF and MAF. We have demonstrated previously that the chromosome changes we continue to observe in several canine cancers are shared with the corresponding cancers in humans. These data provide strong evidence for a shared pathogenetic origin of several cancers affecting both human and dog. Analysis of our data has revealed we are well on the way towards development of more sophisticated molecular subclassification of canine (and maybe even human) cancers, a process that should facilitate the emergence of improved and tailored therapies. Comparing the molecular cytogenetics of recurrent changes in human and canine cancers is allowing us to refine key signatures to a subset that are shared, thus reducing the size of regions of interest. By considering the canine and human genomes in such a comparative context, we have identified that the genomic complexity of cancers may be less than human studies alone have suggested. Overall these studies are advancing rapidly and indicate that the keys to unlocking some of nature’s most intriguing puzzles about cancers may be found in the genome of the dog. Finding such keys in the dog will also lead to improved understanding of human cancers. For every penny spent on dog research, it saves $1 in human research. For 15,000 years the dog has been man’s best friend, in the 21st Century it is becoming increasingly evident that the dog is also man’s best biomedical friend.

Canine Degenerative Myelopathy:
A Translational Medicine Approach To Amyotrophic Lateral Sclerosis - Lou Gehrig's Disease

Dr. Joan Coates, DVM;
University of Missouri, Columbia August 12, 2011,
Canine Health Foundation Canine Health Conference

Summary by Pat Long

Dr. Joan Coates is a Full Professor in the Department of Veterinary Medicine and Surgery at the College of Veterinary Medicine at the University of Missouri. She is board-certified in neurology by the American College of Veterinary Internal Medicine. As a clinician, she is Service Leader for the Neurology and Neurosurgery service and Co-Director for the Physical Rehabilitation Program at the University of Missouri Veterinary Medical Teaching Hospital. As a researcher, she is a member of the Comparative Neurology Program at the University of Missouri which explores the impact of genetics in developmental and degenerative diseases of the nervous system. Her main research focus involves the study of canine degenerative myelopathy.

Canine Degenerative Myelopathy (DM) is a degenerative disease of the spinal cord, there is no sex predilection. It was first described by Averill in 1973 of German Shepherd Dogs. The age of onset is 8 - 14 years, with a mean of 9 years [note: we are seeing DM like symptoms in some Berners as young as 6 years old]. The disease duration is 6 months to 3 years, but depends on the time of euthanasia. It is an adult onset disease, it starts with rear end weakness and eventual paralysis. Initially stiffness and spasticity, progressing to muscle wasting and flaccidity. It mimics intertribal disc disease (IVDD), cancer, cysts, and compression of the spinal cord. There is no effective treatment for the disease, although physiotherapy may slow the onset. It is a presumptive diagnosis of elimination, and can only be definitively diagnosed after death. A mutation of the superoxide dismutase or SOD1 gene is responsible for a familial for of the human disease Amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease). The average age at onset is about 50 years, and death occurs in 3 - 5 years. Since the initial discovery in 1993 that mutations in SOD1 could cause ALS, more than 145 SOD1 mutations have been identified, accounting for about 2% of all cases. Most are autosomal recessive, except for one which is recessive. A mutation of the SOD1 gene was identified in canines at University of Missouri. The researchers showed a significant association between homozygosity for the mutation and DM in Pembroke Welsh Corgis, Boxers, Chesapeake Bay Retrievers, German Shepherd Dogs, and Rhodesian Ridgebacks. After DNA testing 18,564 dogs and 200 different breeds, they have found the mutation in 109 breeds. The gene mutation frequency in several breeds exceeds 70%: Wire Fox Terriers, Pembroke Welsh Corgis, and the Boxer. Results of the genetic test for DM allele At Risk Carrier Clear Total frequency BMDs 179 504 429 1112 .39 Total 4876 5591 10907 21374 .36 Initially, the researchers concluded that the disease was autosomal recessive with incomplete penetrance. All dogs that are homozygous for the disease do not get the disease, which explains the incomplete penetrance. Are there other modifying genes? More research is needed. The breakdown of the pathology done by the lab shows the following: Dogs studied post mortem for DM: Total DM At Risk Carrier Clear BMDs 17 15 12 2 1 Total 134 127 6 1 The Bernese Mountain Dog that was clear of the mutation in the gene test was found to have a different mutation of the SOD1 gene. This mutation has not been found in any other breed to date. Three other breeds (GSD (2), Rhodesians (1), Chessie (1)) also had carrier dogs affected with DM. 4.5% of all dogs determined to have DM had a carrier status on the gene test. The researchers are now suggesting that the mutation may result in a disease phenotype that also shows dominant inheritance. Thus, although considered rare, it is possible that carrier dogs may develop DM. --------------- Personal Comments I feel that it is too early to conclude that the carrier status is a causative factor in these cases of DM. Given the number of mutations causing ALS in humans, I would be more likely to assume that there is a different mutation in canines and the carrier status is just a coincidence. Again, more research is needed before this issue can be better understood. Something we need to learn in our breed is how many at risk Berners can be expected to develop the disease. What is the penetrance of the genetic mutation? Would 5% of them eventually get DM? 10%? 50%? 75%? It may take years to learn, if we are ever able to do so. I would think that we would need to look at samples of at risk Berners who live to be at least 10 - 12 years old, then determine what percentage of them actually get DM. Breeding a carrier to a carrier would produce 25% of the puppies with an at risk genotype on average. Choosing to do this type of breeding is very different if 5% of all at-risk Berners can be expected to get DM versus 75% of all at-risk Berners. Dr. Jerold Bell held a breakout session, and he was asked how best to use a genetic test like the one we have for DM. He replied that he would have the test done in order to have the knowledge, and he would avoid any carrier to carrier matings if there were any cases of DM in the immediate family of either line.

Factors Influencing Development of New Veterinary Medicine Oncology Products
Karen Greenwood, BSc
Pfizer Animal Health Director,
Companion Animal Internal Medicine Unit

Summary by Joye Neff

Karen Greenwood is currently employed at Pfizer Animal Health in Kalamazoo, Michigan having moved to the United States from England in November 2006. She received a BSc (Hons) in Biochemistry at Southampton University, England, in 1988, and then took a role with Pfizer Animal Health Veterinary Medicine Research and Development (VMRD) in the Fermentation Titer Improvement group. After two years she transferred to the VMRD Biology group to work on in vitro screen design and development, which was a major focus for the next 16 years along with leadership of teams seeking new treatments for various diseases states, in particular antiparasitics. She moved to Kalamazoo to lead the Companion Animal Discovery Unit, with responsibility for finding new treatments for diseases in dogs, cats and horses, from identification of potential targets through proof of concept. Karen enjoys the intricacies of drug discovery and development, and the opportunity to be able to turn cutting edge science into products that benefit pets and owners. She serves on the Grants Committee of the AKC Canine Health Foundation. Karen lives just outside Kalamazoo with her husband Sean, a synthetic chemist with Pfizer, and her two small children, Zoe and Hayley.

The presentation covered the process involved in identifying and registering new oncology treatments for canines and the factors that influence successful registration and launch. It included observations on the challenge and complexity of development for agents specifically developed for pets versus off-label use of human health products, the MUMS (minor use, minor species) process as it relates to oncology, and the benefits of translational oncology for canine cancer patients.

Currently there are two canine cancer drugs: Palladia for the treatment of mast cell tumors and Merial’s Therapeutic Melanoma Vaccine. Off label use of non-canine medications is being used to treat some cancers. The incidence of dog cancers (2006): lymphoma (18%), mast cell (16%), Hemangiosarcoma (10%), osteosarcoma (8%). In 2010 mast cell was 18% and lymphoma was 8%. The first step is to select a target using tissue samples that is essential to the tumor but not important in the dog’s healthy tissue. Identify a compound from human compounds, libraries of compounds, potential cell surface antigens. Confirm that the drug kills cancer in lab compound screening. Next, increase confidence in the compound by testing in cells from real tumors (test in mice – some kill mice tumors but do not translate to clinic.) The dosing regime and safely must be determined, then tested in mice, then dogs, then humans. The manufacturing process is the single greatest expense and must be the same each time it is made and must be able to be stored without losing its potency. Development studies are then done on 100 animals to ensure safety and efficacy. The three regulatory agencies are: FDA, USDA, and the EPA. Currently a human health compound can be used off label in dogs. To register the new drug they must show the efficacy, safety and that it can be manufactured. After approval, marketing and promotion takes place. For rare tumors, there is no return on investment so those drugs are not high on the priority list. Lymphomas are common, and those developed drugs may treat other tumors. Preventative vaccines or biological treatments for common tumors are drugs that will be targeted.

History of Veterinary Medicine and Canine research
Donald Smith, DVM,
Cornell University,

Summary by Julie Jackson

Because of his interest in history and public policy, he has conducted interviews with vets of all ages, but with special affinity for those who graduated prior to 1940. His collection of “lost voices of the profession” is available at www.vet.cornell.edu/legacy. Smith writes a log on veterinary medicine and public policy that reaches readers in over 80 countries at www.veterninarylegacy.blogspot.com. He lectures nationally on topics ranging from “One Medicine, One Health” to the history of veterinary medicine.

Modern veterinary medicine in the U.S. had its roots during the Civil War when over one million horses and mules were lost due to starvation, disease and trauma. During the ensuing half century, over 30 veterinary colleges sprang up in major cities, including five in New York and two in Chicago. In 1910, there were 12,000+ vets in NYC, including physicians and horse shoers, also working as vets. Though most veterinary colleges were proprietary, non university-based institutions, Harvard and New York University also developed veterinary colleges as outgrowths of their medical schools. The equine species was the prime interest in all of these schools.

With the precipitous decline of the horse in the early 1920’s due to the advent of the internal combustion engine, all but one of the colleges in the major cities closed. The era of the land-grant, agricultural–oriented veterinary colleges that had also started during the last few years of the 19th century in places like Cornell, Ohio State and Washington State Universities prevailed, but veterinary medicine transitioned to a rural-based profession focusing primarily on farm animals, public health, and working horses. The majority of vet students were from agricultural backgrounds, in part because of their experience working with animals.

Though dogs and cats became more important as pets in the early decades of the 20th century, their medical care remained a low priority for both academic and private practice veterinarians. Most of the veterinary research in the first half of the 20th century was related to diseases of livestock, poultry and horses, public health and zoonotic diseases. However, many discoveries were made during private practice, i.e., stader splint.

Physicians, meanwhile, used dogs to study comparative physiology and pathology and to develop surgical techniques for use in people. Human medicine proceeded on science based clinical advancements, and was less interested in comparative medicine. Aseptic surgical techniques were used in medical schools on their dog colonies several decades before they were commonplace in veterinary colleges. Canine research derived from medical schools in the pre-WWII era crept into veterinary clinical medicine, complemented by new techniques developed by private practitioners and the occasional faculty clinician staffing companion animal hospitals.

Following WWII, a second wave of land-grant veterinary colleges was established and returning GI’s and their families began to demand better veterinary services for the growing number of pets that began to populate cities and suburbia. Clinical specialties and board certification starting in the mid 1960’s met a critical need in the provision of advanced individual pet care, as well as providing an academic infrastructure for companion animal research. Because very few veterinary colleges were located in major metropolitan areas, specialty hospitals like the Animal Medical Center (NYC), and Angell Memorial Hospital (Boston) became urban centers for advancing canine medicine and research. And later a few vet schools aligned with medical colleges, i.e., Harvard and Penn State. Federal and state funding for veterinary research remained largely restricted to agricultural animals and diseases of public health importance, however, companion animal-oriented veterinary scientists funded canine research on private donations of “piggy-backed” NIH research protocols that used dogs and other animals to study human disease. It was not until the last two decades of the 20th century that major foundations, corporations, and individual donors began to devote substantial resources for companion animal research.

Veterinary medicine today is still a small profession with insufficient political influence to manifest robust financial support for companion animal research. Ironically, despite this fact, over 80% of government-sponsored research goes to diseases of production and farm animals, and to public health.

Sadly, the increasing acknowledged human health benefits that accrue to people who have pets as part of their family structure are not considered worthy of funding by the federal government. Ironically, this occurs at a time when the soaring cost of human health can be modulated by better understanding the role that pets play in reducing costly physical, mental and emotional conditions in people. The great tragedy of the 2010 federal health care bill is that animals and veterinary medicine remain estranged in the public policy arena from people and human medicine. In addition to promoting the human-animal bond, contemporary canine research has taken an enormous step forward with the advent of molecular biology and genetics, and the elucidation of the canine and human genome. Not only does this allow researchers and breeders to focus on genetically-based diseases and conditions for both prevention and therapy, it also allows individual animal testing and broadly-based screening of breeding lines to improve phenotype in succeeding generations. The homology between an increasing number of recognized canine and human conditions is another important byproduct of the genome, allowing us to analyze and interpret DNA from individual animals with spontaneously-occurring diseases compared to normal dogs from breed-specific cohorts.

Infectious diseases that were so miraculously prevented with the development of a wide range of vaccines and anti-parasitic agents starting in the middle decades of the 20th century remain a serious problem in dogs as new diseases (or variants of former diseases) emerge. That some of these represent potent zoonotic threats to human health (especially for an increasing immune-compromised population) lends further credence to the need for advancing the theme of comparative medicine in public and private research funding.

A political imperative for veterinary medicine is to move from agricultural as principal justification for public support to human health lobby. Pets aren’t for agricultural use—they’re for therapy and love. The number of vet schools is in decline, with only 2600 graduates/year, and only 8% are for agricultural medicine. The future of canine research is in a balanced approach. Public (federal grants) should be the largest portion of support, followed by foundation, private, corporate, and colleges and institutional dollars.

CHF & Grant Sponsors – Working Together for a Healthier World for Dogs
Christine Haakenson, PhD
AKC Canine Health Foundation,
Chief Scientific Officer

Summary by Joye Neff

The relationship between the AKC Canine Health Foundation and Parent Clubs, breed health foundations, and other sponsor organizations is very important and is part of the Foundation’s distinction. They all share the goal to improve the health and lives of dogs through funding scientific research. The focus of this presentation was on this relationship and it provided information about available resources and tools for organizations and their designated CHF Health Liaison. The CHF Health Liaison is a very important person in the Foundation’s relationship with breed organizations and they want to ensure that the Liaisons have what they need to perform this role. This person is the breed organization member who functions as the main contact for communication with CHF regarding the health and wellbeing of their breed, research projects, and grant sponsorships. They are also critical in communicating with their club about research discoveries, new programs, and canine health educational resources.

Dr. Haakenson described: (1) the grant sponsorship process; (2) what the Health Liaison should expect from the Foundation; (3) the tools and resources available to them, including a soon to be released electronic, quarterly newsletter for Health Liaisons; and (4) where to find information on the CHF website. They are also working on a new Health Liaison Handbook to be released in the next few months. Dr. Haakenson listed the benefits of working through the AKC CHF to the breed clubs: (1) rigorous research review process, (2) identifying researchers for potential grants, (3) grant management, (4) project monitoring and sharing of non-confidential information, (5) sponsorship collaboration, so we get more value for our money, (6) receipt of progress summaries to share with our breed clubs, and (7) sponsorship acknowledgement.

The benefits to the AKC CHF are: (1) identification of health concerns for each breed club, (2) participants in the research studies, (3) sponsorship collaboration, which gives more value for the money invested, (4) sharing of ideas, (5) passion and dedication of the breed clubs and its members, and (6) working together to reach goals.

The CHF website offers a wealth of knowledge and is constantly being updated with the latest grants, research findings, and news and events, including ‘Success Story’ articles that highlight scientific discoveries and the latest podcasts to listen to your favorite researcher. The Liaison can always contact CHF at the Foundation for questions regarding administration of funds, identification of researchers, and sponsorship opportunities. They are also able to pull reports regarding Donor Advised Fund (DAF) information, grant sponsorship history, grants seeking sponsorship, grants specific to a breed and/or disease, and more! They want to provide information and resources that we need to be successful in building our breed’s health programs.

Dr. Haakenson introduced Samantha Wright who has recently joined the AKC Canine Health Foundation team as the new Program Manager. Samantha is excited about this new opportunity and is looking forward to increasing her interactions with the Fancy through dog club communications, health liaison relationships, presentations and dog events.


Canine-derived Antibody Fragments for Targeted Therapy of Cancer
Nicola Mason, BVetMed, PhD,
University of Pennsylvania,
Assistant Professor of Medicine & Pathobiology

Summary by Joye Neff

Dr. Mason graduated from the Royal Veterinary College, University of London and spent a year in private practice in Peterborough. She then performed a small animal medicine internship at theUniversity of Bristol and a small animal internal medicine residency at the University of Pennsylvania’s School of Veterinary Medicine. She went on to complete her PhD in Immunology at the University of Pennsylvania and performed a post-doctoral fellowship in thelaboratory of Dr. Carl June at the Abramson Cancer Center, within the University of Pennsylvania. Dr. Mason is currently an assistant professor of medicine at the University of Pennsylvania’s School of Veterinary Medicine. Dr. Mason is a Diplomate of the American College of Veterinary Internal Medicine, she is the associate director of translational research at the school’s Mari Lowe Comparative Oncology Center and the director of the PennVet Tumor Tissue Bank. Her research focuses on targeted therapies for the treatment of canine cancers withparticular emphasis on lymphoma, osteosarcoma and hemangiosarcoma. Antibodies that target tumor cells or neutralize their growth factors have revolutionized the treatment of many different human cancers. However such targeted antibody therapy is not currently available in veterinary medicine. Humanized antibodies used to target human cancerscannot be used in dogs because they don’t cross-react with dog tumor cells and they are rapidly destroyed by the dog. In order to develop targeted antibody therapies for use in our canine patients, we have developed a platform technology to generate libraries of canine-derived antibody fragments from the white blood cells or lymphocytes of dogs with cancer. We have previously shown that libraries of antibody fragments generated from dogs vaccinated againstcanine parvovirus contain antibody fragments that bind to canine parvovirus. These findings provide proof-of-principle that libraries of canine-derived antibody fragments re-capitulate the antibody repertoire of the dog. We have now utilized libraries, generated from the spleens of dogs with hemangiosarcoma, to isolate antibody fragments that bind and neutralize the biological activity of Vascular Endothelial Growth Factor (VEGF). VEGF is considered to be one of themajor factors that stimulates the growth of blood vessels in and around tumors, which is necessary for the survival of the tumor. Neutralization of VEGF has led to prolonged overall survival times in human patients with several different types of cancers. These canine-derived VEGF-specific antibody fragments represent the first targeted biological antibody therapy that may be employed in dogs to retard the growth of a number of different tumor types includingcanine hemangiosarcoma. Furthermore, libraries generated from dogs with different tumor types such as osteosarcoma and lymphoma may contain novel antibody fragments that could be used to target these cancer types in the future.

What We Know About the Inheritance of Dilated Cardiomyopathy, Arrhythmogenic - Right Ventricular Cardiomyopathy and Subaortic Stenosis in the Dog
Kathryn M. Meurs, DVM, PhD,
North Carolina State University College of Veterinary Medicine,
Professor and the Associate Dean of Research and Graduate Studies

Summary by Joye Neff

Dr. Meurs is a Professor and the Associate Dean of Research and Graduate Studies at North Carolina State University College of Veterinary. She completed her DVM in 1990 at the University of Wisconsin – Madison and completed a small animal internship at North Carolina State University in 1991. She completed a Cardiology residency at Texas A&M University and is board certified from the American College of Veterinary Internal Medicine (Cardiology).

Cardiomyopathy is a primary muscle disease that has been shown to be inherited in the dog as well as several other species. There are two common forms, dilated and arrhythmogenic. Dilated cardiomyopathy is characterized by heart muscle dysfunction and enlargement of the heart chamber, particularly the left. This generally first occurs at five or more years of age. Affected dogs may die suddenly or develop congestive heart failure as characterized by coughing and shortness of breath. There is no cure. The disease looks the same in all breeds on echocardiogram, but is from different causes. It has been known to be inherited in the Newfoundland, Irish Wolfhound, Scottish Deerhound, Great Dane and Doberman Pinscher, among other breeds. In North America, the most commonly reported breed is the Doberman Pinscher and the largest number of studies have been done on this breed. In the Doberman Pinscher the disease is inherited in an autosomal dominant mode and at least in some families is associated with a mutation in a gene involved in the energy metabolism of the heart. The cause of the disease in the other breeds is not known. In human beings there are now 20 different genes that cause the development of this disease. It is likely that there is more than one cause in the dog, and even in the Doberman Pinscher as well. An important aspect of all cardiomyopathies is that they are impacted by variable penetrance, meaning that not all dogs that have the genetic cause will show the same severity of disease, some will show severe clinical signs, while others will remain free of symptoms there whole life. In Great Danes, it is carried on the X chromosome and females can be a silent carrier of the disease.

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a heart muscle disease characterized by cardiac arrhythmias that result in fainting or sudden death. It is most commonly observed in the Boxer dog, but has been observed in English Bulldogs as well. A deletion mutation has been identified in many affected Boxers. The mutation prevents the cells from holding together properly and this leads to cardiac arrhythmias and sudden death. As in other cardiomyopathies, variable penetrance exists meaning that not all dogs that have the mutation will have the same severity of disease. Although English Bulldogs also suffer from this disease they do not have this mutation. Subvalvular Aortic Stenosis is the second most common heart birth defects in dogs. It is known to be inherited in the Newfoundland, Rottweiler and Golden Retriever. Affected dogs can live comfortably with the mild form of the disease, but severely affected dogs have an average life span of 2 years. The speed of the blood flow shows the severity of the disease. This disease does not exist in humans. We have some preliminary data that suggests that the disease may have a similar genetic cause in the Rottweiler and Golden Retriever (on chromosome 21) but each breed may have additional genetic modifiers as well.

Vitamin D and Cancer
Rondo P. Middleton, PhD
Nestlé Purina Research
Senior Research Scientist,
Pet Care Basic Research

Summary by Joye Neff

Dr. Rondo P. Middleton completed his PhD in biochemistry in 1999 at the University of California, Riverside where he studied 1,25(OH)2 vitamin D3’s ability to regulate gene expression at the transcriptional, translational and post-translational levels. He was hired by Ralston Purina as a research scientist in 1998. Dr. Middleton is currently a senior research scientist at Nestlé Purina Research Center where his research interests include osteoarthritis, cancer, aging, weight management, among others. Most of his work focuses on the molecular aspects (gene expression, metabonomics, systems biology) supporting these health and disease areas.

Since its discovery as a molecule necessary for proper calcium and phosphate metabolism, vitamin D, and more specifically the hormonally active form, 1,25-dihydroxyvitamin D3 (calcitriol), has become known as an important player in many other biological systems. These areas include cancer, heart disease, autoimmune diseases, and skin disorders, among others. Physiological responses to calcitriol are mediated through the vitamin D receptor (VDR). The VDR elicits its actions by binding to specific regions on DNA and promotes or inhibits the expression of vitamin D-responsive genes. It was the discovery that the VDR was present in many tissues not involved in calcium homeostasis that led to the finding of the pleotropic actions of calcitriol. Research has shown that higher levels of vitamin D in the blood are associated with reduced incidence and recurrence, and greater survival in various types of cancers. Dogs and cats do not produce a lot of the compound, so they do not get vitamin D from sunlight; they must get it from their diet. Mortality rates are higher in the northeast vs. the southwest and may be from the lower sun in the northeast. When there are low levels of D3 there is an increase in cancers. The expression of many genes encoding for enzymes involved in the metabolism of vitamin D, as well as other proteins regulated by vitamin D, are altered in cancer. These vitamin D- responsive genes and their respective proteins affect many processes involved in cancer.These include antiproliferation, pro-differentiation, and pro-apoptotic effects. We have previously shown that calcitriol and some associated vitamin D analogs can decrease the proliferation and induce differentiation in canine cancer SCC 2/88 cells in vitro. In order to further understand the molecular mechanisms associated with calcitriol’s antiproliferation and pro-differentiation effects, we recently investigated the gene expression changes involved in canine transitional cell carcinoma cells in response to calcitriol and some of its associated analogs. Additionally, due to the involvement of reactive oxygen species (oxidative stress) in cancer, we have investigated the role of antioxidant enzymes in these canine cancer cells. Antioxidant enzymes appear to interact with the identified differentially expressed genes and show beneficial modulation of key cancer processes in our study.

Recent Progress in Molecular Genetics of Cancer and Challenges Ahead
Jaime F. Modiano, VMD, PhD
University of Minnesota,
Director, Animal Cancer Care and Research Program, College of Veterinary Medicine Perlman
Professor of Oncology and Comparative Medicine, Veterinary Clinical Sciences

Summary by Joye Neff

Jaime Modiano, from Mexico City, did undergraduate work in Biomedical Sciences at Texas A&M University in College Station, TX before moving on to veterinary school at the University of Pennsylvania in Philadelphia. He completed his residency in Veterinary Clinical Pathology at Colorado State University in Fort Collins, CO and a post-doctoral fellowship at the National Jewish Center for Immunology and Respiratory Medicine in Denver, CO. In July of 2007, Dr. Modiano joined the College of Veterinary Medicine, School of Medicine, and Masonic Cancer Center at the University of Minnesota, where he continues his research program as Alvin and June Perlman Endowed Professor of Oncology and Comparative Medicine. His research program has had uninterrupted support from federal and private sources for 15 years, leading to co-authorship of more than 70 peer-reviewed scientific manuscripts, and more than 200 abstracts, presentations, and book chapters focused on various aspects of immunology, cancer cell biology, the genetic basis of cancer and applications of gene therapy.

The last decade has seen dramatic improvements in molecular genetic research of canine cancer. This includes new and improved diagnostic tests and approval of the first immune-based cancer therapy (ONCEPT, Merial canine melanoma vaccine) and the first targeted small molecule inhibitor (Palladia, Pfizer c-Kit inhibitor for treatment of mast cell tumors). There also has been significant progress defining breed-associated cancer susceptibility. Our efforts have focused on defining the role that "breed" plays, not only on the frequency of tumor occurrence, but also on tumor behavior. At the same time, we have dedicated considerable effort to understand the mechanisms that drive tumor behavior as a means to improve our diagnostic precision, our prognostic capacity, and the development of new therapies. To help achieve these goals, AKC CHF has supported eight research projects in our laboratory since 1998. These projects have allowed us to build a sample bank that has been used extensively by the research community worldwide (more than 40 investigators at more than 30 companies, universities, and research institutes in seven countries and four continents). The projects also have formed a robust foundation for clinical translation, verifying the notion that oftentimes tumors are as unique as patients and we must beware of generalizations and oversimplification. This presentation underscored the differences that exist within tumors and among dog breeds, and illustrated how we have started to overcome these challenges to achieve our clinical goals. Cancer, a disease of aging, is many diseases in which dogs have heterogeneous responses to treatment. The first step of molecular classification is microscopic assessment, refined by genotype. Causes can be sporadic mutational events or inherited (less than 5% of cancers are inherited in humans.) In the last ten years there have been dramatic changes in the standards of practice for treating patients.

Canine lymphoma is 30 different diseases with differences in age of onset. No breed will get a specific type of lymphoma. Canine lymphoma can be stratified using molecular tools according to ontogeny (T-cell vs. B-cell phenotypes.) T-cells can further be sub-stratified according to biological behavior.There is a big difference in high and low cells in T-cells, but not as much difference in B-cells; the prognostic information about T-cell grade is important. Research and clinical trials are being done with stem cells and lymphoma initiating cells.

Hemangiosarcoma, a disease of cancer stem cells, has no environmental factor that increases risk of getting this disease. It grows anywhere and goes places, remaining indefinitely and is able to grow into tumors. Researchers are looking for therapies that change the host environment so tumors don't grow. Therapeutic targets for hemangiosarcoma may not be intuitive and responses may be heterogeneous among tumors and among different breeds of dogs. Dr. Modiano's team discovered a gene pattern that distinguishes the more severe form of osteosarcoma (bone cancer) from a less aggressive form in dogs. Both nature and nurture contribute to the biology of osteosarcoma. Gene suppression profiling describe two distinct molecular subtypes of osteosarcoma with different survivals. Breed and survival appear to be independent of each other. Their findings pave the way to develop laboratory tests that can predict the behavior of this tumor in dogs and children at the time of diagnosis, allowing them to tailor individualized therapy to meet the patient's needs. The dogs who get the disease at a young age have less severe cancer. With no treatment dogs survive approximately 7 weeks, but with amputation and treatment, they survive about 11 months. They look at 7 to 10 genes and run the signature, which enables them to predict who will do well with treatment. Research with dogs will help predict how children with osteosarcoma will respond to treatment and how they will be treated. Patients with less aggressive disease could be treated conservately, reducing the side effects and the risks associated with treatment. Patients with the more aggressive disease could be treated with more intense therapy.

Ten Years Later for the Search and Rescue Dogs
Cynthia M. Otto, DVM, PhD,
University of Pennsylvania,
Associate Professor, Critical Care,
Director, Penn Vet Working Dog Center

Summary by Joye Neff

Dr. Otto, a board-certified emergency and critical care veterinarian, is currently a tenured associate professor of Critical Care at the University of Pennsylvania, School of Veterinary Medicine. She graduated from the Ohio State University, completed a rotating internship at the University of Pennsylvania and a residency in internal medicine and PhD in veterinary physiology at the University of Georgia. Dr. Otto has also been involved in disaster medicine as a member of the Pennsylvania Urban Search and Rescue Task Force 1 between 1994 and 2010 (including deployments to Hurricane Floyd and 9/11), and the Veterinary Medical Assistance Team-2 since 1999 (deploying to Hurricane Katrina). She has been monitoring the health and behavior of Urban Search and Rescue canines since October of 2001, through an AKC-CHF funded grant (now in its third renewal). She has organized the PennVet Working Dog Conference in 2010, and the upcoming conference in Sept of 2011 and serves as the co-chair of the 10 year anniversary 9/11 Tribute to the Search Dogs and Veterinarians. She was named Pennsylvania’s 2002 “Veterinarian of the Year” and received an Alumni Recognition Award in 2006 and the OSU Distinguished Alumnus Award in 2008 from the Ohio State University.

September 11, 2001 was an unprecedented day in the history of the United States. In response to the terrorist attacks in New York, Washington DC and the downed plane in Pennsylvania, hundreds of search and rescue and other canine teams were deployed. During the deployments in New York, both at Ground Zero and at the Staten Island Landfill, and in Washington DC at the Pentagon, the health and well-being of the dogs was monitored. Remarkably, the dogs coped with the adverse conditions with minimal morbidity. The dogs wore no protective gear and the medium age was five years. There were 300 total dogs representing eleven breeds and the top three breeds represented were: 31 German Shepherd Dogs, 28 Labrador Retrievers, 12 Golden Retrievers. The most commonly reported problems reported by handlers were cuts and scrapes, most of with were minor. Only four dogs required stitches. Problems related to the intensive work included fatigue, weight loss and dehydration. Interestingly enough, respiratory problems were rare.

The presentation opened with a video of the September 11th tragedy and the entire room of almost 300 people was completely silent while the video was on. Please feel free to share these findings with your fellow fanciers and colleagues who were unable to join us.

The Search & Rescue Dog 10th Anniversary Tribute video shown at the conference is available at:

Highlights of Research Findings• Both clinical reports and X-ray findings show minimal lung abnormalities. There were only 8 dogs with mild signs of respiratory distress. In fact, there have been no systematic conditions that have been identified in deployed search and rescue dogs that did not also occur in control (non-deployed) search and rescue dogs. It was interesting to note that dogs do not get asthsma. This is in stark contrast to the findings in the human responders suggesting important differences between the humans and dogs. Although not associated with clinical disease, the review of the first 5 years of chest x-rays identified more heart abnormalities identified in the deployed dogs. Surprisingly, there was minimal lung pathology in both groups both on x-rays and at post mortem examination.• The average age at the time of death of the 75/95 deceased deployed dogs was 12.5 years and of the 35/55 deceased control dogs was 11.8 years.• Approximately 40% of both groups succumbed to cancer although there was no statistical difference in incidence of cancer. Both groups had an equal incidence of hemangiosarcoma and we are continuing to monitor for differences in incidence of other cancer types.• Handlers that suffered the loss of their canine partner within 3 years of the 9/11 response had ahigher incidence of PTSD demonstrating the importance of dogs to human health.

There is currently a critical shortage of detection dogs. The legacy of 9/11 has been an increased awareness of the important role that these dogs play and the need for continued research in behavior, genetics and sports medicine to enhance their capacity and safety. To that end, the Penn Vet Working Dog Center has been established at the University of Pennsylvania.

Highlights of Research Findings• Both clinical reports and X-ray findings show minimal lung abnormalities. This is in stark contrast to the findings in the human responders suggesting important differences between the humans and dogs.• The average age at the time of death of the 75/95 deceased deployed dogs was 12.5 years and of the 35/55 deceased control dogs was 11.8 years.• Approximately 40% of both groups succumbed to cancer although there was no statistical difference in incidence of cancer. Both groups had an equal incidence of hemangiosarcoma and we are continuing to monitor for differences in incidence of other cancer types.• Handlers that suffered the loss of their canine partner within 3 years of the 9/11 response had a higher incidence of PTSD demonstrating the importance of dogs to human health.

Canine Oncology Trials
Douglas H. Thamm, VMD DACVIM,
Colorado State University Animal Cancer Center,
Associate Professor and Barbara Cox Anthony Chair in Oncology,
Director of Clinical Research

Summary by Joye Neff

Dr. Thamm is an Associate Professor and Barbara Cox Anthony Chair in Oncology at the Colorado State University Animal Cancer Center, within the College of Veterinary Medicine and Biomedical Sciences. He is also a member of the Developmental Therapeutics Section of the University of Colorado Comprehensive Cancer Center and the Cell and Molecular Biology Graduate Program at Colorado State University. Dr. Thamm received his Bachelor’s and V.M.D. degrees from the University of Pennsylvania. He completed a Residency in Medical Oncology at the University of Wisconsin, and was a researcher there for 5 additional years before joining the faculty at CSU in 2004. He is the author of over 65 peer-reviewed publications and was Oncology Section Editor for the most recent edition of Kirk’s Veterinary Therapy. His clinical and research interests include novel targeted therapies for animal and human cancer and ways to integrate these therapies with existing treatment.

What is a clinical trial?
Although there are many definitions of clinical trials, they are generally considered to be health-related research studies that follow a pre-defined protocol. These can include both interventional and observational types of studies. Interventional studies are those in which the research subjects are assigned by the investigator to a treatment or other intervention, and their outcomes are measured. Observational studies are those in which subjects are observed and their outcomes are measured by the investigators.

Why are clinical trials conducted in dogs with cancer? One obvious reason is to investigate new and hopefully better ways to diagnose, treat and monitor cancer in dogs. However, many naturally occurring cancers in pet animals closely resemble human cancer and provide meaningful systems for cancer research to benefit both species. Thus, sometimes therapies are studied in dogs to provide important information about whether this form of treatment might be appropriate for testing in humans. The cost to study dogs is about 10% of the cost to study humans. The canine genome in dogs is very similar to humans and because of the favorable body size, the same machinery such as human CTs and MRIs can be used. The dogs tend to be less heavily pre-treated as patients, there is good compliance by owners with 80 to 90% necropsy vs. 15% humans autopsy.,and there is faster progression of diseases so shorter turn around in the study.

What are the different types of clinical trials?
• Treatment trials test new treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.
• Prevention trials look for better ways to prevent disease in patients that have never had the disease or to prevent a disease from returning. These approaches may include medicines, vaccines, vitamins, minerals, or lifestyle changes.
• Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition.
• Screening trials test the best way to detect certain diseases or health conditions.
• Quality of Life trials (or Supportive Care trials) explore ways to improve comfort and the quality of life for individuals with illness.

What are the phases of clinical trials?
Clinical trials are conducted in phases. The trials at each phase have a different purpose and help scientists answer different questions: In Phase I trials, researchers test a new drug, drug combination, or treatment in a small group of patients, often with different types of cancer for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. Typically, a very low dose of a new drug is tested initially, and if there are no side effects, that dose is gradually increased in additional patients. In Phase II trials, the new study drug or treatment is given to a larger group of 15 to 30 patients, usually with the same type of disease, to see if it is effective and to further evaluate its safety. In Phase III trials, the new study drug or treatment is given to still larger groups of patients to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the treatment to be used safely. These trials are usually the types of trials necessary for the regulatory approval of a new drug or treatment by agencies such as the FDA or USDA. In Phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

When are clinical trials appropriate for a pet? Some clinical trials, for example, studies that involve simple procedures such as blood collection or special handling of tissues to be removed at surgery, may be appropriate for any dog with cancer. Participation in therapeutic trials with new drugs or treatments, especially early-phase trials, needs to be considered more carefully, as the effectiveness of these treatments is generally not as well known, and potential toxicity may not be as well established.

Questions to ask when weighing the decision about whether to participate in a clinical trial include:
• What is the “standard of care” for treatment of my dog’s disease, and how well does it work?
• Is this a disease that could be effectively treated with a simple surgery? If so, is it appropriate to do something else?
• How expensive is the “standard of care”?
• Unfortunately, sometimes the standard of care therapy may be unaffordable for a given owner. In these cases, considering an alternative such as participation in a clinical trial may mean the difference between a pet receiving an investigational therapy or no therapy.
• Are there other treatment alternatives besides the “standard of care”, and how well do they work? How expensive are they?
• How much is known about the safety and effectiveness of the treatment being studied for my dog’s cancer?

How can I find information about available clinical trials for dogs with cancer? There are multiple websites that list ongoing clinical trials for pets with cancer. The most frequently updated and comprehensive is the site managed by the Veterinary Cancer Society.

(For human clinical trials see: clinicaltrails.gov)

Since the majority of (but not all) clinical trials are conducted at Veterinary Teaching Hospitals associated with Universities, making contact with the nearest University Veterinary Teaching Hospital may provide a simple way to find out about trials available in your area.

The AKC CHF will be releasing the podcasts soon so people can hear the presentations.

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