Genes, Dogs and Cancer:
2nd Annual Canine Conference
Hosted by the AKC Canine Health Foundation, September 19-20, 2002, Aurora, Ohio
Summary by Dr. MaryDee Sist, DVM
I was very fortunate to be one of about 50 attendees at this outstanding seminar. The meeting was hosted by the AKC Canine Health Foundation whose major focus of funding are grants involving cancer and genetic research. It was a gathering of MD, Ph.D. and DVM cancer researchers updating their colleagues and the board and staff of the CHF on current investigations and various laboratory projects on cancer and genetics. Seminars on state of the art research efforts were presented which were often very technical. It was an incredible opportunity for me to learn about current cancer studies and discuss with principal investigators how best to proceed exploring the cancer incidence in Salukis.
Training Stem Cells to Home: The Role of Drug Resistance Gene Transfer - The keynote speaker, Dr. Gerson, discussed how his studies into gene transfer in stem cells and therapy can protect bone marrow from damage by toxic chemotherapy in cancer treatments.
Examination of the Population Genetics and Inheritance Patterns of Cancer in the Flat-Coated Retriever - To explore the incidence of soft tissue tumors, a tumor and pedigree registry was set up by the Flat-Coated Retriever Society of America. Since the incidence of malignant histiocytoma in the breed was high, a survey was conducted and genealogy was compiled for analysis. Dr. King, a statistician and epidemiologist documented that there was significant heritability or a genetic basis and is now analyzing the mode of inheritance. I did spend time discussing the hemangiosarcoma incidence in Salukis with her. She was extremely interested in exploring this in a manner similar to the study she presented. This is the next step that needs to be done before genetic screening can be attempted.
Genetic Mapping of Cancer Susceptibility Genes in Dogs - The Norwegian Cancer Registry was set up as a unique resource to study canine cancers. They have now banked 15,000 growths (from the 4 Scandinavian countries) confirmed by histology with half being malignant. 30% of the growths are mammary masses and of these, 94% are pre or malignant, since most of their dogs are not spayed. Data from the registry has shown that there is a higher frequency of specific cancers in certain breeds. This has also led to the initiation of a project studying "Feeding, growth speed and bone disease" in four breeds (Irish Wolfhounds> Labrador Retriever> Leonberger> Newfoundland) at risk for developing osteosarcoma which will serve as a resource in the future for genetic mapping. The presenter has also been involved in genetic mapping of the cancer syndrome, Renal Cystadenocarcinoma and Nodular Dermatofibrosis in German Shepherd Dogs, that is similar to a human renal cancer. This study showed that continued banking of Saluki tumors by SHR is a needed resource for future studies.
Comparative approaches to understanding metastases: Dependence of osteosarcoma metastasis on ezrin, a membrane-cytoskeleton linker protein. - This study at National Institutes of Health used a cross-species comparative approach to identify, validate and evaluate a gene (ezrin) linked to aggressive metastases in osteosarcoma, since even with successful control of the primary tumor and adjuvant chemotherapy, most deaths occur from pulmonary metastasis.
Molecular cytogenetic analysis of recurrent chromosome aberrations in canine multicentric lymphomas - This presentation outlined a method of screening for chromosomal aberrations by finding additions or deletions to specific chromosomes in canine lymphomas. Genomic gains were twice as common as losses in the lymphoma cases.
Canine Molecular Cytogenetics - Development of higher resolution resources for studies of canine cancer - Chromosome aberrations are known to be associated with human cancer however, this has been difficult to study in dogs because there was no way to reliably identify dog chromosomes. Dr. Breen's development of chromosome-specific reagents has allowed identification of each chromosome of the dog and the first integrated canine genome map. "With such strong foundation data in place we are now in a unique position to be able to interrogate the genomes of canine cancers with a level of confidence previously unattainable." His methods, which include those outlined in the previous presentation, have allowed a much more rapid mode of analysis and he is currently involved in a variety of ongoing cancer studies. However, with his recent move from the UK to the US, his time is currently overtaxed. He did express interest in working with the fixed Saluki HSA samples next year.
Canine histocytic neoplasia: cell lineages and disease classification -
Histiocytomas are common, benign cutaneous neoplasms of young dogs that spontaneously regress. This presentation covered the lineage and transformation of these cells into cancerous disease syndromes. The disease is best recognized in Bernese Mt. Dogs, but Rottweilers, Golden Retrievers and Flat-Coated Retrievers are also predisposed.
Gene Therapy for Cancer - This presentation covered some of the technical difficulties in gene therapy and targeting with the goal of reduced toxicity and increased therapeutic index.
The Canine Hereditary Urothelial Malignancy Study (CHUMS): A Potentially Useful Approach to Understanding Human Urothelial Malignancy - Scottish terriers have an increased risk for bladder and urethral cancers. Dr. Leach's lab is investigating the genetic basis by extensive pedigree and molecular analysis of blood samples from affected dogs and relatives with the hope of identifying homologous genes in man through comparative analysis. A parallel study is needed to explore the hemangiosarcoma incidence in Salukis.
Focused Expression Profiling of Cyclin and Cyclin-Dependent Kinase Integration Complex Components -
Regulators in a Spontaneous Model of Canine Breast Cancer and Differential Cyclin-Dependnt Kinase (CKI) Expression in a Spontaneous Model of Canine Breast Cancer - Both of these presentations were extremely technical discussions of research efforts in molecular pathways of cell biology that alter cell growth to allow or inhibit malignant cell proliferation.
Kinase Inhibitors in the Treatment of Canine Cancer - Dr London's presentation covered her clinical trial of cancer treatment with an experimental oral drug - KIT (kinase inhibitors competitively bind ATP, which is needed for cells to grow and divide). There was a good response rate with tumor regression observed in 68% of the dogs. The drug worked best in Mast cell tumors and where there were KIT mutations. There was also some effect in mammary adenocarcinomas, soft tissue sarcomas and multiple myelomas. There was no response in the 3 HSA dogs treated, all with internal bleeding probably due to tumor necrosis.
Tetrathiomolybdate Therapy for Cancer (and Other Things!) in Dogs (and Other Species!) - Dr. Brewer from the U of MI has developed a novel copper binding drug that halts tumor growth by inhibiting angiogenesis. It is currently in human clinical trials and has also been found to be useful in fibrotic and inflammatory conditions such as arthritis.
Inhibition of Angiogenesis and Tumor Growth by Interleukin-12 in a Canine Hemangiosarcoma Xenograft Model - Improved treatment of cancer relies on models to test the safety and efficacy of innovative angiogenic therapies. Dr. Helfand has developed a mouse model from a cutaneous canine hemangiosarcoma to evaluate tumor treatment in his laboratory and is currently evaluating the effects of IL-12, which inhibits the neovascularization induced by hemangiosarcomas. I had approached his group about including the Saluki HSA samples in CHF Golden Retriever sponsored study last year. They declined because their procedure utilized fresh biopsy HSA samples and his lab was over extended. He said that the study exploring a tumor suppressor gene, PTEN, is not yielding the expected results.
Dietary and Environmental Risk Factors for Transitional Cell Carcinoma of the Urinary Bladder in Scottish Terrier Dogs: Preliminary Findings - Dr. Glickman, an epidemiologist, conducted a case-controlled study of histologically confirmed TCC in Scottish Terriers, the breed previously shown to be the highest risk. An owner questionnaire was used to assess potential host, environmental and dietary risk factors for affected and disease free dogs. His analysis showed an increased risk for dogs with a family history of TCC, increased weight, and regular exposure to the inert ingredients in lawn chemicals or flea and tick products. A protective effect was found with regular consumption vitamins and cruciferous vegetables (broccoli and cabbage) and a history of non-steroidal anti-inflammatory drug use. The data is being analyzed further to show that there are environmental factors as well as genetic predispositions that affect the TCC incidence. Dr. Glickman did express a willingness to assist in the formulation of a questionnaire to address the environmental influences in the development of HSA in Salukis.
Regulation of COX-2 Expression in Canine Cancer - Prostaglandins increase cell growth, invasiveness, angiogenesis, resistance to cell death and decrease immune response. COX is a rate-limiting enzyme in prostaglandin biosynthesis. Research has shown that COX-2 is elevated in some cancers and these cancer cells produce more prostaglandins. Non-steroidal anti-inflammatory drugs, which effect prostaglandins decrease the incidence of some cancers. Thus this study of COX inhibition might be used to prevent and treat some forms of cancer.
Of Mice & Men (and Dogs): Development of a Xenogeneic DNA Vaccine Program for Malignant Melanoma - Malignant melanoma is the most common oral tumor and if larger than 2cm at the time of removal it has already spread leading to rapid progression and death. It is not very responsive to chemotherapy. However, in Dr. Bergman's clinical trial, the vaccine derived from immunizing mice with DNA vaccines encoding human homologues of melanocytic differentiation antigens greatly prolonged the survival times of the dogs. Dogs with minimal disease always responded the best.
The complete conference proceedings are available online from International Veterinary Information Service (click here).