01889-G: Innovations in Prevention, Diagnosis, and Treatment of Cancer - Goldens Lead the Way

Grant Status: Closed

Grant Amount: $360,933
Dr. Jaime F Modiano, VMD PhD; University of Minnesota
January 1, 2014 - December 31, 2017
Sponsor(s): Golden Retriever Foundation, Akita Club of America, Inc., American Bullmastiff Association, American German Shepherd Dog Charitable Foundation, Inc., American Shih Tzu Club, Inc., Australian Shepherd Health & Genetics Institute, Basset Hound Club of America, Inc., Clumber Spaniel Health Foundation, English Cocker Spaniel Club of America, Flat-Coated Retriever Foundation, German Shorthaired Pointer Club of America, Inc., Gordon Setter Club of America, Inc., Irish Setter Club of America Foundation Inc., Jeffrey Pepper, Newfoundland Club of America Charitable Trust, Portuguese Water Dog Foundation, Rottweiler Health Foundation, Saluki Health Research, Inc., Starlight Fund, United States Australian Shepherd Association, Vizsla Club of America Welfare Foundation, Yorkshire Terrier Club of America Foundation, Inc.
Breed(s): Golden Retriever
Research Program Area: Oncology - Lymphoma

Abstract

Lymphoma and hemangiosarcoma are major health problems in Golden Retrievers, causing both suffering and premature death. Through ongoing collaboration, Drs. Jaime Modiano, Matthew Breen, and Kerstin Lindblad-Toh have identified several regions of the genome that contain genetic heritable risk factors for lymphoma and hemangiosarcoma in Golden Retrievers. They have tumor-specific mutations that occur recurrently in both cancers, some of which are linked to duration of remission when treated with standard of care. Their results indicate that a few heritable genetic risk factors account for as much as 50% of the risk for these cancers. These findings offer the potential to develop tests and strategies for DNA tests that can predict risk for individual dogs, as well as to manage risk across the population as a whole. Indeed, both the inherited risk factors and tumor mutations point to pathways that have been implicated in the pathogenesis of lymphoma and hemangiosarcoma, and thus should inform the development of targeted therapies. In the current study, Drs. Modiano, Breen, and Lindblad-Toh will find the precise mutations for the heritable genetic risk factors and to validate markers (mutations) used to determine risk at the heritable loci in a larger independent population of Golden Retrievers from the United States and from Europe in order to develop robust risk prediction tools and an accompanying DNA test. Further, they will identify and characterize tumor mutations and study their relationship to the heritable risk factors, tumor pathogenetic mechanisms, and disease outcome.

Publication(s)

-Borgatti, A., Koopmeiners, J. S., Sarver, A. L., Winter, A. L., Stuebner, K., Todhunter, D., … Vallera, D. A. (2017). Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR. Molecular Cancer Therapeutics.

-Gorden, B. H., Kim, J. H., Sarver, A. L., Frantz, A. M., Breen, M., Lindblad-Toh, K., ... & Dickerson, E. B. (2014). Identification of three molecular and functional subtypes in canine hemangiosarcoma through gene expression profiling and progenitor cell characterization. The American journal of pathology, 184(4), 985-995.

-Elvers, I., Turner-Maier, J., Swofford, R., Koltookian, M., Johnson, J., Stewart, C., ... & Thomas, R. (2015). Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background. Genome research, 25(11), 1634-1645.

-Seelig, D. M., Ito, D., Forster, C. L., Yoon, U. A., Breen, M., Burns, L. J., ... & Rizzardi, A. E. (2017). Constitutive activation of alternative nuclear factor kappa B pathway in canine diffuse large B-cell lymphoma contributes to tumor cell survival and is a target of new adjuvant therapies. Leukemia & lymphoma, 58(7), 1702-1710.

-Kim, J. H., Frantz, A. M., Sarver, A. L., Gorden Klukas, B. H., Lewellen, M., O'Brien, T. D., ... & Modiano, J. F. (2017). Modulation of fatty acid metabolism and immune suppression are features of in vitro tumour sphere formation in ontogenetically distinct dog cancers. Veterinary and comparative oncology.

-Im, K. S., Kim, J. H., Graef, A. J., Cornax, I., Seelig, D. M., O'Sullivan, M. G., ... & Modiano, J. F. (2017). Establishment of a Patient-Derived Xenograft of Canine Enteropathy-Associated T-Cell Lymphoma, Large Cell Type. Journal of comparative pathology, 156(1), 37-41.

-Im, K. S., Graef, A. J., Breen, M., Lindblad‐Toh, K., Modiano, J. F., & Kim, J. H. (2017). Interactions between CXCR4 and CXCL12 promote cell migration and invasion of canine hemangiosarcoma. Veterinary and comparative oncology, 15(2), 315-327.

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