01131: Genetic Background and the Angiogenic Phenotype in Cancer

Project Summary

Certain dog breeds are prone to develop certain types of cancer; yet, there has been little progress to define genes or other factors that account for this risk. Our recent work on hemangiosarcoma was the first to demonstrate that a dog's genetic background, defined by "breed," can influence the profile of genes that are expressed by tumors. Among other important implications, this implies that certain breeds are diagnosed with specific cancers more frequently than others because of the behavior of tumors after they arise, and not simply because they arise more frequently. Specifically, this may apply to the observed predisposition for hemangiosarcoma seen in Golden Retrievers, German Shepherd Dogs, and Portuguese Water Dogs. Here, we continued to test this premise by evaluating genome-wide gene expression profiles in samples from dogs of various breeds. Our results suggest that, while there are subtle differences that are influenced or modulated differently in tumors from dogs of different breeds, these differences may disappear when tumors are considered in their context as "tissues" that include microenvironment constituents. Rather, there appear to be distinct subtypes of hemangiosarcoma (perhaps with different biological behavior and prognosis?), which might arise from different cells of origin, or more likely, which develop in response to adaptation of the hemangiosarcoma cells to environments that show different patterns of inflammation, angiogenesis, coagulation, and hypoxia, each of which alters not only the predominant or favored differentiation of the tumor cells themselves, but also the way they instruct microenvironment cells to create a favorable niche. This underscores the importance of looking at these tumors in their context as "new tissues" or "new growths" rather than at the cells in isolation as we work to develop more effective strategies for detection, diagnosis, and therapy. To follow on this premise, we evaluated new therapy approaches that target both tumor and microenvironment compartments. Specifically, one such approach also shows efficacy to kill tumor-initiating cells. Data funded by this project grant and others allowed us to validate the therapy and move it to the clinic. Angiosarcoma Awareness, Inc. provided the initial funds to support a dose finding and efficacy trial where we will treat ~20 dogs with hemangiosarcoma using a bispecific ligand targeted toxin. We completed production of the molecule under "Good Manufacturing Practices" (i.e., suitable for use in human patients) and enrollment is ongoing. Finally, we identified other potential drugs to treat this disease - or perhaps more likely, the pathways they disrupt as potential targets for development of new therapies.

Publication(s)

Borgatti, A. (2014). Binding of VEGF-A to canine cancer cells with preferential expression of VEGFR1. Veterinary World, 7(1), 1–6. https://doi.org/10.14202/vetworld.2014.1-6

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. https://doi.org/10.1016/j.ajpath.2013.12.025

Kim, J.-H., Frantz, A. M., Sarver, A. L., Gorden Klukas, B. H., Lewellen, M., O’Brien, T. D., … Modiano, J. F. (2018). 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, 16(1), E176–E184. https://doi.org/10.1111/vco.12368

Kim, Jong-Hyuk, Frantz, A. M., Anderson, K. L., Graef, A. J., Scott, M. C., Robinson, S., … Modiano, J. F. (2014). Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment. Experimental Cell Research, 323(1), 155–164. https://doi.org/10.1016/j.yexcr.2014.02.020

Koopmeiners, J. S., & Modiano, J. (2014). A Bayesian adaptive Phase I-II clinical trial for evaluating efficacy and toxicity with delayed outcomes. Clinical Trials (London, England), 11(1), 38–48. https://doi.org/10.1177/1740774513500589

Rinz, C. J., Levine, J., Minor, K. M., Humphries, H. D., Lara, R., Starr-Moss, A. N., … Clark, L. A. (2014). A COLQ Missense Mutation in Labrador Retrievers Having Congenital Myasthenic Syndrome. PLoS ONE, 9(8), e106425. https://doi.org/10.1371/journal.pone.0106425

Schappa, J. T., Frantz, A. M., Gorden, B. H., Dickerson, E. B., Vallera, D. A., & Modiano, J. F. (2013). Hemangiosarcoma and its cancer stem cell subpopulation are effectively killed by a toxin targeted through epidermal growth factor and urokinase receptors: Bispecific ligand-targeted toxins. International Journal of Cancer, 133(8), 1936–1944. https://doi.org/10.1002/ijc.28187

Tonomura, N., Elvers, I., Thomas, R., Megquier, K., Turner-Maier, J., Howald, C., … Lindblad-Toh, K. (2015). Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers. PLOS Genetics, 11(2), e1004922. https://doi.org/10.1371/journal.pgen.1004922

Megquier, K., Turner-Maier, J., Swofford, R., Kim, J.-H., Sarver, A. L., Wang, C., … Lindblad-Toh, K. (2019). Comparative Genomics Reveals Shared Mutational Landscape in Canine Hemangiosarcoma and Human Angiosarcoma. Molecular Cancer Research, 17(12), 2410–2421 https://doi.org/10.1158/1541-7786.MCR-19-0221