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Hemangiosarcoma

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Canine hemangiosarcoma is an incurable tumor of cells that line blood vessels (endothelial cells). Based on current estimates of the lifetime risk of cancer in dogs and the prevalence of hemangiosarcoma, we predict that of 65 million pet dogs living in the United States today, as many as two million may get this cancer and die from it. Although dogs of any age and breed are susceptible to hemangiosarcoma, it occurs more commonly in dogs beyond middle age, and in breeds such as golden retrievers, German Shepherd Dogs, Portuguese Water Dogs, and Skye terriers, among others. Hemangiosarcoma is extremely indolent – that is, it develops slowly and is essentially painless – so clinical signs are usually not evident until the advanced stages when the tumors are resistant to most treatments. Less than 50% of dogs treated with standard-of-care of care for this tumor (surgery and intensive chemotherapy) survive more than six months. Many dogs die from severe internal bleeding before there is an opportunity to institute treatment. For this reason, our lab is working to develop a test for early detection, which will allow us to diagnose the disease before it is clinically evident. Similarly, a number of novel approaches using targeted therapies and tumor vaccines to treat canine hemangiosarcoma are in preclinical development or in the early stages of clinical testing.

The following article was prepared in collaboration with the Portuguese Water Dog Club of America and the Portuguese Water Dog Foundation:

Recent Advances in Hemangiosarcoma Research – Light at the End of the Tunnel

 

Jaime F. Modiano, VMD, PhD

Perlman Professor of Oncology and Comparative Medicine

Director, Animal Cancer Care and Research Program

College of Veterinary Medicine and Masonic Cancer Center, University of Minnesota

 

It has been a little over six years since we wrote the article, “Canine Hemangiosarcoma - the Road from Despair to Hope,” for the Courier (Vol. 35, Issue 1, pp. 48-51, 2007), also available on our website by clicking here. The intent of the present article is to update what we have learned since then about the causes and treatment options for this disease. It is worth noting that we have assembled a collection of Frequently Asked Questions (FAQs link), and the information included therein will not be duplicated here.

 

A Comprehensive Approach to Beat Canine Hemangiosarcoma

The landscape of canine hemangiosarcoma research continues to evolve. The past few years have shaken firmly held misconceptions and seen a convergence of research on hemangiosarcoma and angiosarcoma in dogs, humans, and laboratory animals. Our group has adopted a comprehensive strategy to attack canine hemangiosarcoma, including developing new therapies to help dogs currently with the disease and new methods to reduce the number of cases of hemangiosarcoma in the future. Our improved understanding of hemangiosarcoma has allowed us to make significant gains on both fronts of the battle against this aggressive tumor.

 

Advances in Therapy

Treatment options for canine hemangiosarcoma remain limited. Therapy is focused on reducing the likelihood of a lethal hemorrhagic event, and so the standard of care includes removal (whenever possible) of the primary tumor that is at greatest risk for bleeding, followed by adjuvant chemotherapy to delay tumor spread to other sites. The prognosis depends on the location of the tumor, the extent of metastatic disease, the presence of concurrent illness or other health problems (co-morbidities), and the choice of treatment; there is still much room for improvement on this front.

 

Our research into what causes hemangiosarcoma and how it progresses led us to design and test a totally new treatment strategy to track and kill the cells that are responsible for initiating and maintaining the tumor. This work, described in a recent publication in the International Journal of Cancer (Schappa et al, 2013), shows that we can deliver a genetically engineered, lethal bacterial toxin to the tumor cells and kill them with high specificity. Our targeting strategy not only enhances delivery to the tumor cells, but also opens a line to strike the blood vessels that feed the tumor, enhancing the potential efficacy of this compound in cancer patients (Oh et al, 2011). These promising results provided the necessary foundation for translation to the clinic with a new clinical trial, SRCBST, designed to treat dogs with hemangiosarcoma by testing a new drug that was developed at the University of Minnesota. Enrollment for this trial has begun and is expected to continue through 2014. Our design uses an innovative method that assesses safety and efficacy simultaneously. Additionally, we have built increments into the trial that will allow us to evaluate a new method for imaging -- positron emission tomography and x-ray computed tomography (PET-CT) -- to detect metastatic spread, including the presence of circulating tumor cells (CTCs), and to find minimal residual disease and relapse in treated patients.

 

Advances in Causation

Work from our lab and others has highlighted the heterogeneity of canine hemangiosarcoma and other sarcomas and demonstrated how normal cells in the tumor microenvironment contribute to this heterogeneity (Tamburini et al, 2010; Scott et al, 2011). The diversity of cells and the resultant range of clinical behaviors create both challenges and opportunities. Through some of our most recent efforts, we found that hemangiosarcoma tumors are highly dependent on the local environment to grow and survive. One component of this environment is inflammation. We found that an important mediator of inflammation, called interleukin-8, is essential to provide hemangiosarcoma tumors a favorable environment to grow and metastasize (Kim et al, 2012). Our research further showed canine hemangiosarcomas failed to establish tumors that survived in laboratory models when we interfered with the activity of this molecule, suggesting that anti-inflammatory strategies could be part of a comprehensive prevention program (Kim et al, 2014).

 

As part of another related but independent project, we have shown that the cells which maintain canine hemangiosarcoma have properties that are typically present in normal stem cells (Frantz et al, 2011; Gorden et al, 2011; Gorden et al, 2014). These properties include the capacity to differentiate along various pathways, to elude drug therapy, and to modulate the surrounding microenvironment to favor their growth and dissemination. In this regard, hemangiosarcoma shares some properties with other aggressive tumors, but it also has features that make it unique, different from virtually every other type of cancer. In our ongoing work, we seek to use this discovery to our advantage; by controlling their metabolism and by defining the signals that control the capacity of these hemangiosarcoma “cancer stem cells” to differentiate and become distinct cell types, we believe we may be able to convert these malignant, lethal cells into an innocuous, more benign tissue, like fat. This research is part of our multi-pronged approach to treat and control hemangiosarcoma and remains a major focus of our laboratories.

 

Advances in Risk Assessment and Prediction

Our important advances in treatment and causation are complemented by progress in our understanding of risk, which will allow us to develop robust strategies for prevention. As part of a multi-institutional collaboration with Dr. Kerstin Lindblad-Toh from the Broad Institute (Cambridge, MA) and Uppsala University (Sweden) and Dr. Matthew Breen from North Carolina State University (Raleigh, NC), we have identified heritable traits that contribute to risk of hemangiosarcoma in golden retrievers (Tonomura et al, 2012; Tonomura et al, 2014). We are currently using this information to design tests that can be used to predict and reduce hemangiosarcoma risk as part of breeding strategies. We also believe that understanding risk in one breed will inevitably help us to understand risk in others, thus allowing us to use genetic information and counseling to reduce the frequency of this disease.

 

Our results and our progress have not gone unnoticed by our physician colleagues. We are establishing new collaborations that will similarly help human patients with angiosarcoma.

 

How You Can Help

There are many ways to help our research. One is to spread the word about what we do. We benefit from the ability to reach a broader audience and from the opportunity to increase awareness about cancer in general and about hemangiosarcoma in particular. We are delighted when people give us feedback that helps us do our job better. We welcome comments and suggestions, which can be submitted through our website. Feedback is essential to help us align our priorities with those of the constituencies we serve. We also encourage people to visit our website (Study info page) as well as the website for our Clinical Investigation Center (CIC home) for updates on ongoing studies. There, you will also be able to obtain information on our research investigating other types of cancer as well as other diseases that are significant causes of morbidity and mortality in companion animals and humans alike. And finally, financial support is essential. Our ability to drive innovation and to stay at the forefront of cancer prevention and treatment requires flexibility to support talented faculty and students, as well as ongoing projects and new ideas.

 

References

 

Frantz AM, Gorden BH, Dickerson EB, O’Brien TD, Modiano JF (2011). Shared properties of tumor-initiating cells defined by sphere-forming culture of ontogenetically distinct cancers Proceedings Keystone Symp: Stem Cells, Cancer, and Metastasis C4

Gorden BH, Frantz AM, Ito D, Modiano JF, Dickerson EB (2011). Identification of a cancer stem cell-like population in canine hemangiosarcoma. Proceedings Keystone Symp: Stem Cells, Cancer, and Metastasis C4

Gorden BH, Kim JH, Sarver AL, Frantz A, Breen M, Lindblad-Toh K, O’Brien TD, Sharkey LC, Modiano JF, Dickerson EB. (2014). Identification of three molecular and functional subtypes in canine hemangiosarcoma through gene expression profiling and progenitor cell characterization. Am J Pathol, 2014 Feb 10. pii: S0002-9440(14)00030-3. doi: 10.1016/j.ajpath.2013.12.025. [Epub ahead of print]. PMID: 24525151

Kim JH, Frantz AM, Graef AJ, Hwang TH, Scott MC, Sarver AL, Sharkey LC, O’Brien TD, Dickerson EB, Modiano JF (2012). Relationship between IL-8 and Slug in proliferation and survival of canine hemangiosarcoma cells. Proceedings of the 2nd World Veterinary Cancer Congress

Kim JH, Frantz AM, Anderson KL, Graef AJ, Scott MC, Robinson SR, Sharkey LC, O’Brien TD, Dickerson EB, Modiano JF. (2014). Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment. Exp Cell Res, 2014 Feb 25. pii: S0014-4827(14)00083-4. doi: 10.1016/j.yexcr.2014.02.020. [Epub ahead of print]. PMID: 24582862

Oh S, Tsai AK, Ohlfest JR, Panoskaltsis-Mortari A, Vallera DA (2011). Evaluation of a bispecific biological drug designed to simultaneously target glioblastoma and its neovasculature in the brain. J Neurosurg. 2011 Jun;114(6):1662-71. PMID: 21294620

Schappa JT, Frantz AM, Gorden BH, Dickerson, EB, Vallera DA, Modiano JF. (2013). Hemangiosarcoma and its cancer stem cell subpopulation are effectively killed by a toxin targeted through epidermal growth factor and urokinase receptors. Int J Cancer, 133(8), 1936-1944. PMID: 23553371

Scott MC, Sarver AL, Gavin KJ, Thayanithy V, Getzy DM, Newman RA, Cutter GR, Lindblad-Toh K, Kisseberth WC, Hunter LE, Subramanian S, Breen M, Modiano JF (2011). Molecular subtypes of osteosarcoma identified by reducing tumor heterogeneity through an interspecies comparative approach. Bone, 49, 356-367. PMCID: PMC3143255

Tamburini BA, Phang TL, Fosmire S, Trapp S, Slansky J, Sharkey LC, Cutter GR, Bellgrau D, Gemmill RM, Hunter LE, Modiano JF (2010). Gene expression profiling identifies inflammation and angiogenesis as distinguishing features of canine hemangiosarcoma. BMC Cancer, 10, 619. PMCID: PMC2994824

Tonomura N, Thomas R, Megquier K, Perloski M, Swofford R, Davis B, Barber L, Burgess K, Azuma C, Modiano JF, Breen M, Lindblad-Toh K (2012). GWAS identifies risk loci for two hematologic malignancies in golden retriever. Proceedings of the 6th International Conference on Advances in Canine and Feline Genomics and Inherited Disease

Tonomura N, Thomas R, Karlsson E, Megquier K, Turner-Maier J, Sarver AL, Frantz AM, Ito D, Elvers I, Mauceli E, Arendt M, Howald C, Perloski M, Swofford R, Kim JH, Barber L, Burgess K, Lander E, Azuma C, Modiano JF, Breen M, Lindblad-Toh K (2014). Submitted for publication