Mitochondrial Dysfunction and mtDNA Mutations in Canine Hemangiosarcoma: Novel Biomarkers for Early Diagnosis and Personalized Therapy

Posted on by Crystal Smith

SUMMARY: Researchers will study if dysfunction of the mitochondria, the cell’s “powerhouses,” are drivers of tumor aggressiveness.

THE PROBLEM: Hemangiosarcoma is a highly aggressive and rapidly progressing cancer of dogs. Hemangiosarcoma is usually diagnosed when the tumor is in an advanced stage. Nearly 90% of all dogs die within the first year of diagnosis, and long-term survival is rare. New treatments are desperately needed.

THE PROJECT: Recent findings in human oncology strongly indicate that mitochondrial dysfunction serves as a crucial driver of cancer progression, metastasis, and treatment resistance. Unfortunately, there is a lack of information about how mitochondrial dysfunction could influence cancer progression dogs. This innovative study aims to address this critical gap by investigating mitochondrial dysfunction and associated mitochondrial DNA (mtDNA) mutations within canine HSA tumors. Utilizing advanced techniques, including spatial transcriptomics, cutting-edge mtDNA sequencing and comprehensive bioenergetic profiling, this study will identify regions of tumors exhibiting severe mitochondrial impairment and hyperactivation. Identifying region-specific mitochondrial dysfunction is vital, as it reveals different metabolic and genetic signatures directly linked to tumor aggressiveness. We hypothesize that region-specific mitochondrial dysfunction drives tumor aggressiveness through oxidative stress, mtDNA mutations, and synergy with oncogenic mutations.

POTENTIAL IMPACT: Identifying mitochondrial molecular signatures could lead to non-invasive blood-based biomarkers, enabling earlier detection and personalized therapies, offering new hope for veterinarians, pet owners, and affected dogs alike.

Co-sponsored with the Morris Animal Foundation, Grant Number: 26CAANFT-0005

RESEARCHERS

Krysztof Marycz, Ph.D, CVT; International Institute of Translational Medicine (MIMT)

Amount: $10,000

A combined sensor approach to examine volatile organic compounds as potential markers of canine hemangiosarcoma

Posted on by Crystal Smith

SUMMARY: Researchers will determine the volatile organic compound (VOC) profile of hemangiosarcoma using bio-detection dogs as a step toward a diagnostic test for the disease.

THE PROBLEM: Canine hemangiosarcoma (HSA) is a deadly cancer in dogs that is often diagnosed too late for effective treatment, making early detection crucial. Despite years of research, early detection of the disease remains elusive, and new approaches are needed.

THE PROJECT: This study aims to take the next step toward developing a simple, non-invasive test for HSA by identifying a specific odor fingerprint linked to the disease. Characterizing the VOC profile using analytical techniques is a vital step, providing foundational data that can benefit researchers across various disciplines. Trained bio-detection dogs have been able to correctly identify canine HSA blood serum samples from line-ups which included serum from healthy dogs and dogs unwell with other conditions, with an average accuracy of 71%. Building on this finding, the proposed study will chemically analyze the volatile organic compounds (VOCs), in the blood of dogs with confirmed HSA, healthy dogs, and dogs with other illnesses. These VOCs will be recreated as synthetic odors and presented to the trained dogs to help confirm which parts of the odor are most important for detecting the disease. While we do not anticipate the bio-detection dogs as part of the final diagnostic test, they serve as critical biosensors in this research. Their ability to detect specific odors present in HSA will help us define the VOC signature of the disease.

POTENTIAL IMPACT: This results from this study will inform the development of future non-invasive tests, like a blood test, that could be used in regular screenings for at-risk dogs, enabling earlier detection and improving survival rates.

Co-sponsored with the Morris Animal Foundation, Grant Number: 25CAINEI-0038

RESEARCHERS

Cynthia Otto, DVM, PhD,; University of Pennsylvania

Amount: $10,000

Studying Hemangiosarcoma Subtypes and Treatment Response

Posted on by Crystal Smith

SUMMARY: Researchers are studying if hemangiosarcoma subtypes influence how affected dogs respond to treatment – a step toward precision medicine for these  patients.

DESCRIPTION: Research suggests that hemangiosarcoma, a deadly cancer in dogs, is not one disease but made up of many different subtypes. The team found that dogs with one type of HSA are more likely to live longer than dogs that have a different  type of HSA. This may explain why current treatments fail to help most dogs with HSA live longer despite aggressive care. To address this issue, researchers will identify the HSA type or signature in tumors from dogs that have lived longer than other dog patients with HSA. The team is using data from a study in progress to inform their evaluation of archived tissues to assess prevalence and survival. They hope their  findings will help uncover the best treatment options for individual dogs with specific types of HSA and improve outcomes for this challenging canine cancer.

POTENTIAL IMPACT: If the team is successful, their findings could have a major impact  on how HSA is treated in dogs as well as provide information on long-term prognosis based on subtype. These results could help both veterinarians and pet parents make more informed decisions for dogs diagnosed with this terrible cancer.

Co-sponsored with the Morris Animal Foundation, Grant Number: D24CA-535

RESEARCHERS

Erin Dickerson, PhD; University of Minnesota

Amount: $10,000

Identification of Bartonella henselae Immunodominant Epitopes for Diagnosis and Prevention of Canine Bartonelloses

Posted on by Crystal Smith

Bartonella species are associated with severe diseases in dogs, including endocarditis, myocarditis, hepatitis, lymphadenitis, hemangiosarcoma, vasculitis, arthritis, uveitis,  meningitis, and others.

Despite diagnostic advances, current tests lack sensitivity. Bartonella infections pose a serious threat to dogs and public health due to potential transmission to humans. This study will identify Bartonella henselae B-cell and T-cell epitopes (parts of proteins recognized by the immune system) using immunoproteomic approaches. The results  will help develop a reliable ELISA diagnostic test and provide insights into proteins  that should be targeted in future vaccines to prevent Bartonella infection in dogs.

Relevance to PWDs: As with the companion Bartonella study, improved diagnostics  and potential preventive measures would benefit all breeds, especially those involved  in outdoor sports and activities.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 03337

RESEARCHERS

Edward Breitschwerdt, DVM, DACVIM; North Carolina State University

Amount: $5,000

Towards Curative Outcomes in Canine Hemangiosarcoma

Posted on by Crystal Smith

This nationwide clinical trial aims to achieve curative outcomes for 400 dogs with splenic hemangiosarcoma—a highly aggressive cancer that disproportionately affects  older, large breed dogs. Despite aggressive treatment, more than 50% of affected  dogs die within 6 months due to metastatic spread. The research will leverage  genomic insights to: (1) identify molecular biomarkers for prognosis; (2) define  genomic subgroups that may benefit from specific anticancer drugs; and (3) develop  new therapeutic approaches to prevent cancer spread. This approach follows the  roadmap used in transforming childhood leukemia from a fatal diagnosis to a commonly cured disease.

Relevance to PWDs: PWDs are at risk for hemangiosarcoma. This study could  transform treatment approaches for this devastating disease that currently has poor outcomes. The innovative approach could lead to personalized treatment protocols  and potentially curative therapies for affected dogs.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 02946

RESEARCHERS

Chand Khanna, DVM, PhD; Ethos Discovery

Amount: $10,000

Discovery of public tumorspecific neoantigens (pTSNAs) and pTSNAreactive T cells arisen from hotspot mutations in canine hemangiosarcoma

Posted on by PWDF Dev

Researchers will build on their discovery of “hotspot” mutations (tumor mutations shared between patients with the same cancer) to see if they can identify public tumor-specific neoantigens (pTSNAs) that are thought to play a role in immune response to cancer. Researchers hope findings will be a step toward a new immunotherapy that can be used in many different dogs suffering from hemangiosarcoma.

A no cost extension has been approved by MAF (April 2026) as a result of the following request of the researcher:

We request a one-year No-Cost Extension (NCE), extending the project end date to March 31, 2027, to investigate longitudinal T cell receptor (TCR) repertoire dynamics using yearly blood samples from healthy dogs and dogs that developed hemangiosarcoma, collected through the Golden Retriever Lifetime Study (GRLS). This work will be performed using our newly developed, highly innovative, dog[1]specific, rhPCR-based TCR-seq protocol (Aim 2). The study will provide novel insights into the role of TCR repertoire aging in hemangiosarcoma development and may identify potential biomarkers for disease detection and treatment response through liquid biopsy.

Our sample request has been approved by the GRLS committee, and we are currently in the process of selecting and receiving the samples. We will begin rhPCR TCR-seq analysis immediately upon sample arrival.

During the NCE period, we will also complete three manuscript submissions to peer-reviewed journals reporting our findings: 1) MHC-II genotyping results (Aim 1), 2) neoantigen discovery results (Aims 1 and 2), and 3) canine TCR repertoire characterization (Aim 2).

Co-sponsored with the Morris Animal Foundation, Grant Number: D24CA-536

RESEARCHERS

Shaying Zhao, PhD, University of Georgia
Amount: $10,000

Reprogramming the Tumor Immune Niche in Canine Hemangiosarcoma

Posted on by Janet Boyd

Hemangiosarcoma (HSA) is a common, devastating disease of dogs. The malignant tumor is seen frequently in older Golden Retrievers, German Shepherd Dogs, Portuguese Water Dogs, Labrador Retrievers, and Schnauzers, but it can occur in any dog of any breed at any age. Survival times of dogs with the tumor are short, even with surgical removal and standard of care treatment. Inflammation within the tumor tissue is common in canine HSA, and the immune response may contribute to tumor heterogeneity and prognosis for the dog. Yet, the immunological features in the context of the HSA niche are virtually unknown. The investigators have found that HSA cells have a strong capacity to promote proliferation and differentiation of hematopoietic stem and progenitor cells, with increased inflammatory cytokines, suggesting a niche regulatory function of HSA cells.

This study will focus on understanding the functional relationships between HSA cells and immune cells that contribute to the tumor niche to identify molecular mechanisms that regulate critical signaling pathways in canine HSA. This approach will improve our understanding of the tumor immunity and heterogeneity, as well as aid in patient selection for novel immunotherapies.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 2759

RESEARCHERS

Jong Hyuk Kim, DVM, PhD; University of Minnesota
Amount: $5,000

Strategic Prevention of Canine Hemangiosarcoma: Lifetime Follow-Up (Shine-On)

Posted on by Janet Boyd

The Shine On project is designed to utilize complementary technologies to reduce the impact of hemangiosarcoma in companion dogs. This novel, potentially disruptive approach is the first of its kind where artificial intelligence applied to the results of a blood test will be used to assign dogs to a risk category for the development of hemangiosarcoma. The test, called the Shine On Suspicion (SOS) Test is designed to detect hemangiosarcoma at its earliest stages of development before it becomes a clinically-detectable disease. Dogs that are considered to be at high risk based on the SOS Test results will be eligible to receive the drug eBAT for strategic prevention; that is, to eliminate emergent hemangiosarcoma tumors before they form. eBAT is a rationally designed drug developed in the laboratory to attack the cells that initiate and maintain the cancer, as well as to make the environment inhospitable for their growth.

For the initial phase of the Shine On project, investigators developed and refined the SOS Test and the artificial intelligence methods to assign dogs to specific diagnostic categories and started to establish the utility of the test in early detection in a group of 209 presumably healthy, pedigreed Golden Retrievers, Boxers, and Portuguese Water Dogs, 6 years of age or older.

In this continuation phase of the Shine On project, this group of dogs that had the SOS Test will be followed for their lifetimes to identify any diagnosis of cancer or another chronic disease, the cause of death, and date of death. In addition, a subset of dogs determined to be at high risk using the SOS Test will receive eBAT in the setting of prevention and also followed over their lifetime to establish their outcomes. This project expects to develop firm proof of concept to support larger clinical trials, and eventual deployment of this approach to the veterinary community setting for all dogs at risk of developing hemangiosarcoma.

Co-sponsored through the collaborative efforts and generosity of the Golden Retriever Foundation and American Boxer Charitable Foundation, Grant Number: 02806-MOU

RESEARCHERS

Jaime Modiano, VMD, PhD ; University of Minnesota
Grant Period: 8/1/2020 – 8/5/2025
Amount: $269,238

Clinical Trial for Evaluation of Propranolol and Doxorubicin in the Treatment of Canine Hemangiosarcoma

Posted on by Janet Boyd

Canine hemangiosarcoma is a largely incurable cancer in dogs, and treatment approaches to improve outcomes have remained relatively stagnant over the past few decades. Treatment remains a challenge partly because the cancer is frequently detected at an advanced stage and because these tumors are often resistant to chemotherapies. Recently published reports showed that propranolol, a drug used to treat heart disease in humans and dogs, substantially increased the survival time of human angiosarcoma patients when used in combination with standard of care treatments. Propranolol was also shown to sensitize hemangiosarcoma cells to doxorubicin, providing a more effective way to kill tumor cells. Because angiosarcoma is strikingly similar to canine hemangiosarcoma, this multi-institutional clinical trial has been designed to determine the efficacy of propranolol in dogs with hemangiosarcoma when used in combination with surgery and chemotherapy.

The main goal of the study is to establish whether propranolol in combination with doxorubicin following surgery improves outcomes for dogs when compared to the use of chemotherapy and surgery alone. The investigators will also evaluate the plasma concentrations of propranolol achieved during dosing to assess whether the levels of propranolol correlate to survival times. If successful, the findings from this approach will be rapidly conveyed to the veterinary community, and the guidelines provided to clinicians for the use of propranolol and doxorubicin for the treatment of canine hemangiosarcoma.

Co-investigators: David R. Brown, PhD, University of Minnesota; Michael O. Childress, DVM, MS, Purdue University; Jennifer Mahoney, DVM and Pascale Salah, DVM, University of Pennsylvania

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 02534

RESEARCHERS

Erin Dickerson, PhD and Brian Husbands, DVM; University of Minnesota
Amount: $10,000

Prevalence of Bartonella spp. Infection in Dogs with Cardiac and Splenic Hemangiosarcomas within and between Geographic Locations

Posted on by Janet Boyd

Splenic masses comprise ~50% of all canine splenic disease. Despite advances in imaging and pathologic definition, the etiology and medical relevance of splenic lesions in dogs are often ambiguous. While some splenic tumors are benign, approximately two-thirds are highly malignant and carry a poor prognosis. Hemangiosarcoma (HSA) accounts for the majority of canine malignant splenic tumors and occurs in many large dog breeds, including mixed breeds.A less common site of HSA localization is the heart (cardiac HSA). Risk factors for both cardiac and splenic HSA remain unclear, confounding development of preventative strategies.

The investigators recently reported a high prevalence of species of the bacterial genus Bartonella in dogs with HSA from North Carolina, suggesting a potential role in the initiation and/or progression of this cancer. Bartonella species exist worldwide and are transmitted by blood-sucking arthropods (e.g. ticks, fleas) and their presence in splenic tissue could potentially be explained by the fact that the spleen is primarily responsible for removal of blood-borne parasites from the systemic circulation.

The investigators will perform a comprehensive examination of the potential association between Bartonella infection and HSA by comparing the prevalence of Bartonella DNA in tumor and blood samples from both splenic and cardiac HSA cases, and also within and between distant geographical locations in the US. Ultimately, demonstration of a robust association between Bartonella infection and the development of HSA may lead to new opportunities for improved diagnosis, treatment and prevention of this devastating cancer.

Co-sponsored with the AKC Canine Health Foundation, Grant Number: 02519

RESEARCHERS

Edward Breitschwerdt, DVM
North Carolina State University Office of Sponsored Programs
Amount: $10,000 in 2018, $10,000 in 2019