Cancer is among the most common causes of death for dogs (and cats) and humans in the developed world, even though it is uncommon in wildlife and other domestic animals. We provide a rationale for this observation based on recent advances in our understanding of the evolutionary basis of cancer. Over the course of evolutionary time, species have acquired and fine-tuned adaptive cancer-protective mechanisms that are intrinsically related to their energy demands, reproductive strategies, and expected lifespan. These cancer-protective mechanisms are general across species and/or specific to each species and their niche, and they do not seem to be limited in diversity. The evolutionarily acquired cancer-free longevity that defines a species' life history can explain why the relative cancer risk, rate, and incidence are largely similar across most species in the animal kingdom despite differences in body size and life expectancy. The molecular, cellular, and metabolic events that promote malignant transformation and cancerous growth can overcome these adaptive, species-specific protective mechanisms in a small proportion of individuals, while independently, some individuals in the population might achieve exceptional longevity. In dogs and humans, recent dramatic alterations in healthcare and social structures have allowed increasing numbers of individuals in both species to far exceed their species-adapted longevities (by two to four times) without allowing the time necessary for compensatory natural selection. In other words, the cancer-protectiveThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Cancer mortality has surpassed all other causes of human death in parts of the developed world. Domestic dogs and cats are the only other species where cancer has an equivalent impact in overall mortality. Rapid gains in longevity over the past two centuries are sufficient to explain the increased incidence of cancer in all three species. Not only does longevity increase the probability of exposures to environmental mutagens, but it also allows for introduction of mutations in each somatic cell replication. In this context, an increase in the incidence of cancer becomes almost inevitable because the evolutionary, cancer protective adaptations of humans, dogs, and cats are insufficient to provide protection over the 2 to 6-fold extension in lifespan achieved by these species. We believe this problem is addressable by developing tests to detect malignancies at their earliest stages and pairing these tests with strategic interventions to eliminate tumors before they form. To test this premise, we have developed a blood test to detect the presence of hemangiosarcoma in dogs, a rapidly fatal malignancy. The shorter lifespan of dogs, compared to humans, and the similar shorter latency of disease provide an ideal opportunity to assess the feasibility of our approach. The test uses flow cytometry for detection of rare, non-leukocyte nucleated cells in blood, combining 42 parameters for analysis in a machine learning environment. Samples from 126 dogs with a confirmed diagnosis of hemangiosarcoma (n=28); other cancers (n=29); benign vascular pathology of the spleen (n=27); or apparently healthy and under 4 years of age (n=41) were used for training and 10-fold cross validation. The expected sensitivity and specificity for the diagnosis of hemangiosarcoma in this training set were approximately 90% and 95%, respectively. We then used our trained models to assign a risk category to apparently healthy dogs, 6 years of age or older, from three breeds with a predisposition for hemangiosarcoma (up to 20% lifetime risk): samples from 105 golden retrievers, 52 boxers and 52 Portuguese Water Dogs (N=209) were included in the study. Our results suggest that the probability of developing hemangiosarcoma or one of the other included pathological conditions within 6-18 months of testing was less than 2% in dogs with a negative result (low risk), but >90% in dogs with a positive result (high risk). We will follow the dogs in this study for the duration of their lifetime to assess the predictive value of the blood test over time. Dogs at high risk of hemangiosarcoma are eligible to receive eBAT, a drug capable of eliminating the cells that maintain and propagate the tumor, while making the environment inhospitable for tumor growth. This will provide means to explore the safety and efficacy of eBAT in the setting of prevention. This study serves as proof of concept for a new paradigm of early detection and strategic prevention to reduce the societal impact of canine and human cancers. Citation Format: Jaime F. Modiano, Taylor A. DePauw, Ali Khammanivong, Ashley J. Schulte, Amber L. Winter, Jong Kim, Kathleen Stuebner, Andrea Fahrenkrug, Daniel A. Vallera, Antonella Borgatti, Erin B. Dickerson, Michael S. Henson. Early detection for strategic prevention of a terminal canine cancer: A model to reduce the impact of cancer in our society [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4592.
Aims: We developed a test to detect hemangiosarcoma (HSA)-associated cells in the circulation of dogs prior to the onset of grossly detectable disease. Our objective is to assign dogs into risk categories for development of HSA, allowing for the rational deployment of eBAT, a drug to target the cancer-stem cell compartment and the tumor niche in these dogs, as an effective means for cancer prophylaxis. Methods: We used samples from 125 dogs (28 with hemangiosarcoma, 29 with other cancers, 27 with benign vascular pathology, and 41 for healthy) as a training set for machine learning. We used 10-fold cross validation, “leave-one-out” analyses to establish parameters of the test for detection of HSA-associated cells, and to determine sensitivity and specificity. We then applied the algorithms to a prospective cohort of 209 clinically healthy golden retrievers, boxers, and Portuguese Water Dogs older than 6 years of age as a validation set to assess the performance of the test in the early detection setting. Results: Using 10-fold cross validation, the test achieved a classification accuracy of 85% for healthy dogs and up to 89% for dogs with HSA, with 89% sensitivity and 95% specificity for detection of HSA. In the prospective cohort, more than 50% of clinically healthy dogs were categorized into one of the three conditions indicative of pathology (HSA, other cancer, benign splenic pathology). The test seems to have outstanding specificity and acceptable sensitivity for use in early detection: the false negative rate at 6-months after testing was <1% (1 of 99 dogs). Twenty-one dogs in the prospective cohort have developed cancer or another chronic condition. Nineteen that had a prediction of cancer-associated pathology were diagnosed with cancer (90%). Only two of these 21 dogs (10%) were misclassified. One had a prediction of cancer-associated pathology but died from a nonmalignant condition, and one had a prediction of “healthy” but died of cancer. Conclusions: We developed a blood test that can successfully detect the presence of HSA-associated cells in dogs with active disease, and that can be used in the early-detection setting to categorize risk of developing HSA. Our results from a prospective cohort of 200 dogs over 6 years of age suggest as many as 50% of these dogs have inapparent disease. The performance of the test is acceptable for use as an actionable component of a cancer prevention platform. Clinical Significance: To our knowledge, this is the first test that can accurately assign risk for development of hemangiosarcoma to clinically healthy dogs, providing a rationale for cancer chemoprophylaxis. Our study also provides proof of concept for prospective, large-scale trials for early cancer detection in companion dogs. Citation Format: Taylor A. DePauw, Ali Khammanivong, Jaime F. Modiano. A method for early detection of hemangiosarcoma in dogs [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B22.
Osteosarcoma is a rare disease with a disproportionate impact, as it is seen mostly in children and adolescents. Despite aggressive treatment, more than 50% of patients succumb to their disease within 10 years of diagnosis, making safe and effective treatments a huge unmet need. Immunotherapy, including immune checkpoint blockade, is drastically changing cancer treatment by increasing the antitumor immune response. Mechanisms of resistance to immune checkpoint blockade are incompletely understood; therefore, there is currently no available method to specifically identify patients who will respond favorably to immunotherapy. Exosomes are extracellular vesicles that can carry proteins, lipids, mRNA, microRNA, and DNA and play a role in extracellular communication. Exosomes can be found in circulation, making them an attractive tool for diagnostic testing. One potential mechanism of immunotherapy resistance could be destabilization of the CD28 coreceptor in T cells by microRNAs secreted in tumor-derived exosomes. Utilizing next-generation RNA-sequencing, we previously identified 2 microRNAs in dogs and 2 microRNAs in humans that were inversely correlated with CD28 expression in 44 human and 39 canine osteosarcoma tissues. Current work entails isolating exosomes from canine and human osteosarcoma tumor cell lines. Using a species mismatched approach, we can identify canine microRNAs in human T cells that were treated with canine exosomes, and vice versa, to verify delivery of microRNAs to T cells via tumor-derived exosomes. We are also using the CRISPR-Cas system to genetically engineer a human osteosarcoma cell line (HOS) that expresses the exosome marker CD63 linked to GFP so we can track exosome uptake by T cells by flow cytometry and determine the effect on CD28 expression levels. Identifying mechanisms of resistance will lead to improved patient selection and identification of therapeutic targets to combat this resistance. Citation Format: Ashley J. Schulte, Lauren J. Mills, Kelly M. Makielski, Taylor A. DePauw, Jaime F. Modiano. Impact of tumor-derived exosomes on CD28 expression in T cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A33.
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