BACKGROUND:Immune checkpoint inhibitors (ICIs) have transformed oncology in human medicine, providing clinical benefit in a broad spectrum of cancers. Widely available ICIs for dogs are lacking. HYPOTHESIS/OBJECTIVES:Evaluate efficacy and safety of gilvetmab, a caninized anti-PD-1 monoclonal antibody. ANIMALS:Fifty-one client-owned dogs were evaluated, 25 with stages II-III melanoma and 26 with stages I-III mast cell tumor (MCT). Fifteen dogs with stages III-V lymphoma were also evaluated. METHODS:Multi-institutional, open-label study. Enrolled dogs were treated with gilvetmab IV at 6 mg/kg q28d or 10 mg/kg q14d; 8 dogs receiving the lower dosage underwent dose escalation with their owners' consent. Safety was evaluated by physical examinations, laboratory testing, and clinical observations made by veterinarians or the dogs' owners. Efficacy was assessed by objective response rate (ORR) and time to progression (TTP) using cRECIST v1.0 and lymphoma response criteria. RESULTS:For melanoma, the ORR was 20% (95% confidence interval [CI], 7%-41%) and median TTP was 56 days. For MCT, the ORR was 46% (95% CI, 27%-67%) and median TTP was not reached. No objective responses were observed in dogs with lymphoma. Serious adverse events of anaphylaxis, hypotension, or tumor hemorrhage occurred in 3 dogs (3/51, 5.9%). Tumor enlargement before regression, consistent with possible pseudoprogression, was observed in 2 dogs with melanoma. CONCLUSIONS AND CLINICAL IMPORTANCE:Gilvetmab has a reasonable expectation of efficacy and an acceptable preliminary safety profile in dogs with MCT stages I-III and melanoma stages II and III.

Abstract Angiosarcoma (AS) is a rare and aggressive endothelial malignancy, representing <2% of soft tissue sarcomas in humans. Progress in developing effective therapies has been hindered by its low incidence, genomic heterogeneity, and the scarcity of representative preclinical models.Integrative genomic analyses of two cBioPortal cohorts (n=131) identified recurrent alterations in TP53 (26%), KDR (17.6%), POT1 (17.6%), PIK3CA (14.5%), FLT4 (11.5%), PTPRB (11.5%), and NRAS (5.3%), highlighting pervasive disruptions of DNA damage response, PI3K/AKT/mTOR, and angiogenic receptor signaling. However, the rarity of AS limits functional validation and biomarker-driven therapy development.Canine hemangiosarcoma (HSA) is a biologically analogous vascular tumor that occurs spontaneously with far higher incidence, offering a unique opportunity to model AS in an immunocompetent host. Large-scale profiling of HSA from the FidoCure Precision Medicine Platform (n=1,177) revealed overlapping mutations in TP53 (54.9%), PIK3CA (29.9%), NRAS (15.3%), FLT4 (3.6%), PTEN (3.4%), and KDR (2.6%), mirroring the human landscape.Cross-species analyses showed striking molecular parallels. PIK3CA mutations in both species clustered in the helical and kinase domains, consistent with pathway activation. While mutation at the canonical hotspot (H1047R/L/Y) predominated in HSA, AS was found to harbor heterogeneous variants (P124L, T957P, M1043V/I). TP53 variants localized to conserved DNA-binding regions (human R175, R248, R273; canine R164H, C228R/Y, R263H, R272H), indicating convergent loss of tumor-suppressor function. KDR, NRAS, and PTEN alterations similarly disrupted VEGFR2, RAS/MAPK, and PI3K signaling pathways across species.Collectively, these findings reveal deep evolutionary conservation of molecular drivers in vascular sarcomagenesis. Canine HSA faithfully recapitulates the genetic complexity and therapeutic vulnerabilities of human AS, establishing a robust comparative platform for biomarker discovery, targeted therapy validation, and translational oncology research within an immunocompetent context. Citation Format: Lucas Rodrigues, Garrett Harvey, Gerald Post, Benjamin Lewis, Abigail Hull, Aubrey O'Grady, Lindsay Lambert, Christina Lopes, Thaddeus Allen. Conservation of driver mutations and oncogenic pathway alterations revealed through a comparative genomic analysis of human angiosarcoma and canine hemangiosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5572.

Splenic hemangiosarcoma (HSA) is a common canine tumor with histology and genetics analogous to human angiosarcoma (AS), a rare and aggressive malignancy arising from vascular cells. To assess biomarkers and inform therapeutics options, spontaneously arising HSAs were systematically profiled for genetic mutations prior to long-term assessment of patient response to chemotherapy and/or targeted therapy. We leveraged the real-world clinical-genomic data of dogs from the FidoCure® platform, a next-generation sequencing (NGS) screen of cancer loci. For all dogs, regardless of therapeutic approach, PTEN and P53 mutations were overall predictors of poor outcome, while NRAS mutation predicted better outcome. However, P53, PIK3CA, ATRX and NRAS predicted a better response to therapies that specifically included a targeted drug. Analyzing gene-drug interactions, we found tumors with P53 mutation were highly responsive to HDAC or MTOR inhibition, while tumors with PIK3CA mutation only predicted response to MTOR inhibition. For veterinarians, this real-world evidence bridges an important translational gap for targeted therapies, demonstrating a comparable or better outcome compared to standard adjuvant chemotherapy alone and an even further enhancement of survival with combined targeted therapy and chemotherapy. The investigation also uncovered a relationship between specific therapeutic interventions and outcomes when particular gene mutations were present, suggesting they could serve as biomarkers. Since canine HSA is a likely correlate for human AS, the study highlights the benefit of canine HSA as a model to inform precision medicine for AS, a rare human malignancy.

Osteosarcoma (OS) is the third most prevalent tumor in adolescence, histologically characterized by the proliferation of abnormal osteoid-producing mesenchymal cells. Surgery remains the primary approach for OS treatment, but outcomes are poor without chemotherapy. Combining surgery, radiotherapy, and chemotherapy has improved results, yet 5-year survival rates persist at 60-70%. Despite advances in molecular medicine, progress in the treatment of OS has been limited, no significant breakthroughs have been achieved in systemic therapy, particularly for relapsed OS. Additionally, there is no consensus on the optimal treatment for these cases, leaving a substantial unmet need for effective therapies.Precision medicine trials (PMTs) have gained traction due to the ability to map the genomic profiles of individual tumors and match them to targeted therapies, but is still a challenge for OS due to limited efficacy and low enrollment rate. This low enrollment rate is due to several challenges, including tumor heterogeneity, limited molecular targets, and logistical in conducting trials. These barriers hinder the full realization of the potential benefits of PMTs to improve patient outcomes. One promising avenue is the use of naturally occurring canine OS, which share strong biological and molecular similarities with humans. Canine OS is estimated to be 10 times more common in pet dogs than in humans. Moreover, dogs develop these tumors spontaneously, with an intact immune system and comparable environmental exposures to humans, making them a valuable model for studying OS and improving the design of human trials. This study leverages data from 202 spontaneous canine OS, aiming to bridge the gap between preclinical investigations and clinical application. We utilized real-world clinical-genomic data from the FidoCure® platform, a canine precision medicine initiative that uses next-generation sequencing (NGS) to screen for cancer-associated genomic alterations. We identified that the most common genomic alterations occurred in tumor suppressor genes TP53, SETD2, PTPRJ, PTEN, RB1, DMD, BRCA1/2, and oncogene PIK3CA. These findings are consistent with the genomic profile seen in humans, reinforcing the value of the canine model. We also analyzed the correlation between small-molecule targeted therapies and genomic alterations. Through FidoCure®, veterinarians can leverage insights from the NGS panel to apply any of 11 human-approved therapies. Our analysis identified significant benefits from small-molecules when used as adjuvant treatment alongside chemotherapy with median survival of 354 days compared to 194 days when just chemotherapy is used (P=0.0011). Our study demonstrates the potential of combining small-molecule targeted therapies with traditional treatments, emphasizing the value of cross-species models in advancing osteosarcoma research and treatment. Lucas Rodrigues, Kevin Wu, Garrett Harvey, Gerald Post, Aubrey Miller, Lindsay Lambert, Christina Lopes, James Zou. Leveraging canine osteosarcoma as a model to advance precision medicine and targeted therapies in human osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3914.

Abstract The widespread application of Poly-ADP ribose polymerase (PARP) inhibitors in anti-cancer therapy is constantly increasing their role as a treatment strategy across various neoplasms, the majority of which are linked with BRCA deficiency. While the most significant advantages are observed in cancers with BRCA1/2 mutations, it is evident that the benefits extend beyond this specific group. Preclinical evidence encourages the exploration of PARP inhibitors in neoplasms demonstrating BRCAness or homologous recombination deficiency (HRD), both as monotherapy and in combination with chemotherapy. This study employs spontaneous canine tumors as a complementary model for cancer research, aiming to seamlessly bridge the transition from preclinical investigations to clinical application. Leveraging the FidoCure® Precision Medicine Platform, we identified biomarkers associated with prognosis and treatment prediction, specifically with the PARP inhibitor olaparib, facilitating a smoother translation from laboratory findings to practical clinical use. Analyzing real-world clinico-genomic data from 1278 dogs with cancer revealed intriguing insights of specific targeted treatments developed for humans showing a positive prognosis when applied to canine tumors with specific genomic alterations. Notably, olaparib exhibited efficacy in TP53 and BRCA1-mutated cases (OS HR 0.34, P < 0.001; HR 0.39, P = 0.004), while rapamycin (mTOR inhibitor) demonstrated promising outcomes in TP53 and RB1-mutated canine tumors (OS HR 0.73, P = 0.028; HR 0.32, P = 0.024). Further stratification by tumor types unveiled noteworthy correlations. TP53 mutant osteosarcomas exhibited improved prognosis with olaparib treatment (OS HR 0.11, P < 0.001), and soft tissue sarcomas with TP53 mutations demonstrated favorable responses to rapamycin and olaparib therapy (OS HR 0.11, P = 0.012; HR 0.07, P = 0.011). These findings underscore the potential of leveraging canine tumor models and clinico-genomic analyses to inform targeted treatment strategies, offering valuable insights for advancing precision medicine in both veterinary and human oncology. Further investigation into the association between TP53 mutation and olaparib response is warranted. The intriguing aspect lies in the role TP53 mutation has been linked in previous studies to heightened chromosomal instability and elevated HRD scores. Utilizing real-world evidence and data tools within the FidoCure dataset, we have effectively pinpointed correlations between gene mutations and survival, particularly in relation to responses to targeted therapy treatment. Canine models, mirroring human diseases with intact immune systems and comparable tumor genomic profiles, as verified by the FidoCure database, expedite clinical studies of novel treatments that face significant scalability challenges. Citation Format: Lucas Rodrigues, Kevin Wu, Garrett Harvey, Gerald Post, Abigail Hull, Aubrey Miller, Lindsay Lambert, Christina Lopes, James Zou. Expanding the therapeutic application of PARP inhibitor: AI evaluation of real-word clinico-genomic data from spontaneous canine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1454.

Precision medicine focuses on the clinical management of the individual patient, not on population-based findings. Successes from human precision medicine inform veterinary oncology. Early evidence of success for canines shows how precision medicine can be integrated into practice. Decreasing genomic profiling costs will allow increased utilization and subsequent improvement of knowledge base from which to make better informed decisions. Utility of precision medicine in canine oncology will only increase for improved cancer characterization, enhanced therapy selection, and overall more successful management of canine cancer. As such, practitioners are called to interpret and leverage precision medicine reports for their patients.

Quality of life (QOL) in dogs with cancer is a key consideration in the assessment of cancer treatment options. Despite interest in dietary strategies to improve management of oncology patients, there have been very few clinical studies showing the impact of diet on adverse effects of chemotherapy in dogs. This study was a randomised, controlled, double-blinded, multicenter clinical trial to investigate a high-protein, increased-fibre diet supplemented with omega-3 fatty acids, for dogs with cancer undergoing standard-of-care chemotherapy. Client-owned dogs with newly diagnosed grade 2 or higher mast cell tumours (or non-resectable/incompletely resected tumours) or multicentric lymphoma were randomised to receive the test diet (n = 24) or control diet (n = 21) for 8 weeks. Primary outcomes were QOL assessments, faecal scores, and blood concentrations of C-reactive protein and monocyte chemoattractant protein-1. Of 12 QOL parameters, 10 significantly improved from baseline to Week 8 in the test group compared with one in the control group. However, differences between the two groups were only statistically significant for 'frequency of signs of illness' (P = .009). There were no significant differences in the incidence of any adverse events, including gastrointestinal adverse events or clinically significant differences in laboratory parameters or faecal scores between the two groups. The absence of an observed negative impact of the test diet, combined with the magnitude of QOL improvements associated with the diet, suggest that a larger trial is warranted.

Table S1: KTN0158 Dosing Cohorts Table S2: Summary of Anti-KTN0158 Antibody Titers in Dogs with Mast Cell Tumors Following KTN0158 Treatment

Skin tumors are the most common type of neoplastic lesion affecting humans and dogs, and their incidence is increasing for both species. Skin tumor initiation and progression are associated with chronic exposure to ultraviolet (UV) radiation, mainly for light-skinned individuals, that can activate different oncogenes and pathways. Solar UV-induced mutations, characterized by C to T or CC to TT mutations, are well described in the TP53 gene in human skin cancers such as ​​basal cell carcinoma, squamous cell carcinoma and melanoma. This study evaluated TP53 mutations in 2201 canine tumors enrolled in FidoCure Precision Medicine Platform. Tumors were classified in 26 different types according to their histology and anatomic location. Gastrointestinal tumors, insulinomas and mesotheliomas did not carry any TP53 mutation as opposed to cutaneous squamous cell carcinoma (CSCC) and cutaneous hemangiosarcoma (CHSA) that had higher number of TP53 mutations in 88.9% and 77.8% of cases, respectively. Canine CSCC had a similar frequency of TP53 mutations compared to humans, previously identified in 83.64% of cases (MSKCC, Nat Med 2017). The C to T transitions were the most prevalent type of mutations in both canine CSCC and CHSA representing 66.67% and 55.55% of TP53 mutations, respectively. On the other hand, C>T corresponded to just 23.36% of TP53 mutations for the other 24 tumor types. R261H, G290R, R184*, S229F, N143K and R201* variants were identified more than 10 times in all canine tumors. Canine CSCC and CHSA were enriched with R201* (P<0.0001; P=0.004) and R184*(P<0.0001; P=0.048). These two nonsense variants are C>T changes at the position 601 and 550, respectively. They are homologous to human R213* (637C>T) and R196* (586C>T). Canine R201* was identified in 44.4% of CSCC, and human R213* in 73.91% of cases (MSKCC, Nat Med 2017). This study identified a high frequency of TP53 mutations in canine cutaneous tumors consistent with solar induced lesions. These results position canines as excellent spontaneous models of human solar induced cancers that can be utilized to elucidate elements of cancer biology, prognosis and responses across a wide spectrum of therapies. Citation Format: Lucas Rodrigues, Thaynan Vieira, Garrett Harvey, Dorothy Girimonte, Gerald Post, Lindsay Lambert, Aubrey Miller, Abigail Hull, Chase Schwalbach, Christina Lopes, Michelle White. High frequency of TP53 mutations in canine skin tumors recapitulates solar induced human lesions representing an important research model of spontaneous diseases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 55.

Serum KTN0158 concentration over time

Supplementary Movie 1 from Hydrophilic Agarose Macrobead Cultures Select for Outgrowth of Carcinoma Cell Populations That Can Restrict Tumor Growth

Canine hemangiosarcoma (HSA) is an aggressive cancer of endothelial cells with short survival times. Understanding the genomic landscape of HSA may aid in developing therapeutic strategies for dogs and may also inform therapies for the rare and aggressive human cancer angiosarcoma. The objectives of this study were to build a framework for leveraging real-world genomic and clinical data that could provide the foundation for precision medicine in veterinary oncology, and to determine the relationships between genomic and clinical features in canine splenic HSA. One hundred and nine dogs with primary splenic HSA treated by splenectomy that had tumour sequencing via the FidoCure (R) Precision Medicine Platform targeted sequencing panel were enrolled. Patient signalment, weight, metastasis at diagnosis and overall survival time were retrospectively evaluated. The incidence of genomic alterations in individual genes and their relationship to patient variables including outcome were assessed. Somatic mutations in TP53 (n = 44), NRAS (n = 20) and PIK3CA (n = 19) were most common. Survival was associated with presence of metastases at diagnosis and germline variants in SETD2 and NOTCH1. Age at diagnosis was associated with somatic NRAS mutations and breed. TP53 and PIK3CA somatic mutations were found in larger dogs, while germline SETD2 variants were found in smaller dogs. We identified both somatic mutations and germline variants associated with clinical variables including age, breed and overall survival. These genetic changes may be useful prognostic factors and provide insight into the genomic landscape of hemangiosarcoma.

Naturally occurring canine cancers have remarkable similarities to their human counterparts. To better understand these similarities, we investigated 671 client-owned dogs from 96 breeds with 23 common tumor types, including those whose mutation profile are unknown (anal sac carcinoma and neuroendocrine carcinoma) or understudied (thyroid carcinoma, soft tissue sarcoma and hepatocellular carcinoma). We discovered mutations in 50 well-established oncogenes and tumor suppressors, and compared them to those reported in human cancers. As in human cancer, TP53 is the most commonly mutated gene, detected in 22.5% of canine tumors overall. Canine tumors share mutational hotspots with human tumors in oncogenes including PIK3CA , KRAS , NRAS , BRAF , KIT and EGFR . Hotspot mutations with significant association to tumor type include NRAS G61R and PIK3CA H1047R in hemangiosarcoma, ERBB2 V659E in pulmonary carcinoma, and BRAF V588E (equivalent of V600E in humans) in urothelial carcinoma. Our findings better position canines as a translational model of human cancer to investigate a wide spectrum of targeted therapies.

In recent years, clinico-genomic databases integrating real-world data (RWD) from electronic health records and tumor genomic profiles have been used to expedite development of new, precision medicine therapies for cancer treatment. Clinical trials in humans for new targeted therapies are often limited to approved use only as second- or third-line chemotherapies, complicating the ability to make conclusions about the efficacy of the drug alone. Pre-clinical trials in murine models with induced or xenograft tumors often fail to predict response in the intended human population. Several studies have qualified spontaneous tumors in dogs as important models for human cancers. Tumors in dogs are highly similar to human cancers histologically, genetically, molecularly and clinically, which provides an opportunity to investigate biomarkers and outcomes. Canine cancers progress over an accelerated timeline compared to human cancers due to several factors including differences in expected lifespan. Additionally, more flexibility exists in treatment options for canine cancers than in the more tightly regulated and standardized human care model. These key similarities and differences make dogs a powerful model for cancer research including interrogating the clinical benefit of new and existing cancer therapies. Over 3,500 dogs have enrolled into the FidoCure® Precision Medicine Platform. Our current, ongoing studies use clinico-genomic data from dogs with cancer including those with naïve or early stage tumors as a tool to evaluate and inform clinical response to small-molecule targeted therapies, and our model allows for expansion into trials for additional, diverse therapy types. Using the FidoCure® Next-Generation Sequencing (NGS) panel, molecular targets are identified in canine tumors for treatment regimens with one or combinations of 12 small molecules approved for use in humans. Clinical information and outcomes data from participating dogs is collected and analyzed. In an unbiased, AI-driven analysis of our dataset, several significant prognostic findings with translational relevance included association of TP53 mutations with worse prognosis (OS HR 1.48, P<0.01) across 14 canine tumor types. Conversely, ATM and KIT mutations were associated with better prognosis (OS HR) of 0.51 and 0.43, respectively (P=0.01, P=0.02). We are now developing a tool called Fetch for real-time exploration of our dataset for use by external partners including clinicians and biopharmaceutical collaborators to visualize correlations between single or combinations of factors such as cancer type, breed, gene mutated, and treatment regimen with survival outcomes in our canine patient population. This tool can accelerate R&D by making real-time, real-world data on thousands of dogs with translationally relevant disease available to clinicians and researchers looking to advance cancer treatment. Citation Format: Chase Schwalbach, Lucas Rodrigues, Garrett Harvey, Dorothy Girimonte, Gerald Post, Lindsay Lambert, Aubrey Miller, Abigail Hull, Christina Lopes, Michelle E. White. Use of real-world data of dogs with cancer to drive drug development strategy and inform human clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 934.

Spontaneous tumors in canines share significant genetic and histological similarities with human tumors, positioning them as valuable models to guide drug development. However, current translational studies have limited real world evidence as cancer outcomes are dispersed across veterinary clinics and genomic tests are rarely performed on dogs. In this study, we aim to expand the value of canine models by systematically characterizing genetic mutations in tumors and their response to targeted treatments. In total, we collect and analyze survival outcomes for 2119 tumor-bearing dogs and the prognostic effect of genomic alterations in a subset of 1108 dogs. Our analysis identifies prognostic concordance between canines and humans in several key oncogenes, including TP53 and PIK3CA. We also find that several targeted treatments designed for humans are associated with a positive prognosis when used to treat canine tumors with specific genomic alterations, underscoring the value of canine models in advancing drug discovery for personalized oncology.

Canine cancer patients represent an important translational model for human cancer research with their spontaneous tumor pathogenesis and the many histological, genetic, molecular and clinical similarities between canine and human tumors. Canine tumors provide an opportunity to investigate shared biomarkers and their response to therapeutic interventions over an accelerated timeline compared to human cancers due to differences in expected lifespan and other factors. Dogs, like humans, have three related RAS genes, HRAS, KRAS, and NRAS, with extremely similar genetic sequence and resultantly high protein homology. These proteins have many key molecular functions including roles in cell proliferation and survival. Across multiple human cancer types, recurrent gain-of-function missense mutations in the RAS-family genes occur primarily at codons 12, 13, and 61. These mutations result in constitutively active RAS proteins. The frequencies of mutations across the three RAS genes and codons have been hypothesized to lead to distinct biological behaviors. Mutations are most common in KRAS, then NRAS followed by HRAS. We investigated RAS-family genetic mutations in a dataset of 213 canine patients with hemangiosarcoma (HSA), a common, aggressive malignancy derived from endothelial cells for which treatment with both surgery and traditional chemotherapies often fail to prolong survival beyond six months. Recent publications show that genomic profiling of canine HSA tumors can help group tumors into subtypes with potential for guiding therapy selection and improving outcomes. All 213 dogs had tumor tissue sequenced via the FidoCure® Precision Medicine Platform targeted sequencing panel and were followed until time of death or were censored to the date patients were last known to be living. All SNVs and Indels detected were missense mutations. Unlike human pan-cancer data, somatic mutations in NRAS (n=32) were most common with only 1 dog with a somatic KRAS mutation and no dogs with somatic HRAS mutations. Similar to human RAS mutations, affected codons were primarily codon 61 (n=28), codon 13 (n=5), and codon 12 (n=1). Pairwise survival comparisons between dogs with missense mutations in NRAS codon 61 showed that this mutation was associated with better prognosis (n=28, MST 251 [CI 213;327]) compared to dogs with missense mutations at other codons in the NRAS and KRAS genes (n=5, MST 66 [CI 64;NA], p=1.58E-05) and compared to dogs without missense mutations in the RAS family of genes (n=180, MST 123 [CI 100;149], p=0.036). These preliminary findings of similarities between canine and human tumors and associations between mutated codons and prognosis in our growing dataset create an important opportunity to accelerate cancer research, including clinical and biopharmaceutical studies, with great potential benefit to both dogs and humans. Citation Format: Michelle E. White, Garrett Harvey, Lucas Rodrigues, Chase Schwalbach, Dorothy Girimonte, Aubrey Miller, Abigail Hull, Lindsay Lambert, Christina Lopes, Gerald Post. Canine hemangiosarcoma as a model for RAS-mutated human cancers: Preliminary data [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr A005.

ABSTRACT Background Canine hemangiosarcoma (HSA) is an aggressive cancer of endothelial cells associated with short survival times. Understanding the genomic landscape of HSA is critical to developing more effective therapeutic strategies. Objectives To determine the relationships between genomic and clinical features including treatment and outcome in canine splenic HSA. Animals 109 dogs with primary splenic HSA treated by splenectomy that had tumor sequencing via the FidoCure® Precision Medicine Platform targeted sequencing panel. Methods Patient signalment, weight, metastasis at diagnosis, treatment, and survival time were retrospectively evaluated. The incidence of genomic alterations in individual genes and their relationship to patient variables and outcome were assessed. Results Somatic mutations in TP53 (n = 45), NRAS (n = 20), and PIK3CA (n = 19) were most common. Survival was associated with metastases at diagnosis, germline variants in SETD2 and NOTCH1 , and nominally with breed. Age at diagnosis was associated with NRAS mutations and breed. TP53 and PIK3CA mutations were found in larger dogs, germline SETD2 variants in smaller dogs. Doxorubicin (DOX) treatment did not significantly improve survival time, while targeted therapies had a significant early survival benefit. Conclusions and clinical importance DOX treatment may provide limited clinical benefit for dogs with splenic HSA, while targeted therapy may provide early survival benefit. Genetic signatures associated with splenic HSA may be useful in guiding targeted therapy to improve outcomes. Germline variants, age, size, and breed may be useful prognostic factors and provide insight into the genomic landscape of the tumor.

Spontaneous tumors in dogs are highly similar to human cancers histologically, genetically, molecularly and clinically. In this presentation we explore similarities found across species when associating cancer biomarkers and outcomes. Our findings validate concordance across the cancer journeys. This is important to deepen the field of comparative oncology and affirming spontaneous cancer in dogs as an ideal ‘model’ for precision oncology, building upon recent work in tumor biology concordance. Our machine learning analysis prognosis and predictive effect of genomic alterations in 1303 client-owned tumor-bearing dogs identified TP53 and PTPRD as prognostic markers for poor survival in dogs with an overall survival hazard ratio (OS HR) of 1.732, 1.914, respectively (P<0.001 and P=0.023). These results are aligned with non-small cell lung cancer, metastatic breast cancer and pancreatic cancer in people correlated with poor survival when carrying TP53 mutation, and PTPRD also correlated with poor survival in gliomas. Besides that, we also identified ALB1 and PIK3CA prognostic markers for poor survival in canine tumors with an overall survival hazard ratio (OS HR) of 1.707, 1.689, respectively (P=0.01, and P=0.002). This data reaffirms the similarity between canine and human cancers not just in the genomic profiles but also the tumor biology and treatment strategy for both species. Among tumor types, lymphoma and hemangiosarcoma showed the worst survival times (N=32, OS HR=1.929, P=0.002, and N=202, OS HR=1.743, P<0.001). Interestingly, we also identified that dogs with RET mutations respond better to toceranib, a veterinary oral multikinase inhibitor against RET, VEGFR2, PDGFR, FLT3 and c-KIT; this is in concordance with sunitinib a tyrosine kinase inhibitor that target RET used in humans thyroid carcinomas and other tumors carrying RET mutations. To the best of our knowledge, this is the largest canine tumor clinical genomic dataset analysis. Applying real-world evidence and data tools in the FidoCure® dataset, we successfully identified associations between gene mutations and survival associated with response to target therapy treatment. These associations can benefit dogs by enabling better therapeutic recommendations and also benefit human cancer research since canine models recapitulate human disease with intact immune systems and similar tumor genomic profiles, confirmed by the FidoCure® database, accelerating clinical studies of novel treatments that currently have significant barriers to study at scale. Citation Format: Kevin Wu, Lucas Rodrigues, Gerald Post, Garrett Harvey, Aubrey Miller, Lindsay Lambert, Christina Lopes, Benjamin Lewis, James Zou. Concordance between dogs and humans: The use of AI in evaluating clinical cancer genomic datasets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 635.