Rodrigues Lucas, Wu Kevin, Harvey Garrett, Post Gerald, Miller Aubrey, Hull Abigail, Lambert Lindsay, Lopes Christina, Zou James
One Health Company, 530 Lytton Ave, 2nd Floor, Palo Alto, CA, 94301, USA.
Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
Sci Rep. 2025 May 14;15(1):16442. doi: 10.1038/s41598-025-89862-9.
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.
脾血管肉瘤（HSA）是一种常见的犬类肿瘤，其组织学和遗传学与人类血管肉瘤（AS）相似，后者是一种源自血管细胞的罕见侵袭性恶性肿瘤。为了评估生物标志物并为治疗方案提供参考，在对患者对化疗和/或靶向治疗的反应进行长期评估之前，对自发产生的HSA进行了基因突变的系统分析。我们利用了来自FidoCure平台的犬类真实世界临床基因组数据，这是一个癌症基因座的下一代测序（NGS）筛查。对于所有犬只，无论治疗方法如何，PTEN和P53突变总体上是预后不良的预测指标，而NRAS突变则预测预后较好。然而，P53、PIK3CA、ATRX和NRAS预测对专门包含靶向药物的治疗反应更好。通过分析基因-药物相互作用，我们发现具有P53突变的肿瘤对HDAC或MTOR抑制高度敏感，而具有PIK3CA突变的肿瘤仅预测对MTOR抑制有反应。对于兽医来说，这一真实世界的证据填补了靶向治疗的一个重要转化差距，表明与单独的标准辅助化疗相比，其预后相当或更好，并且联合靶向治疗和化疗能进一步提高生存率。该研究还揭示了特定基因突变存在时特定治疗干预与预后之间的关系，表明它们可用作生物标志物。由于犬类HSA可能与人类AS相关，该研究突出了犬类HSA作为一种模型为人类罕见恶性肿瘤AS的精准医学提供信息的益处。
