Credentialing a Cross-Species Platform to Investigate Cancer Therapy-Associated Cardiovascular Toxicity

随着癌症护理的进步，生存率提高，与治疗相关的心血管(CV)并发症 已经变得更加普遍。传统化疗的效果众所周知，但 小分子抑制剂和免疫疗法的结合导致了新的和 意外的毒物。其中许多问题背后的机械驱动因素还没有得到很好的描述， 破坏了适当的监测和有效的干预。由于依赖于 不能完全概括人类癌症复杂情况的CV毒性模型。而在体外 研究允许解剖细胞和分子变化对药物暴露的反应，但它们缺乏背景 对发病起作用的整个有机体。啮齿动物模型在定义 治疗所致心血管并发症的基本特征，但在 接受治疗的时间和没有可能影响结果的合并症。此外， 它们体积小，寿命短，限制了仪器、纵向分析和重复采样。宠物狗 患有自发性癌症的患者通常使用已知会产生心血管毒性的抗癌药物进行治疗，包括 阿霉素，酪氨酸激酶抑制剂，以及最近的免疫检查点抑制剂，因此可以提供 在更具临床相关性的背景下进行机械性讯问的机会，以弥合细胞和 从老鼠到人类。它们更大的尺寸和更长的寿命允许在环境中使用前瞻性研究设计 更能代表人类经验的标准癌症治疗方法，从而克服了一些 啮齿动物模型的局限性。因此，这项提议的基本前提是没有单一的 肿瘤治疗诱导的血管紧张素转换酶毒性模型系统足以有效地探讨其机制 司机和评估治疗干预的方法。取而代之的是，协调、综合的努力 需要多个体外和体内模型系统来有效地识别和验证 早期干预的生物标记物，评估解决并发症的新疗法，并最终开发 用于预测联合治疗环境中潜在的CV毒性的算法。因此，我们建议 纳入用已知诱导剂治疗的自发性癌症犬产生的数据 CV毒性将允许更准确地描述和确认关键机械驱动因素和 治疗干预战略对提高人类结局至关重要。为了实现这一点，我们创建了 用于分析在实验室、小鼠模型、狗中生成的数据的非简约主义、多物种框架 自发性癌症和人类病人。这项建议中的研究将证明并优化这一点 使用两种已确定但独特的CV毒性的新平台，这些毒性限制了癌症患者的有效治疗 -蒽环类药物引起的心脏毒性和VEGFRI引起的高血压-最终创造了一幅更好的蓝图 解决现有和紧急癌症治疗引起的心血管毒性，并提高长期存活率。

As survival improves with advances in cancer care, cardiovascular (CV) complications associated with treatment have become more prevalent. Effects of traditional chemotherapeutics are generally well known, but incorporation of small molecule inhibitors and immunotherapeutics has led to the emergence of new and unexpected toxicities. The mechanistic drivers underlying many of these have not been well characterized, undermining both appropriate monitoring and effective intervention. This is further complicated by reliance upon models of CV toxicity that do not fully recapitulate the complicated landscape of human cancer. While in vitro studies permit dissection of cellular and molecular alterations in response to drug exposure, they lack context of the whole organism that contributes to pathogenesis. Rodent models have been instrumental in defining fundamental characteristics of treatment induced CV complications, but, there are significant differences in duration of exposure to therapeutics and an absence of co-morbidities that likely influence outcome. Moreover, their small size and short lifespan limit instrumentation, longitudinal analysis, and repeated sampling. Pet dogs with spontaneous cancer are routinely treated with anti-cancer agents known to produce CV toxicity including doxorubicin, tyrosine kinase inhibitors, and more recently immune checkpoint inhibitors and may thus provide an opportunity for mechanistic interrogation in a more clinically relevant context to bridge the gap from cells and mice to humans. Their larger size and longer lifespan permit the use of prospective study designs in the setting of standard cancer treatment that more closely represent the human experience, thereby overcoming some limitations of rodent models. As such, the fundamental premise underlying this proposal is that no single model system of cancer treatment-induced CV toxicity is sufficient to effectively interrogate mechanistic drivers and assess approaches to therapeutic intervention. Instead, a coordinated, integrated effort across the landscape of multiple in vitro and in vivo model systems is required to efficiently identify and validate biomarkers for early intervention, evaluate novel treatments to address complications, and ultimately develop algorithms for predicting potential CV toxicity in the setting of combination therapy. We therefore propose that inclusion of data generated from dogs with spontaneous cancer treated with agents known to induce CV toxicity will permit a more accurate characterization and confirmation of key mechanistic drivers and therapeutic intervention strategies critical for advancing human outcomes. To accomplish this, we created a non-reductionist, multi-species framework for analyzing data generated in the laboratory, mouse models, dogs with spontaneous cancer, and human patients. The studies in this proposal will credential and optimize this novel platform using two established yet unique CV toxicities that constrain effective treatment in cancer patients -anthracycline induced cardiotoxicity and VEGFRI induced hypertension- ultimately creating a blueprint to better address both existing and emergent cancer treatment induced CV toxicities and enhance long-term survivorship.