Improving Outcomes in Cancer Treatment-Related Cardiotoxicity

项目概要/摘要 蒽环类药物，如阿霉素（DOX），可有效治疗许多癌症（卵巢癌、多发性骨髓瘤、乳腺癌 骨髓瘤、卡波西肉瘤、白血病、骨肉瘤、乳腺癌、子宫内膜癌、胃癌、肝癌、肾癌及其他 癌症）。全球DOX市场每年都在增长，预计到2026年将达到13亿美元。DOX毒性是 因此与许多癌症相关。然而，化疗诱导的心脏毒性具有显著的 发病率和死亡率。DNA损伤化疗的毒性和恢复是剂量依赖性的。 到2025年，美国估计有1900万癌症幸存者，Dox诱导的心脏毒性被认为是 成为“心脏肿瘤流行病”的一部分。 开发新的方法来减少化疗引起的心脏毒性是必不可少的。 Dexrazoxane（Dex）是FDA批准用于“在患有以下疾病的女性中给予多柔比星”的特定适应症： 已接受累积多柔比星剂量300 mg/m2且将继续接受治疗的转移性乳腺癌患者 接受阿霉素治疗以维持肿瘤控制”。地塞米松有骨髓毒性的风险（5）。超说明书使用 在其他癌症人群中，Dex的心脏保护不完全。在儿科人群中，Dex提供 “不完全的急性心脏保护”和“对慢性心脏保护或总存活率无影响”。 LightSeed组建了一个经验丰富的团队（肿瘤学家-癌症生物学家（具有先前的 生物技术公司的专业知识），心脏肿瘤学家，高通量铅发现专家，免疫癌症 生物学家-小鼠遗传学家），以鉴定和重新利用FDA批准的具有“双重功能”的化合物 （增强DOX对癌细胞的杀伤，但保护免受DOX心脏毒性）。三种药管局的化合物- 已批准的化合物库已经过验证。我们正在寻求额外的“双功能”化合物， 图书馆.我们已经部署了一个创新的转基因小鼠测试系统，该系统：（i）。允许 与现有技术（Dex）的比较，（ii）。为肿瘤免疫提供正常的免疫系统 反应（iii）。允许使用双敲入荧光报告基因分析宿主免疫应答。 （iv）。允许使用用于体内进展分析的第三荧光报告基因检测肿瘤生长。 LightSeed将通过高通量筛选，在 在HTS筛选方面经验丰富的核心总监（之前是 Janssen 15年）。LightSeed将使用来源于合并的iPSC-CM（iPSC衍生的 心肌细胞）和癌细胞。本提案将：（SA 1）。筛选由FDA和EU组成的库 批准的化合物，使用保护人心肌细胞免受DOX诱导的心脏毒性的测定 并增强癌细胞杀伤。（SA2）。将这些化合物在组织培养中和（SA 3）在新的“双重”培养基中进行培养。 功能”的记者鼠标系统。

Project Summary/Abstract Anthracyclines, such as Doxorubicin (DOX), are effective for the treatment of many cancers (Ovarian, Multiple Myeloma, Kaposi Sarcoma, Leukemia, Bone Sarcoma, Breast, Endometrial, Gastric, Liver, Kidney, and other Cancers). The global DOX market is increasing annually and expected to reach $1.3B by 2026. DOX toxicity is therefore relevant to a broad number of cancers. However, chemotherapy induced cardiac toxicity has substantial morbidity and mortality. Cardiotoxicity and recovery from DNA damaging chemotherapy is dose-dependent. With cancer survivors estimated at 19 million in the USA by 2025, Dox-induced cardiotoxicity is considered to be part of the “cardio-oncology epidemic”. The development of new approaches to reduce chemotherapy-induced cardiotoxicity is essential. Dexrazoxane (Dex), is FDA approved for the specific indication of “doxorubicin administration in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m2 and who will continue to receive doxorubicin therapy to maintain tumor control”. Dex has the risk of myelotoxicity(5). In off label use of Dex in other cancer populations, cardiac protection was incomplete. In the pediatric population Dex provided “'incomplete acute cardioprotection and “no impact on chronic cardioprotection or overall survival”. LightSeed has assembled a highly experienced team (oncologist-cancer biologist (with prior biotechnology company expertise), cardio-oncologist, high throughput lead discovery expert, immune cancer biologist- mouse geneticist) in order to identify and repurpose FDA-approved compounds with “dual function” (enhance cancer cell killing by DOX but protection from DOX cardiotoxicity). Three compounds from the FDA- approved compound library have been validated. We are seeking additional “dual function” compounds from the libraries. We have deployed an innovative genetically modified murine testing system which: (i). allows comparison with the incumbent technology (Dex), (ii). provides a normal immune system for the tumor immune response. (iii). allows analysis of the host immune response using double knockin fluoresecent reporter genes. (iv). allows detection of the tumor growth using a third fluorescent report gene for in vivo progression analysis. LightSeed will identify additional “dual function” compounds by high throughput screening under the direction of a core director who is highly experienced with HTS screening (previously head of Lead Discovery at Janssen for 15 yrs). LightSeed will use cardiomyocyte cells derived from pooled iPSC-CM (iPSC-derived cardiomyocytes) and cancer cells. This proposal will: (SA1). Screen a library that consists of FDA and EU approved compounds, using an assay that protects human cardiac myocytes from DOX-induced cardiac toxicity and enhances cancer cell killing. (SA2). Validate these compounds in tissue culture and (SA3) in a novel “dual function” reporter mouse system.