Improving Outcomes in Cancer Treatment-Related Cardiotoxicity

项目摘要/摘要 多柔比星(DOX)等蒽环类药物可有效治疗多种癌症(卵巢癌、多发性卵巢癌 骨髓瘤、卡波西肉瘤、白血病、骨肉瘤、乳腺、子宫内膜、胃、肝、肾等 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，它与多种癌症相关。然而，化疗引起的心脏毒性是相当大的。 发病率和死亡率。心脏毒性和从DNA损伤化疗中恢复是剂量依赖的。 到2025年，美国估计有1900万癌症幸存者，Dox引起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至关重要的。 Dexrazoxane(Dexrazoxane)，FDA批准其用于治疗以下疾病的特定适应症： 已接受300毫克/平方米阿霉素累积剂量的转移性乳腺癌，并将继续 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)。在标签外使用 在其他癌症人群中，心脏保护是不完整的。在德克斯提供的儿科人口中 “不完全的急性心脏保护和”对慢性心脏保护或总体生存没有影响“。 LightSeed组建了一支经验丰富的团队(肿瘤学家-癌症生物学家(与之前的 生物技术公司的专业知识)、心脏肿瘤学家、高通量领先发现专家、免疫癌症 生物学家-小鼠遗传学家)，以识别和重新利用FDA批准的具有“双重功能”的化合物 (增强DOX对癌细胞的杀伤力，但保护其免受DOX的心脏毒性)。来自FDA的三种化合物- 批准的化合物文库已得到验证。我们正在寻找额外的“双功能”化合物 图书馆。我们部署了一种创新的转基因小鼠检测系统，该系统：(I)。允许 与现有技术的比较(Dex)，(Ii)。为肿瘤免疫提供正常的免疫系统 回应。(三)。允许使用双敲击荧光报告基因分析宿主免疫反应。 (四)。允许使用第三个荧光报告基因检测肿瘤生长，以进行体内进展分析。 LightSeed将通过高通量筛选，根据 指导一位在HTS筛选方面经验丰富的核心导演(曾担任 Janssen 15年)。LightSeed将使用来自IPSC-CM(IPSC衍生)的心肌细胞 心肌细胞)和癌细胞。这项提议将：(SA1)。筛选包含FDA和EU的文库 批准的化合物，使用一种保护人类心肌细胞免受DOX诱导的心脏毒性的试验 并增强对癌细胞的杀伤力。(SA2)。验证这些化合物在组织培养和(SA3)在一个新的“双重” 功能“报告鼠标系统。

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.