Improving Outcomes in Cancer Treatment-Related Cardiotoxicity

改善癌症治疗相关心脏毒性的结果

基本信息

批准号：
10693265
负责人：
Anthony W Ashton
金额：
$ 32.39万
依托单位：
LIGHTSEED, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10693265
关键词：
Acute Address Animals Anthracycline Biological Assay Biotechnology Breast Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Cancer Survivor Cardiac Cardiac Myocytes Cardiomyopathies Cardiotonic Agents Cardiotoxicity Cardiovascular system Cell Death Cells Childhood Chronic Clinical Communities DNA Damage Detection Development Dexrazoxane Disease Dose Doxorubicin Endometrial Epidemic European Experimental Designs FDA approved Genes Goals Head Heart Heart Transplantation Human Immune Immune response Immune system Immunocompetent Kaposi Sarcoma Kidney Knock-in Lead Libraries Literature Liver MDA MB 231 Malignant Neoplasms Marketing Mediating Metastatic breast cancer Mission Modeling Morbidity - disease rate Multiple Myeloma Mus Myocardium National Heart, Lung, and Blood Institute Neoplasm Metastasis Oncologist Oncology Ovarian Patients Population Publications Publishing Recovery Reporter Reporter Genes Reporting Research Personnel Risk Stomach System Technology Testing Therapeutic Tissues Toxic effect Treatment-Related Cancer Validation Woman cancer cell cardioprotection cell growth cell killing chemotherapy effective therapy experience fluorophore high throughput screening improved outcome in vivo induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes innovation leukemia mortality mouse model novel novel strategies off-label use osteosarcoma screening synergism therapeutic evaluation tissue culture tumor tumor growth

项目摘要

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.

项目概要/摘要蒽环类药物，如阿霉素 (DOX)，可有效治疗多种癌症（卵巢癌、多发性癌症）骨髓瘤、卡波西肉瘤、白血病、骨肉瘤、乳腺、子宫内膜、胃、肝、肾等全球 DOX 市场每年都在增长，预计到 2026 年将达到 $1.3B。DOX 毒性是因此与多种癌症相关。然而，化疗引起的心脏毒性具有显着性。心脏毒性和 DNA 损伤性化疗的恢复是剂量依赖性的。到 2025 年，美国癌症幸存者估计将达到 1900 万，Dox 引起的心脏毒性被认为成为“心脏病流行病”的一部分。开发减少化疗引起的心脏毒性的新方法至关重要。右雷佐生 (Dex) 已被 FDA 批准用于“女性患有多柔比星给药”的特定适应症已接受阿霉素累积剂量 300 mg/m2 且将继续接受治疗的转移性乳腺癌接受阿霉素治疗以维持肿瘤控制”。在超说明书使用时，Dex 有骨髓毒性的风险。 Dex 在其他癌症人群中提供的心脏保护作用并不完整。 “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（具有先前生物技术公司的专业知识）、心脏肿瘤学家、高通量先导药物发现专家、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 对癌细胞的杀伤作用，但可防止 DOX 心脏毒性）。FDA 的三种化合物-。我们正在从批准的化合物库中寻找其他“双功能”化合物。我们部署了一种创新的转基因小鼠测试系统，该系统可以：（i）。与现有技术（Dex）相比，（ii）为肿瘤免疫提供了正常的免疫系统。 (iii).允许使用双敲入荧光报告基因分析宿主免疫反应。 (iv)允许使用第三荧光报告基因检测肿瘤生长以进行体内进展分析。 LightSeed 将通过高通量筛选来识别其他“双功能”化合物一位在 HTS 筛选方面经验丰富的核心总监（之前是 Lead Discovery 的负责人）的指导 Janssen 已使用 15 年）。LightSeed 将使用源自汇集 iPSC-CM（iPSC 衍生）的心肌细胞。该提案将： (SA1) 筛选由 FDA 和 EU 组成的库。批准的化合物，使用保护人类心肌细胞免受 DOX 诱导的心脏毒性的检测并增强癌细胞杀伤力 (SA2) 在化合物组织培养中和 (SA3) 中进行新型“双重”验证。功能”记者鼠标系统。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Endogenous Cyclin D1 Promotes the Rate of Onset and Magnitude of Mitogenic Signaling via Akt1 Ser473 Phosphorylation.

内源性 Cyclin D1 通过 Akt1 Ser473 磷酸化促进有丝分裂信号传导的发生率和强度。

DOI：
发表时间：
2023-06-27
期刊：
影响因子：
8.8
作者：
Chen, Ke;Jiao, Xuanmao;Di Rocco, Agnese;Shen, Duanwen;Xu, Shaohua;Ertel, Adam;Yu, Zuoren;Di Sante, Gabriele;Wang, Min;Li, Zhiping;Pestell, Timothy G;Casimiro, Mathew C;Skordalakes, Emmanuel;Achilefu, Samuel;Pestell, Richard G
通讯作者：
Pestell, Richard G