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.

项目摘要/摘要蒽环类药物（例如阿霉素（DOX））对许多癌症的治疗有效（卵巢，多重骨髓瘤，卡波西肉瘤，白血病，骨肉瘤，乳房，子宫内膜，胃，肝，肾脏等癌症）。全球DOX市场每年都在增长，到2026年预计将达到1.3B美元。DOX毒性是因此与许多癌症有关。但是，化学疗法诱导的心脏毒性具有很大的发病率和死亡率。心脏毒性和从DNA损害化疗中恢复是剂量依赖性的。到2025年，由于癌症存活率为1900万，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。降低化疗引起的心脏毒性的新方法的发展至关重要。右旋唑烷（DEX）被FDA批准用于特定指示：“女性阿霉素给药转移性乳腺癌的累积阿霉素剂量为300 mg/m2，他们将继续接受阿霉素治疗以维持肿瘤的控制”。dex具有骨髓毒性的风险（5）。在其他癌症种群中，心脏保护是不完整的。在小儿种群中提供 “'不完全急性心脏保护作用，“对慢性心脏保护或整体生存没有影响”。 Lightseed聚集了一支经验丰富的团队（肿瘤学家 - 癌症的生物学家（先验）生物技术公司专业知识），心脏肿瘤学家，高吞吐量主要发现专家，免疫癌症生物学家 - 小鼠遗传学家）为了鉴定和再现具有“双重功能”的FDA批准化合物（增强DOX杀死癌细胞的杀戮，但可以保护DOX心脏毒性）。 FDA-的三种化合物批准的复合库已得到验证。我们正在寻找其他“双重功能”化合物库。我们已经部署了一个创新的鼠测试系统，该系统：（i）。允许与现有技术（DEX）的比较，（ii）。为肿瘤免疫提供了正常的免疫系统回复。（iii）。允许使用双敲蛋白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进行体内进展分析来检测肿瘤生长。 Lightseed将通过高吞吐量筛选在在HTS筛选方面经验丰富的核心主管的方向（以前是铅发现负责人詹森（Janssen）15年）。 Lightseed将使用来自合并的IPSC-CM（IPSC衍生的）的心肌细胞细胞心肌细胞）和癌细胞。该建议将：（ SA1）。筛选由FDA和欧盟组成的库批准的化合物，使用保护人类心肌细胞免受DOX诱导的心脏毒性的测定并增强癌细胞的杀戮。（SA2）。在组织培养和（SA3）中验证这些化合物在新颖的“双重”中验证函数”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.

DOI：
10.1016/j.celrep.2020.108151
发表时间：
2020-09-15
期刊：
Cell reports
影响因子：
8.8
作者：
Chen K;Jiao X;Di Rocco A;Shen D;Xu S;Ertel A;Yu Z;Di Sante G;Wang M;Li Z;Pestell TG;Casimiro MC;Skordalakes E;Achilefu S;Pestell RG
通讯作者：
Pestell RG