Theranostics of Reduction of Cardiotoxicity Using Targeted Apoptosis Activation Technology

使用靶向凋亡激活技术减少心脏毒性的治疗诊断学

• 批准号: 9407421
• 负责人: KATHLEEN Louise GABRIELSON
• 金额: $ 27.45万
• 依托单位: SCI-ENGI-MEDCO SOLUTIONS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9407421
• 关键词: Animal Model; Annexins; Anthracyclines; Antineoplastic Agents; Apoptosis; Avastin; Biological; Biological Assay; Biological Markers; Biological Process; Brain; Breast; Cancer Patient; Capital; Carboplatin; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cell Death; Cells; Chronic; Clinical; Clinical Research; Colon; Data; Development; Doctor of Philosophy; Dose; Doxorubicin; Drug Combinations; Echocardiography; Exhibits; Food and Drug Administration Drug Approval; Funding; Future; Goals; Guidelines; Heart; Histology; Human; Image; Imaging Device; In Vitro; Industry; Kidney; Laboratories; Left Ventricular Ejection Fraction; Licensing; Lung; MDA MB 231; Malignant Neoplasms; Measurement; Methods; Modeling; Molecular; Monitor; Myocardium; NF-kappa B; Neoadjuvant Therapy; Nude Rats; Oncologist; Outcome; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Poly(ADP-ribose) Polymerases; Preclinical Drug Evaluation; Prostate; Rattus; Refractory; Research; Resistance; Risk; Risk stratification; Small Business Innovation Research Grant; Stomach; Structure; Supervision; Syndrome; TNFRSF6 gene; Technetium 99m; Technology; Therapeutic; Time; Toxic effect; Trastuzumab; Treatment Efficacy; Tumor Biology; Tumor Volume; Tumorigenicity; Universities; Validation; Ventricular Function; X-Ray Computed Tomography; acute toxicity; base; cancer cell; cancer imaging; cancer stem cell; cancer therapy; cancer type; chemotherapy; commercialization; density; experience; gemcitabine; high risk; improved; in vivo; induced pluripotent stem cell; inhibitor/antagonist; neoplastic cell; new technology; non-invasive imaging; novel; novel strategies; patient stratification; preclinical development; professor; receptor; single photon emission computed tomography; synergism; targeted treatment; theranostics; triple-negative invasive breast carcinoma; tumor; tumor xenograft; tumorigenic

Project Summary/Abstract Chronic cardiotoxicity is a clinically unresolved issue for cancer patients who are treated, particularly with anthracycline based drugs. Currently, triple negative breast cancer (TNBC) patients have no option, but to rely on these nonspecific chemotherapeutics. New technologies are needed to reduce the off-target toxicity including anthracycline related cardiotoxicity (ARC) and more importantly, monitor the reduction of cardiotoxicity in vivo. “A priori activation of apoptosis of pathways of tumor” (AAAPT) is a novel technology which sensitizes low responsive tumor cells and cancer stems cells (CSCs) in several types of cancers (e.g. colon, lung, prostate, breast, brain and renal) by multiple mechanisms including a) activating cell death pathway (CD 95), b) inhibiting survival pathway (NF-kB) and c) inhibiting poly (ADP-ribose) polymerase (PARP). Most cancer cells circumvent exogenous and endogenous toxicity by deactivating cell death pathway, activating inhibition pathway and hyperactivating PARP in heart leading to cardiotoxicity. Current guidelines for predicting/monitoring ARC include left ventricular ejection fraction (LVEF), LV volume and diastolic function which appear to be too late as compared to biological functions at molecular level such as cell death in heart. Our collaborators from Johns Hopkins University have demonstrated the prediction of dose dependent cardiotoxicity for doxorubicin using 99mTc- SPECT-CT. Hence, we propose AAAPT leading candidates AMP-001/002 to be neoadjuvant to chemotherapy (e.g. doxorubicin) in order to reduce ARC since combination of AAAPT and doxorubicin has reduced IC50 significantly in vitro compared to doxorubicin alone. Our specific aims are; Specific Aim 1: To a) synthesize leading AAAPT candidates AMP-001-002 and b) validate sensitization of TNBC MDA-MB-231 cells to front line therapeutics (e.g. doxorubicin, gemcitabine, Herceptin and paclitaxel) and c) assess the cardiotoxicity of the combination of drugs in induced pluripotent stem cell derived cardiomyocytes (iPSc) during first 6 months. The objective will be accomplished at Sci-Engi-Medco Solutions associated laboratories under PI/PD supervision. Specific Aim 2: To a) determine the dose at which doxorubicin exhibit cardiotoxicity in orthotopic TNBC MDA-MB- 231 tumor xenograft nude rat (nu/nu) by quantifying cell death in myocardium correlated to cardiotoxicity. The milestones include in vivo tumor cardiotoxicity data corroborated with transthoracic echocardiography and cell death in myocardium by tunnel assays respectively and further correlated to image density in 99mTc-SPECT-CT, which will be carried out by Dr. Pomper/Gabrielson at Johns Hopkins University. Specific Aim 3: To assess the efficacy of AMP-001/AMP-002 and doxorubicin combination for tumor regression with low or no cardiotoxicity in vivo using two animal models namely, TNBC MDA-MB-231 and BT4 tumor xenograft nude rat (nu/nu) model. The milestones include a) tumor volume measurement correlated to tumor cell death using SPECT-CT imaging, histology of tumor ex-vivo with tunnel assays and b) quantification of cardiotoxicity. Expected Outcome: The foremost outcome is a potential use of AAAPT as a neoadjuvant to chemotherapy and SPECT-CT as an imaging tool to risk stratify patients for CRC prior to develop cardiomyopathy. The second outcome would be a potential extension of AAAPT synergy to other front line chemotherapeutics (e.g. doxorubicin, gemcitabine, carboplatin, PI3K inhibitor Novartis) and other cancers (e.g. colon, lung, prostate, breast, brain and renal) which are refractory to current treatments.

项目总结/摘要 慢性心脏毒性是接受治疗的癌症患者的临床上未解决的问题，特别是用 蒽环类药物。目前，三阴性乳腺癌（TNBC）患者别无选择，只能依靠 这些非特异性化疗药物。需要新技术来减少脱靶毒性，包括 蒽环类药物相关的心脏毒性（ARC），更重要的是，监测体内心脏毒性的降低。 “肿瘤途径凋亡的先验激活”（AAAPT）是一种新的技术， 在几种类型的癌症（例如结肠癌，肺癌，前列腺癌， 乳腺、脑和肾）通过多种机制，包括a）激活细胞死亡途径（CD 95），B）抑制 存活途径（NF-kB）和c）抑制聚（ADP-核糖）聚合酶（PARP）。大多数癌细胞 外源性和内源性毒性通过灭活细胞死亡途径，激活抑制途径， 过度激活心脏中的PARP，导致心脏毒性。目前用于预测/监测ARC的指南包括 左心室射血分数（LVEF）、左心室容积和舒张功能，与 分子水平上的生物功能，如心脏细胞死亡。我们来自约翰霍普金斯的合作者 大学已经证明了使用99 mTc预测阿霉素的剂量依赖性心脏毒性， SPECT-CT。因此，我们建议AAAPT领先候选AMP-001/002作为化疗的新辅助治疗 (e.g.因为AAAPT和多柔比星的组合降低了IC 50， 与单独的多柔比星相比在体外显著。我们的具体目标是： 具体目标1：a）合成领先的AAAPT候选物AMP-001-002和B）验证TNBC的致敏性 c）MDA-MB-231细胞与一线治疗剂（例如多柔比星、吉西他滨、赫赛汀和紫杉醇）的比较 评估药物组合在诱导多能干细胞衍生的心肌细胞中的心脏毒性 （iPSc）在前6个月。该目标将在Sci-Engi-Medco解决方案相关的 PI/PD监督下的实验室。 具体目的2：a）确定多柔比星在原位TNBC MDA-MB中表现出心脏毒性的剂量。 231肿瘤异种移植裸鼠（nu/nu）通过定量心肌细胞死亡与心脏毒性相关。的 里程碑包括经胸超声心动图证实的体内肿瘤心脏毒性数据， 分别通过隧道试验检测心肌死亡，并进一步与99 mTc-SPECT-CT的图像密度相关， 将由约翰霍普金斯大学的庞珀/加布里尔森博士进行。 具体目的3：评估AMP-001/AMP-002和阿霉素组合用于肿瘤消退的功效 使用两种动物模型，即TNBC MDA-MB-231和BT4肿瘤异种移植物， 裸大鼠（nu/nu）模型。里程碑包括a）与肿瘤细胞死亡相关的肿瘤体积测量 使用SPECT-CT成像，用隧道测定法离体肿瘤组织学，和B）心脏毒性的定量。 预期结局：最重要的结局是AAAPT作为化疗新辅助治疗的潜在用途， SPECT-CT作为一种成像工具，在发生心肌病之前对CRC患者进行风险分层。第二 结果将是AAAPT协同作用潜在地延伸到其他一线化疗药物（例如， 多柔比星、吉西他滨、卡铂、PI 3 K抑制剂Novartis）和其它癌症（例如结肠癌、肺癌、前列腺癌， 乳腺、脑和肾），这些疾病对目前的治疗是难治的。

项目成果

Rational Drug Design of Targeted and Enzyme-Cleavable Vitamin E Analogs as a Neoadjuvant to Chemotherapy: In Vitro and In Vivo Evaluation on Reduction of the Cardiotoxicity Side Effect of Doxorubicin.

• DOI: 10.1021/acsptsci.2c00091
• 发表时间: 2023-02
• 期刊: ACS pharmacology & translational science
• 影响因子: 6
• 作者: Raghu S Pandurangi;Orsolya Cseh;H. A. Luchman;Cynthia X. Ma;S. N. Senadheera;M. Forrest

Targeted Sensitization of Glioblastoma Multiforme Using AAAPT Technology.

• DOI: 10.1109/ojemb.2023.3336181
• 发表时间: 2023
• 期刊: IEEE open journal of engineering in medicine and biology
• 影响因子: 5.8