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.

项目摘要/摘要 对于接受治疗的癌症患者，慢性心脏毒性是一个临床上未解决的问题，特别是 基于蒽环类药物。目前，三重阴性乳腺癌（TNBC）患者别无选择，但要依靠 在这些非特异性化学治疗剂上。需要新技术来降低脱靶毒性 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）是一种新技术 低反应性肿瘤细胞和癌症是几种类型的癌症中的细胞（CSC）（例如结肠，肺，前列腺，前列腺， 乳房，大脑和肾脏）通过多种机制，包括a）激活细胞死亡途径（CD 95），b）抑制 生存途径（NF-KB）和C）抑制聚（ADP-核糖）聚合酶（PARP）。大多数癌细胞绕过 通过停用细胞死亡途径，激活抑制途径和 心脏过度活化的PARP导致心脏毒性。当前预测/监视弧的指南包括 左心室射血分数（LVEF），LV体积和舒张功能似乎为时已晚 在分子水平上的生物学功能，例如心脏的细胞死亡。我们来自约翰·霍普金斯的合作者 大学证明了使用99mtc-的剂量依赖性心脏毒性的预测 SPECT-CT。因此，我们提出AAAPT领先的候选人AMP-001/002是化学疗法的新辅助 （例如阿霉素）为了减少弧线，因为AAAPT和阿霉素的组合减少了IC50 与单独的阿霉素相比，体外显着。我们的具体目标是； 特定目标1：a）合成领先的AAAPT候选AMP-001-002和b）验证TNBC的灵敏度 MDA-MB-231细胞进行前线治疗（例如阿霉素，吉西他滨，赫赛汀和紫杉醇）和c） 评估在诱导多能干细胞衍生的心肌细胞中药物组合的心脏毒性 （IPSC）在最初的6个月中。该目标将在与Sci-engi-Medco解决方案相关的解决方案中实现 PI/PD监督下的实验室。 具体目的2：a）确定阿霉素在原位TNBC MDA-MB-中暴露的心脏毒性的剂量 231肿瘤异种移植大鼠（NU/NU）通过量化心肌中的细胞死亡与心脏毒性相关。这 里程碑包括经体超声心动图和细胞证实的体内肿瘤性心脏毒性数据 隧道测定法分别在心肌中死亡，并进一步与99mtc-spect-ct中的图像密度相关， 这将由约翰·霍普金斯大学的Pomper/Gabrielson博士进行。 特定目的3：评估AMP-001/AMP-002和阿霉素组合的效率 使用两种动物模型在体内低或没有心脏毒性，即TNBC MDA-MB-231和BT4肿瘤异种移植物 裸鼠（NU/NU）模型。里程碑包括a）肿瘤体积测量与肿瘤细胞死亡相关 使用SPECT-CT成像，带有隧道分析的肿瘤的组织学和b）心脏毒性数量。 预期结果：最重要的结果是将AAAPT作为化学疗法和 SPECT-CT是在发展心肌病之前将CRC患者分层的成像工具。第二个 结果可能是AAAPT协同作用到其他前线化学治疗药的潜在扩展（例如 阿霉素，吉西他滨，卡铂，pi3k抑制剂诺华）和其他癌症（例如，结肠，肺，前列腺，前列腺， 乳房，大脑和肾脏），对当前治疗难治性。

项目成果

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

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