Theranostics of Reduction of Cardiotoxicity Using Targeted Apoptosis Activation Technology

项目摘要/摘要 对于接受治疗的癌症患者来说，慢性心脏毒性是一个临床上尚未解决的问题，特别是 以蒽环类药物为主的药物。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。需要新的技术来减少目标外的毒性，包括 因此，我们不仅要监测与蒽环类药物相关的心脏毒性(ARC)，更重要的是要监测体内心脏毒性的减少情况。 “肿瘤细胞凋亡通路的先验激活”(AAAPT)是一项新的技术，它使 在几种类型的癌症(如结肠癌、肺癌、前列腺癌、 乳腺、大脑和肾脏)通过多种机制，包括a)激活细胞死亡途径(CD95)，b)抑制 生存途径(NF-kB)和c)抑制聚(ADP-核糖)聚合酶(PARP)。大多数癌细胞都能绕过 失活细胞死亡途径，激活抑制途径，发挥外源性和内源性毒性 心脏中PARP的过度激活导致心脏毒性。目前预测/监测ARC的指导方针包括 左心室射血分数(LVEF)、左心室容量和舒张期功能相比似乎为时已晚 在分子水平上的生物学功能，如心脏细胞死亡。我们来自约翰·霍普金斯大学的合作者 美国大学已经证实了用99mTc-TdR预测阿霉素的剂量依赖性心脏毒性。 SPECT-CT。因此，我们建议AAAPT的主要候选者AMP-001/002作为化疗的新辅助。 (例如阿霉素)，以减少ARC，因为AAAPT和阿霉素联合使用降低了IC50 与单独使用阿霉素相比，体外试验效果显著。我们的具体目标是； 具体目标1)合成主要的AAAPT候选者AMP-001-002和b)验证TNBC的增敏作用 MDA-MB-231细胞用于一线治疗(如阿霉素、吉西他滨、赫赛汀和紫杉醇)和c) 联合用药对诱导多能干细胞来源心肌细胞的心脏毒性 (IPSC)在前6个月。这一目标将在Sci-Engi-Medco Solutions Associates实现 在PI/PD监督下的实验室。 具体目标2：a)确定阿霉素在原位TNBC MDA-MB中表现出心脏毒性的剂量 231心肌细胞死亡与心脏毒性相关的裸鼠移植瘤(nu/nu)。这个 里程碑包括经胸超声心动图和细胞学证实的体内肿瘤心脏毒性数据 隧道法检测心肌死亡，并与99mTC-SPECT-CT图像密度进一步相关， 这项研究将由约翰·霍普金斯大学的庞珀/加布里尔森博士进行。 具体目标3：评价AMP-001/AMP-002与阿霉素联合治疗肿瘤的疗效 使用两种动物模型，即TNBC MDA-MB-231和BT4肿瘤移植瘤，在体内低或无心脏毒性 裸鼠(nu/nu)模型。这些里程碑包括a)与肿瘤细胞死亡相关的肿瘤体积测量 使用SPECT-CT成像，体外肿瘤组织学隧道分析和b)心脏毒性的定量。 预期结果：最重要的结果是AAAPT可能被用作化疗和 SPECT-CT作为一种影像工具，用于在发生心肌病之前对结直肠癌患者进行风险分层。第二 结果将是AAAPT协同作用潜在地扩展到其他一线化疗药物(例如： 阿霉素、吉西他滨、卡铂、PI3K抑制剂诺华)和其他癌症(如结肠癌、肺癌、前列腺癌、 乳房、大脑和肾脏)，对目前的治疗方法难以奏效。

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.