Targeted Cancer Therapeutics and Heart Failure: Mechanisms and Post-Injury Rep

靶向癌症治疗和心力衰竭：机制和损伤后恢复

• 批准号: 7488124
• 负责人: Thomas Force
• 金额: $ 34.85万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7488124
• 关键词: ABL1 gene; Accounting; Adverse effects; Antineoplastic Agents; Apoptosis; Automobile Driving; Autophagocytosis; BAY 54-9085; Biology; Cancerous; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cell Cycle Arrest; Cell Death; Cell Proliferation; Cell physiology; Cells; Cellular biology; Cessation of life; Chimeric Proteins; Class; Clinical; Clinical Trials; Collaborations; Dasatinib; Data; Development; Disease; Dropout; Drops; Drug Delivery Systems; Drug Design; EFRAC; Early Intervention; Early identification; Evaluation; Exhibits; Fibrinogen; Functional disorder; Future; Gene Transfer; Gleevec; Heart; Heart failure; Imatinib; In Vitro; Injury; Interruption; JAK2 gene; Lead; Left; Left Ventricular Dysfunction; Left Ventricular Ejection Fraction; Left Ventricular Function; Left Ventricular Mass; Life; Light; Maintenance; Malignant Neoplasms; Measures; Mediating; Molecular; Mus; Muscle Cells; Mutate; Mutation; Necrosis; New Agents; Nexavar; Numbers; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Population; Process; Proliferating; Prospective Studies; Protein Tyrosine Kinase; Proto-Oncogene Protein c-kit; Recovery; Recruitment Activity; Reliance; Reporting; Resistance; Risk; Severities; Side; Signal Pathway; Solid Neoplasm; Stem cells; Subfamily lentivirinae; Sutent; Symptoms; Therapeutic; Toxic effect; Tyrosine Kinase Inhibitor; United States Food and Drug Administration; Withdrawal; Work; angiogenesis; base; c-abl Proto-Oncogenes; cancer cell; cancer therapy; cell killing; cost; design; functional decline; heart function; in vivo; inhibitor/antagonist; injury and repair; insight; leukemia; member; mouse model; mutant; neoplastic cell; novel; novel strategies; prevent; prospective; repaired; response; restoration; small molecule; stem; therapeutic target; vigilance

This Project examines cardiac injury induced by members of the class of small molecule tyrosine kinase inhibitors (TKIs). These drugs target tyrosine kinases, mutations or amplications of which are causal or strongly contributory in various solid tumors and leukemias. They have revolutionized the treatment of a number of these malignancies, converting uniformly fatal malignancies to chronically manageable, if not curable, diseases. Many of these mutated kinases activate pathways that promote proliferation or prevent apoptosis, and the drugs that inhibit them, therefore, lead to cell cycle arrest or cell death of the cancerous cells. However, all of these mutated tyrosine kinases have wild-type counterparts, many of which are expressed in cardiomyocytes and/or in cardiac-resident stem/progenitor cells (CRSCs). This raises concerns that inhibition of wild-type kinases in the heart might have adverse consequences on cardiomyocytes, possibly leading to cardiac dysfunction and even heart failure. Indeed, our clinical collaborators have recently identified cardiotoxicity of two of these agents that are FDA-approved: imatinib (Gleevec) and sunitinib (Sutent). These findings led us to studies in cultured cardiomyocytes and mouse models that have identified molecular mechanisms by which imatinib induces cardiotoxicity. In Specific Aim 1 we will determine the mechanisms by which sunitinib and another agent, sorafenib (Nexavar), two "multi-targeted" TKIs that not only block angiogenesis but also induce apoptosis of cancer cells, induce cardiac dysfunction. These studies are essential because they will 1) identify the specific target of the TKI, inhibition of which induces cardiomyocyte dysfunction and/or death, and 2) identify the signaling pathway(s) activated in response to the TKIs that mediate dysfunction and death. By identifying the specific target and the pathways mediating toxicity, we should be able to: a) predict cardiotoxicity of future agents that also inhibit that target; b) impact future drug design since in some instances the target, inhibition of which mediates toxicity, is not essential for tumor cell killing and the TKI can be modified to avoid these "bystander targets; c) identify novel strategies for cardioprotection in cases such as with imatinib in which the signaling pathway mediating toxicity is not central to tumor cell killing (e.g. JNKs mediate imatinib toxicity, and thus strategies to inhibit JNKs could reduce imatinib cardiotoxicity but leave tumor cell killing intact); d) alert clinicians and regulatory agencies to potential problems with agents still in development (e.g. lestaurtinib, a JAK2 inhibitor), encouraging them to prospectively examine LV function in late phase clinical trials or early post-FDA approval. The second half of this project focuses on mechanisms of repair following withdrawal of TKI therapy. We have found in the case of imatinib and sunitinib, that recovery of LV function in patients is quite dramatic after stopping the TKIs. Furthermore, in studies in mice, we have found clear-cut evidence of myocyte dropout (decline in LV mass), yet there was little evidence of excessive apoptosis, necrosis, or autophagy. It is our hypothesis that at least part of the toxicity and its reversibility are due to adverse effects of TKIs on key functions of CRSCs. Specifically, our preliminary studies will show that imatinib, which in addition to Abl also inhibits c-Kit (the receptor for stem cell factor), which is expressed on many CRSCs, markedly reduces the ability of c-Kit+ CRSCs in culture to differentiate into cardiomyocytes. Furthermore, imatinib also blocks proliferation and induces apoptosis of c-Kit(-) CRSCs (cardiac side population or SP cells). Thus in two different lineages of CRSCs, imatinib leads to dysregulation of proliferation, differentiation, and apoptosis. We will employ lentivirus-mediated gene transfer of imatinib-resistant mutants of kinases targeted by imatinib (Abl, PDGFRs, and c-Kit) to attempt to "rescue" these CRSCs from the adverse effects of imatinib, thereby identifying the critical target(s) regulating these processes. These studies should not only identify novel mechanisms of TKI cardiotoxicity, but also define factors and pathways regulating these critical CRSC functions, thereby advancing our understanding of basic stem cell biology. Finally, we will correlate these findings in vitro with studies in vivo, examining CRSC proliferation and new myocyte formation. Taken together, we believe these studies will shed light on a burgeoning problem in cancer treatment, with the hope being that with early identification and treatment of patients with TKI-induced cardiotoxicity, patients may be able to be maintained on these life-saving therapies.

本项目研究小分子酪氨酸激酶类成员诱导的心脏损伤 抑制剂（TKI）。这些药物靶向酪氨酸激酶，其突变或扩增是因果关系， 在各种实体瘤和白血病中起重要作用。他们彻底改变了 这些恶性肿瘤的数量，将一致致命的恶性肿瘤转化为长期可管理的，如果不是 可治愈的疾病这些突变激酶中的许多激活促进增殖或阻止增殖的途径。 因此，细胞凋亡和抑制它们的药物导致癌细胞的细胞周期停滞或细胞死亡。 细胞然而，所有这些突变的酪氨酸激酶都有野生型对应物，其中许多是 在心肌细胞和/或心脏驻留干/祖细胞（CRSC）中表达。这引发了人们的担忧 抑制心脏中的野生型激酶可能对心肌细胞产生不利影响， 导致心脏功能障碍甚至心力衰竭。事实上，我们的临床合作者最近发现， FDA批准的两种药物：伊马替尼（格列卫）和舒尼替尼（索坦）的心脏毒性。这些 这些发现使我们在培养的心肌细胞和小鼠模型中进行了研究， 伊马替尼诱导心脏毒性的机制。在具体目标1中，我们将确定以下机制： 舒尼替尼和另一种药物索拉非尼（Nexavar），这两种“多靶向”TKI不仅可以阻断 血管生成还诱导癌细胞凋亡，诱发心功能障碍。这些研究 这是必要的，因为它们将1）鉴定TKI的特异性靶点，其抑制诱导心肌细胞 功能障碍和/或死亡，以及2）识别响应TKI激活的信号通路， 介导功能障碍和死亡。通过识别特定的靶点和介导毒性的途径，我们 应该能够：a）预测也抑制靶点未来药剂的心脏毒性; B）影响未来的药物 设计，因为在某些情况下，抑制介导毒性的靶标对于肿瘤细胞不是必需的， 杀伤和TKI可以被修饰以避免这些“旁观者靶标”; c）鉴定用于 在诸如伊马替尼的情况下的心脏保护，其中介导毒性的信号传导途径不是中心的 肿瘤细胞杀伤（例如JNK介导伊马替尼毒性，因此抑制JNK的策略可以减少肿瘤细胞杀伤）。 伊马替尼心脏毒性，但保持肿瘤细胞杀伤完整）; d）提醒临床医生和监管机构注意潜在的 仍在开发中的药物（如JAK 2抑制剂leadetinib）的问题，鼓励他们 在后期临床试验或FDA批准后的早期前瞻性检查LV功能。 该项目的后半部分重点关注TKI治疗停药后的修复机制。我们 在伊马替尼和舒尼替尼的情况下，已经发现患者的LV功能的恢复是相当戏剧性的， 停止TKI此外，在对小鼠的研究中，我们发现了肌细胞脱落的明确证据 （LV质量下降），但几乎没有过度凋亡、坏死或自噬的证据。是我们 假设至少部分毒性及其可逆性是由于TKI对关键 CRSC的功能。具体来说，我们的初步研究将表明，除了Abl之外，伊马替尼还 抑制c-Kit（干细胞因子的受体），它在许多CRSC上表达，显著降低 培养物中c-Kit+ CRSC分化成心肌细胞的能力。此外，伊马替尼还阻断 增殖并诱导c-Kit（-）CRSC（心脏侧群或SP细胞）凋亡。在两个 在CRSC的不同谱系中，伊马替尼导致增殖、分化和凋亡的失调。我们 将采用慢病毒介导的伊马替尼靶向激酶的伊马替尼抗性突变体的基因转移（Ab 1， PDGFRs和c-Kit），以试图“拯救”这些CRSC免受伊马替尼的不良作用，从而 确定调节这些过程的关键目标。这些研究不仅要确定新的 TKI心脏毒性的机制，而且还定义了调节这些关键CRSC的因素和途径 功能，从而推进我们对基本干细胞生物学的理解。最后，我们将这些 体外研究结果与体内研究相结合，检查CRSC增殖和新肌细胞形成。 总之，我们相信这些研究将揭示癌症治疗中的一个新兴问题， 希望通过早期识别和治疗TKI诱导的心脏毒性患者， 也许可以通过这些救命的疗法来维持。