Polynuclear Platinums in Targeted and Combination Glioma Therapy

多核铂在胶质瘤靶向和联合治疗中的应用

• 批准号: 7901448
• 负责人: OLIVER BOGLER
• 金额: $ 26.24万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-09 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901448
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Adenoviruses; Animal Model; Apoptosis; Autophagocytosis; Binding; Biometry; Brain Neoplasms; Cancer Cell Growth; Cell Cycle Arrest; Cell Death; Cells; Chemistry; Cisplatin; Clinic; Clinical; Combined Modality Therapy; Cultured Cells; Cytotoxic agent; DNA Damage; DNA Repair; Data; Development; Disadvantaged; Environment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Family; G2/M Arrest; Glioblastoma; Glioma; Goals; Home environment; Individual; Integrins; Lead; Malignant Neoplasms; Mediating; Modification; Molecular; Mutation; Oncolytic; Oncolytic viruses; PTEN gene; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Platinum; Platinum Compounds; Pre-Clinical Model; Proteins; Relative (related person); Side; Signal Pathway; Signal Transduction; Signal Transduction Inhibitor; Signal Transduction Pathway; Spermine; Testing; Tissues; Toxic effect; Variant; Viral; Virus; Virus Inhibitors; Work; Xenograft procedure; base; cytotoxic; drug development; effective therapy; human FRAP1 protein; improved; inhibitor/antagonist; insight; novel; protein aminoacid sequence; public health relevance; response; small molecule; temozolomide; tumor

DESCRIPTION (provided by applicant): New therapies are needed for brain tumors. Small molecule inhibitors of signal transduction pathways show great efficacy, but recent data suggest that their activity is often restricted to a sub-group of patients, based on the presence of mutations in the target protein (e.g., EGFR) or on the activity of associated pathways (for example, EGFR inhibitors work better in glioma when PTEN is intact). Therefore, a strong rationale remains for the development of more broadly active cytotoxic agents, particularly for use in combination with signal transduction inhibitors. Here we focus on a promising class of polynuclear platinum compounds (PPCs), and pursue strategies to enhance their activity by targeting and combining them with inhibitors in thePI3K pathway. In culture and preclinical models of glioma, PPCs show significantly greater efficacy and less toxicity than conventional platinums. Furthermore, they induce G2/M arrest and autophagy rather than apoptosis, despite triggering some of the same signal transduction pathways. Our lead compound is BBR3610, a spermine linker-based PPC, that is 250x more potent in suppressing clonogenicity of glioma cells than cisplatin. Here, we propose to study the mechanism of action and improve the efficacy of PPCs by: 1) enhancing the cellular response to PPCs by combining them with signal transduction inhibitors targeting PI3K, EGFR, mTOR and Raf; 2) improving delivery of PPCs to glioma by peptide-mediated targeting aimed at integrin and EGFR; and 3) investigate the synergy between PPCs and adenoviral therapy, using the Delta-24-RGD virus, based on the recent insight that DNA-damaging agents enhance oncolytic viral replication. It is our hypothesis that combining targeted PPCs with other therapies, such as oncolytic viruses and inhibitors of signal transduction pathways, represents an important opportunity to develop effective glioma therapies for the majority of patients. We are working with a team of experts in the fields of platinum chemistry, glioma therapy, drug development, peptide targeting, adenoviral therapy and biostatistics to accomplish our goals. PUBLIC HEALTH RELEVANCE: New treatments for glioma are needed. While much effort over the past decade has focused on highly specific inhibitors of signals that drive cancer cell growth, these have not fulfilled their promise in the clinic in the majority of cancers. We are proposing to investigate a new and promising family of cytotoxics, based on polynuclear platinum chemistry. The advantage of these agents is that they should work well with a broader spectrum of cancers as they target aspects of the cancer that are universal, such as proliferation. To reduce the disadvantages, which are toxic side due to effects on normal, healthy tissue, we are combining them with other agents and targeting them to the tumor. The goal is to devise a therapy capable of treating many different variants of cancer with an effective therapy.

描述（由申请人提供）：脑肿瘤需要新的疗法。信号转导途径的小分子抑制剂表现出很大的功效，但最近的数据表明，基于目标蛋白（例如EGFR）中的突变（例如，EGFR抑制剂在PTEN中，PTEN中的glioma in Pertact in Pertact n potact in ptten均可以更好地工作），他们的活性通常仅限于患者的亚组。因此，有强大的理由是开发更广泛的细胞毒性剂，尤其是与信号转导抑制剂结合使用。在这里，我们专注于有前途的多核铂化合物（PPC），并通过将它们与PIBI3K途径中的抑制剂结合起来，采取策略来增强其活性。在神经胶质瘤的培养和临床前模型中，PPC比常规铂显示出明显更大的疗效和更小的毒性。此外，尽管触发了一些相同的信号转导途径，但它们诱导了G2/M停滞和自噬而不是凋亡。我们的铅化合物是BBR3610，这是一种基于精子接头的PPC，在抑制神经胶质瘤细胞的克隆性方面比顺铂高250倍。在这里，我们建议通过以下方式研究作用机理，并提高PPC的功效：1）通过将它们与靶向PI3K，EGFR，MTOR，MTOR和RAF的信号转导抑制剂相结合来增强对PPC的细胞反应； 2）通过针对整联蛋白和EGFR的肽介导的靶向，改善PPC向神经胶质瘤的递送； 3）基于最近的见解，即使用DELTA-24-RGD病毒，研究了PPCS和腺病毒疗法之间的协同作用，即DNA损害剂增强了溶溶性病毒复制的见解。我们的假设是，将靶向PPC与其他疗法相结合，例如溶瘤病毒和信号转导途径的抑制剂，这是为大多数患者开发有效神经胶质瘤疗法的重要机会。我们正在与铂金化学，神经胶质瘤治疗，药物开发，肽靶向，腺病毒疗法和生物统计学的专家团队合作，以实现我们的目标。公共卫生相关性：需要新的神经胶质瘤治疗方法。尽管过去十年中的许多努力集中在高度特异性的信号抑制剂上，这些信号抑制剂驱动癌细胞的生长，但这些疾病尚未实现大多数癌症的诊所的诺言。我们建议根据多核铂金化学研究一个新的且有前途的细胞毒素家族。这些药物的优点是，它们应该与更广泛的癌症相处，因为它们针对普遍的癌症方面，例如增殖。为了减少由于对正常健康组织的影响而导致有毒一面的缺点，我们将它们与其他药物结合在一起，并将其靶向肿瘤。目的是设计一种能够通过有效治疗的癌症治疗许多不同变异的疗法。