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

基本信息

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
项目类别：
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

项目摘要

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显示出巨大的功效，但最近的数据表明，基于靶蛋白（例如 EGFR）中突变的存在或相关蛋白的活性，它们的活性通常仅限于一小部分患者。（例如，当 PTEN 完整时，EGFR 抑制剂在神经胶质瘤中效果更好）。因此，开发更广泛活性的细胞毒剂，特别是与信号转导抑制剂联合使用，仍然有充分的理由。在这里，我们重点关注一类有前途的多核铂化合物 (PPC)，并寻求通过靶向 PI3K 通路中的抑制剂并将其与抑制剂结合来增强其活性的策略。在神经胶质瘤的培养和临床前模型中，PPC 比传统铂类药物显示出显着更高的疗效和更低的毒性。此外，尽管它们触发了一些相同的信号转导途径，但它们诱导 G2/M 期停滞和自噬而不是细胞凋亡。我们的先导化合物是 BBR3610，一种基于精胺连接体的 PPC，其抑制神经胶质瘤细胞克隆形成的功效比顺铂强 250 倍。在这里，我们建议通过以下方式研究PPC的作用机制并提高其功效：1）将PPC与针对PI3K、EGFR、mTOR和Raf的信号转导抑制剂联合增强细胞对PPC的反应； 2) 通过针对整合素和 EGFR 的肽介导靶向改善 PPC 向神经胶质瘤的递送； 3) 基于 DNA 损伤剂增强溶瘤病毒复制的最新见解，使用 Delta-24-RGD 病毒研究 PPC 和腺病毒治疗之间的协同作用。我们的假设是，将靶向 PPC 与其他疗法（例如溶瘤病毒和信号转导途径抑制剂）相结合，代表着为大多数患者开发有效的神经胶质瘤疗法的重要机会。我们正在与铂化学、神经胶质瘤治疗、药物开发、肽靶向、腺病毒治疗和生物统计学领域的专家团队合作，以实现我们的目标。公共卫生相关性：神经胶质瘤需要新的治疗方法。尽管过去十年的大量努力都集中在驱动癌细胞生长的高度特异性信号抑制剂上，但这些抑制剂在大多数癌症的临床中并未兑现其承诺。我们提议研究一个基于多核铂化学的新的、有前途的细胞毒素家族。这些药物的优势在于，它们应该能够很好地治疗更广泛的癌症，因为它们针对的是癌症的普遍特征，例如增殖。为了减少由于对正常健康组织的影响而产生的毒副作用，我们将它们与其他药物结合起来并靶向肿瘤。目标是设计一种能够通过有效疗法治疗许多不同癌症变体的疗法。