Polynuclear Platinums in Targeted and Combination Glioma Therapy

描述（由申请人提供）：脑肿瘤需要新的治疗方法。信号转导途径的小分子抑制剂显示出很大的功效，但最近的数据表明，基于靶蛋白中突变的存在，它们的活性通常限于一个亚组的患者（例如，EGFR）或相关通路的活性（例如，当PTEN完整时，EGFR抑制剂在胶质瘤中更好地起作用）。因此，开发更广泛活性的细胞毒性剂，特别是与信号转导抑制剂联合使用，仍有很强的理论基础。在这里，我们专注于一类有前途的多核铂化合物（PPC），并寻求战略，以提高其活性的目标和结合它们与抑制剂在thepi3 K途径。在神经胶质瘤的培养和临床前模型中，PPC显示出比传统铂类药物显著更高的疗效和更低的毒性。此外，它们诱导G2/M期阻滞和自噬，而不是凋亡，尽管触发一些相同的信号转导途径。我们的先导化合物是BBR 3610，一种基于精胺接头的PPC，其在抑制胶质瘤细胞的克隆形成方面比顺铂强250倍。本研究拟通过以下途径研究PPC的作用机制并提高其疗效：1）通过与靶向PI3K、EGFR、mTOR和Raf的信号转导抑制剂联合使用，增强PPC对细胞的反应; 2）通过针对整合素和EGFR的肽介导靶向，提高PPC向胶质瘤的递送;和3）基于DNA损伤剂增强溶瘤病毒复制的最新认识，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（如溶瘤病毒和信号转导通路抑制剂）相结合，代表了为大多数患者开发有效胶质瘤疗法的重要机会。我们正在与铂化学，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：需要新的神经胶质瘤治疗方法。虽然过去十年的许多努力都集中在驱动癌细胞生长的信号的高度特异性抑制剂上，但这些抑制剂在大多数癌症的临床中并没有实现其承诺。我们建议调查一个新的和有前途的家庭的细胞毒素，基于多核铂化学。这些药物的优点是，它们应该与更广泛的癌症一起工作，因为它们靶向癌症的普遍性方面，如增殖。为了减少缺点，即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并将其靶向肿瘤。目标是设计一种能够用有效疗法治疗许多不同癌症变体的疗法。

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.