Polynuclear Platinums in Targeted and Combination Glioma Therapy

描述(申请人提供)：脑瘤需要新的治疗方法。信号转导通路的小分子抑制剂显示出很好的疗效，但最近的数据表明，它们的活性通常限于亚组患者，基于靶蛋白(例如，EGFR)的突变或相关通路的活性(例如，当PTEN完整时，EGFR抑制剂在胶质瘤中效果更好)。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，仍然是一个强有力的理由。在这里，我们聚焦于一类有前景的多核铂化合物(PPC)，并寻求通过靶向并将它们与PI3K途径中的抑制剂结合来增强其活性的策略。在胶质瘤的培养和临床前模型中，PPC比传统的铂显示出显著更好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，但它们诱导了G2/M期停滞和自噬，而不是凋亡。我们的先导化合物是BBR3610，一种基于精胺连接物的PPC，在抑制胶质瘤细胞克隆形成方面的效力是顺铂的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疗效：1)通过将PPC与针对PI3K、EGFR、mTOR和Raf的信号转导抑制剂相结合来增强细胞对PPC的反应；2)通过针对整合素和EGFR的多肽介导的靶向来改善PPC对胶质瘤的递送；以及3)基于最近的研究发现DNA损伤剂促进溶瘤病毒复制，利用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，靶向PPC与其他治疗方法，如溶瘤病毒和信号转导途径的抑制剂，代表着为大多数患者开发有效的胶质瘤治疗的重要机会。我们正在与铂化学、胶质瘤治疗、药物开发、多肽靶向、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：胶质瘤需要新的治疗方法。尽管过去十年的很多努力都集中在驱动癌细胞生长的高度特异的信号抑制剂上，但这些药物并没有在大多数癌症的临床上实现它们的承诺。我们建议研究一类基于多核铂化学的新的、有希望的细胞毒物家族。这些药物的优势是，它们应该对更广泛的癌症范围很好，因为它们针对癌症中普遍存在的方面，如增殖。为了减少这些副作用，这些副作用会对正常、健康的组织产生影响，我们正在将它们与其他药物结合起来，并将它们靶向肿瘤。其目标是设计一种疗法，能够用一种有效的疗法来治疗多种不同的癌症变种。

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.