Polynuclear Platinums in Targeted and Combination Glioma Therapy

描述（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巨大的功效，但最近的数据表明，它们的活性通常仅限于一个亚组患者，这是基于靶蛋白（例如，EGFR）中突变的存在或相关途径的活性（例如，当PTEN完整时，EGFR抑制剂对胶质瘤的作用更好）。因此，开发更广泛活性的细胞毒性药物，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，我们专注于一类有前途的多核铂化合物（PPCs），并寻求通过靶向和结合pi3k途径中的抑制剂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，PPCs显示出比传统铂更大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阻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体的PPC，在抑制胶质瘤细胞克隆性方面比顺铂强250倍。在此，我们建议通过以下途径研究PPCs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，增强细胞对PPCs的应答；2)通过肽介导的靶向整合素和EGFR，改善PPCs向胶质瘤的递送；3)基于dna损伤剂增强溶瘤病毒复制的最新发现，利用Delta-24-RGD病毒，研究PPCs与腺病毒治疗之间的协同作用。我们的假设是，将靶向PPCs与其他疗法（如溶瘤病毒和信号转导途径抑制剂）相结合，为大多数患者开发有效的胶质瘤疗法提供了重要机会。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：胶质瘤需要新的治疗方法。虽然在过去的十年中，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，但在大多数癌症的临床中，这些抑制剂并没有实现它们的承诺。我们建议研究一个新的和有前途的细胞毒素家族，基于多核铂化学。这些药物的优势在于，它们应该对更广泛的癌症起作用，因为它们针对的是普遍存在的癌症方面，比如扩散。为了减少由于对正常健康组织的影响而产生的毒副作用，我们正在将它们与其他药物联合使用，并将其靶向于肿瘤。我们的目标是设计一种能够有效治疗多种不同类型癌症的疗法。

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.