Temozolomide Perillyl Alcohol Conjugate as Treatment for Recurrent Malignant Brain tumors

 描述(申请人提供)：多形性胶质母细胞瘤(GBM)是所有胶质瘤中最常见和最恶性的，中位生存期为14.6个月。使用替莫唑胺(TMZ)的标准护理化疗最初是有效的，但基底膜不可避免地会复发，而且这些复发的肿瘤对TMZ具有耐药性。对于对TMZ耐药的复发肿瘤患者，目前还没有有效的治疗选择。因此，确定针对TMZ耐药肿瘤的药物至关重要。最近，一种单萜，紫苏醇(POH)，被证明对复发的GBM有适度的成功，但只有在高剂量使用时才被使用，这不幸地导致了毒性。我们的方法是将TMZ与POH偶联，以产生一种新的药物TMZ-POH，以靶向TMZ耐药的复发GBM。基于这些药物结合在一起比任何一种药物单独更有效的假设，在我们的小企业合作伙伴的合作下，我们成功地将TMZ与POH偶联。在初步数据中，我们证明了这种新型结合物对TMZ耐药胶质瘤细胞的细胞毒作用比单独使用任何一种药物或在等摩尔剂量下两种药物的混合物高出10倍。此外，TMZ-POH结合物对多种耐TMZ的GBM细胞和胶质瘤干细胞(GSC)有效，GSC是引起复发GBM的耐化疗和耐辐射群体。体内数据显示，TMZ-POH耐受性良好，对颅内肿瘤有效。本研究的目的是(1)确定TMZ-POH对耐药胶质瘤细胞和脑胶质瘤干细胞的作用机制(S)，(2)确定不同剂量和给药方式对免疫功能低下和免疫活性动物体内脑胶质瘤生长的影响，并测量TMZ-POH在不同方案中的生物分布。完成这些目标将确定方法，以优化该制剂的效力，以确保最大的疗效。本研究将提供临床前数据，以确定TMZ-POH在减少或消除TMZ耐药脑肿瘤方面的疗效。总体目标是验证和建立TMZ-POH作为一种新的化疗药物，对耐药的、复发的GBM肿瘤具有突出的活性。

 DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM), the most common and malignant of all gliomas, has a median survival time of 14.6 months. Standard of care chemotherapy using temozolomide (TMZ) is effective initially, but the GBM inevitably recurs, and these recurrent tumors are resistant to TMZ. There are currently no effective treatment options for patients with TMZ-resistant, recurrent tumors. Therefore identifying drugs that target TMZ-resistant tumors is critical. Recently a monoterpene, perillyl alcohol (POH), was shown to have moderate success for recurrent GBM, but only when used at high doses, which unfortunately results in toxicity. Our approach is to conjugate TMZ to POH to produce a novel agent, TMZ-POH, to target TMZ-resistant recurrent GBMs. Based on the hypothesis that these drugs together are more effective than either drug alone, in collaboration with our small business partner; we have successfully conjugated TMZ to POH. In preliminary data we demonstrate that this novel conjugate has as much as 10 times more cytotoxic against TMZ-resistant glioma cells, as compared to either agent alone or the mixture of the two at equimolar doses. Furthermore, the TMZ-POH conjugate is effective against a variety of TMZ-resistant GBM cells, and glioma stem cells (GSC), the chemo- and radiation resistant population responsible for initiating recurrent GBMs. In vivo data show that TMZ-POH is well tolerated, and is effective in intracranial tumors. The proposed aims will (1) identify the mechanism(s) of TMZ-POH activity on TMZ- resistant glioma cells and glioma cancer stem cells in vitro, and (2) determine effects of TMZ-POH at different doses, and modes of administration on intracranial glioma tumor growth in vivo in immune incompetent and immune competent animals, and measure the biodistribution of TMZ-POH in these different protocols. Completion of these aims will identify ways to optimize the potency of this agent to insure maximum efficacy. The present investigation will provide pre-clinical data to determine efficacy of TMZ-POH in reducing or eliminating TMZ-resistant brain tumors. The overall goal is to validate and establish TMZ-POH as a novel chemotherapeutic agent with outstanding activity against drug-resistant, recurrent GBM tumors.