Temozolomide Perillyl Alcohol Conjugate as Treatment for Recurrent Malignant Brain tumors

替莫唑胺紫苏醇结合物治疗复发性恶性脑肿瘤

• 批准号: 9135751
• 负责人: THOMAS C. CHEN
• 金额: $ 30万
• 依托单位: NEONC TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135751
• 关键词: Address; Alkylating Agents; Animal Cancer Model; Animal Model; Animals; Astrocytes; Autophagocytosis; Biodistribution; Blood - brain barrier anatomy; Bone Marrow; Brain; Brain Neoplasms; Businesses; Cells; Cellular biology; Chemicals; Clinic; Clinical; Clinical Data; Clinical Trials; Collaborations; DNA; DNA Fragmentation; Data; Disease; Dose; Drug Kinetics; Drug Targeting; Drug resistance; Effectiveness; Environment; Glioblastoma; Glioma; Goals; Growth; Human; Immune; In Vitro; Intestines; Intracranial Neoplasms; Intravenous; Investigation; Lead; Link; MGMT gene; Malignant - descriptor; Malignant neoplasm of brain; Mammals; Mass Spectrum Analysis; Measures; Medical; Modeling; Monoterpenes; Mus; Normal Cell; Oral; Organ; Patients; Penetration; Performance; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Population; Preparation; Prevalence; Protocols documentation; Radiosurgery; Reagent; Recurrence; Recurrent tumor; Regimen; Resistance; Rodent Model; Route; Stem cells; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Toxic effect; Universities; Writing; angiogenesis; anticancer activity; base; brain endothelial cell; cancer stem cell; chemotherapeutic agent; chemotherapy; commercialization; cytotoxic; cytotoxicity; effective therapy; efficacy testing; glioma cell line; in vivo; killings; neurosurgery; novel; novel therapeutics; perilla alcohol; pre-clinical; public health relevance; radioresistant; research study; standard of care; success; temozolomide; tumor; tumor growth

 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.

 描述（由申请人提供）：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，中位生存时间为14.6个月。使用替莫唑胺（TMZ）的标准治疗化疗最初是有效的，但GBM不可避免地复发，并且这些复发的肿瘤对TMZ具有耐药性。目前对于TMZ耐药的复发性肿瘤患者没有有效的治疗选择。因此，确定靶向TMZ耐药肿瘤的药物至关重要。最近，一种单萜紫苏醇（POH）被证明对复发性GBM具有中等程度的成功，但仅当以高剂量使用时，这不幸地导致毒性。我们的方法是将TMZ与POH结合，以产生一种新型药物TMZ-POH，用于靶向TMZ耐药复发性GBM。基于这两种药物一起使用比单独使用任何一种药物更有效的假设，与我们的小企业合作伙伴合作，我们成功地将TMZ与POH结合起来。在初步数据中，我们证明，这种新的缀合物对TMZ耐药神经胶质瘤细胞的细胞毒性比单独使用药物或等摩尔剂量的两种药物的混合物高10倍。此外，TMZ-POH缀合物有效对抗多种TMZ抗性GBM细胞和神经胶质瘤干细胞（GSC），即负责引发复发性GBM的化疗和放射抗性群体。体内数据显示，TMZ-POH耐受性良好，并且对颅内肿瘤有效。所提出的目的将（1）在体外鉴定TMZ-POH对TMZ抗性神经胶质瘤细胞和神经胶质瘤癌症干细胞的活性机制，和（2）在免疫功能不全和免疫功能正常的动物中确定不同剂量和给药模式下TMZ-POH对颅内神经胶质瘤肿瘤生长的体内影响，并测量TMZ-POH在这些不同方案中的生物分布。这些目标的完成将确定优化该药剂效力的方法，以确保最大功效。本研究将提供临床前数据，以确定TMZ-POH在减少或消除TMZ耐药脑肿瘤中的疗效。总体目标是验证和建立TMZ-POH作为一种新型化疗药物，对耐药，复发性GBM肿瘤具有突出的活性。

项目成果

NEO212 Inhibits Migration and Invasion of Glioma Stem Cells.

• DOI: 10.1158/1535-7163.mct-17-0591
• 发表时间: 2018-03
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Marín-Ramos NI;Thein TZ;Cho HY;Swenson SD;Wang W;Schönthal AH;Chen TC;Hofman FM
• 通讯作者: Hofman FM