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

基本信息

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
项目类别：
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

项目摘要

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恶性的，使用替莫唑胺 (TMZ) 的标准护理化疗最初是有效的，但 GBM 不可避免地会复发。并且这些复发性肿瘤对 TMZ 具有耐药性，目前对于 TMZ 耐药性复发性肿瘤患者尚无有效的治疗选择，因此需要确定药物。最近，一种单萜紫苏醇（POH）被证明对复发性 GBM 具有一定的成功，但仅在高剂量使用时才有效，不幸的是，这会导致毒性。 POH 与我们的小型商业合作伙伴合作，生产一种新型药物 TMZ-POH，以靶向 TMZ 耐药的复发性 GBM。初步数据表明，与单独的药物或等摩尔剂量的两种药物的混合物相比，这种新型结合物对 TMZ 耐药的神经胶质瘤细胞的细胞毒性高出 10 倍。 -POH 结合物可有效对抗多种 TMZ 耐药 GBM 细胞和神经胶质瘤干细胞 (GSC)，这是导致复发的化疗和放疗耐药细胞群GBM。体内数据表明 TMZ-POH 具有良好的耐受性，并且对颅内肿瘤有效。拟议的目标将（1）确定 TMZ-POH 对 TMZ 耐药神经胶质瘤细胞和神经胶质瘤干细胞的活性机制。 (2) 确定不同剂量和给药方式的 TMZ-POH 对免疫功能低下和免疫功能正常动物体内颅内神经胶质瘤肿瘤生长的影响，并测量TMZ-POH 在这些不同方案中的生物分布的完成将确定优化该药物效力的方法，以确保最大功效。本研究将提供临床前数据，以确定 TMZ-POH 在减少或消除方面的功效。 TMZ 耐药性脑肿瘤的总体目标是验证和建立 TMZ-POH 作为一种新型化疗药物，对耐药性、复发性 GBM 肿瘤具有出色的活性。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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