OSU-03012 therapy for glioblastoma

OSU-03012 胶质母细胞瘤疗法

• 批准号: 7992871
• 负责人: PAUL DENT
• 金额: $ 32.14万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-07 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992871
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; Agonist; Animals; Astrocytes; Autophagocytosis; BAY 54-9085; Biotechnology; Blood - brain barrier anatomy; Cause of Death; Cell Death; Cell Death Induction; Cell Survival; Cells; Ceramides; Chemicals; Clinic; Coxibs; Data; Drug effect disorder; Drug toxicity; Endoplasmic Reticulum; Exposure to; Geldanamycin; Genes; Glioblastoma; Goals; HSP 90 inhibition; Health Benefit; Heat-Shock Proteins 90; Hepatocyte; Human; In Vitro; Ionizing radiation; Laboratories; Lead; Licensing; Malignant Neoplasms; Manuscripts; Modeling; Molecular; Nature; Non-Steroidal Anti-Inflammatory Agents; PTGS2 gene; Parents; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Plasma; Production; Program Development; Property; Proto-Oncogene Proteins c-akt; Public Health; Publishing; Radiation therapy; Radio; Relative (related person); Reporting; Resistance; Rodent; Role; Series; Signal Transduction; Signal Transduction Pathway; TNFRSF6 gene; Therapeutic; Toxic effect; Vertebral column; Vorinostat; Xenograft Model; base; cancer cell; celecoxib; cell killing; cell transformation; dihydroceramide desaturase; endoplasmic reticulum stress; in vivo; inhibitor/antagonist; killings; neoplastic cell; novel; public health relevance; tumor; tumor growth

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is one of the most lethal malignancies in part due to its highly invasive nature and due to the relative resistance of GBM cells to fully respond to radio- or chemo-therapies. A series of compounds have been derived from the chemical backbone of the NSAID Celecoxib that do not possess COX2 inhibitory activity, but are highly bio-available, can cross the blood-brain barrier, and are an order of magnitude more potent at suppressing tumor cell viability than the parent drug. We have shown that the most potent lead compound, OSU-03012, causes a strong induction cell death in established and primary human GBM cells in vitro, but not in cultures of non-transformed primary astrocytes or primary hepatocytes, at concentrations in the 1-5 ¿M range, which is lower than the 15-20 ¿M achievable plasma concentration of this agent in rodents. This compound was selected by the NCI RAID program for development, in part based on our data, and a phase I trial with this drug as a single agent will commence in other tumor types in 2009. We have demonstrated in primary and established human GBM cells that OSU-03012 suppresses short-term viability and colony formation in vitro and that OSU-03012 -induced killing occurs primarily via in the induction of a toxic endoplasmic reticulum (ER) stress / autophagy signal. In vivo we have noted in one GBM model that OSU-03012 can enhance animal survival and interact with radiotherapy to further prolong survival. We have published that the lethality of OSU-03012 is magnified by inhibition of HSP90 or by exposure to ionizing radiation. We hypothesize that: geldanamycin HSP90 agonists via ROS and ceramide production cause CD95 activation in parallel to OSU-03012 -induced toxic autophagy which is responsible for the synergy of GBM cell killing. We hypothesize that: ionizing radiation enhances OSU-03012 toxicity by promoting expression/ activation of ceramide synthase genes which enhances OSU-03012 -induced toxic autophagy. Specific Aim 1: Will determine the molecular mechanism(s) by which OSU-03012 toxicity in primary human GBM cells is promoted by exposure to the HSP90 antagonists (geldanamycins) 17AAG / 17DMAG. Specific Aim 2: Will determine the molecular mechanisms by which OSU-03012 radio-sensitizes primary human GBM cells with specific focus on the regulatory roles of ceramide synthase genes. Specific Aim 3: Will determine, using orthotopic xenograft models of primary human GBM cells, whether OSU-03012 enhances the tumoricidal effects of ionizing radiation or of 17AAG, in vivo. The goal of the studies in this proposal is to provide detailed mechanistic evidence to move OSU-03012 as a therapeutic for GBM from the bench into the clinic. PUBLIC HEALTH RELEVANCE: OSU-03012 was licensed in 2008 to a biotechnology company (Arno) in part based on our data published in three manuscripts, and a phase I trial with this drug as a single agent will commence in 2009 in a variety of malignancies but not with any likely accrual in GBM patients. The goal of the studies in this proposal is to determine in molecular detail using primary human GBM cells the mechanisms of action of OSU-03012 as a single agent and in combination with ionizing radiation; and in combination with geldanamycins to inhibit HSP90 function. Our goal is to provide detailed mechanistic evidence to move OSU-03012 as a therapeutic for GBM into the clinic.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是最致命的恶性肿瘤之一，部分原因在于其高度侵袭性以及GBM细胞对放疗或化疗完全反应的相对抵抗力。一系列化合物源自 NSAID Celecoxib 的化学主链，这些化合物不具有 COX2 抑制活性，但具有高生物利用度，可以穿过血脑屏障，并且在抑制肿瘤细胞活力方面比母体药物更有效一个数量级。我们已经证明，最有效的先导化合物 OSU-03012 在体外可在已建立的原代人类 GBM 细胞中引起强烈的诱导细胞死亡，但在未转化的原代星形胶质细胞或原代肝细胞的培养物中则不会，浓度在 1-5 µM 范围内，低于该药物在啮齿动物中可达到的 15-20 µM 血浆浓度。 NCI RAID 计划部分基于我们的数据选择了该化合物进行开发，并将于 2009 年在其他肿瘤类型中开始使用该药物作为单一药物的 I 期试验。我们已在原代和已建立的人 GBM 细胞中证明，OSU-03012 可以抑制体外的短期活力和集落形成，并且 OSU-03012 诱导的杀伤作用主要通过诱导有毒内质细胞来发生。 网状（ER）应激/自噬信号。在体内，我们在一种 GBM 模型中注意到 OSU-03012 可以增强动物存活率并与放疗相互作用以进一步延长存活率。我们已经发表过，通过抑制 HSP90 或暴露于电离辐射，OSU-03012 的致死率会被放大。我们假设：格尔德霉素 HSP90 激动剂通过 ROS 和神经酰胺产生引起 CD95 激活，同时 OSU-03012 诱导的毒性自噬负责协同杀伤 GBM 细胞。我们假设：电离辐射通过促进神经酰胺合酶基因的表达/激活来增强 OSU-03012 毒性，从而增强 OSU-03012 诱导的毒性自噬。具体目标 1：确定暴露于 HSP90 拮抗剂（格尔德霉素）17AAG / 17DMAG 后 OSU-03012 对原代人 GBM 细胞毒性增强的分子机制。具体目标 2：将确定 OSU-03012 对原代人类 GBM 细胞放射增敏的分子机制，特别关注神经酰胺合酶基因的调节作用。具体目标 3：将使用原代人 GBM 细胞的原位异种移植模型确定 OSU-03012 是否增强体内电离辐射或 17AAG 的杀肿瘤作用。该提案中的研究目标是提供详细的机制证据，将 OSU-03012 作为 GBM 治疗药物从实验室转移到临床。 公共健康相关性：OSU-03012 于 2008 年被授权给一家生物技术公司 (Arno)，部分基于我们在三份手稿中发表的数据，该药物作为单一药物的 I 期试验将于 2009 年开始，用于治疗多种恶性肿瘤，但在 GBM 患者中没有任何可能的效果。本提案中的研究目标是使用原代人 GBM 细胞从分子细节上确定 OSU-03012 作为单一药物以及与电离辐射组合的作用机制；并与格尔德霉素联用抑制HSP90功能。我们的目标是提供详细的机制证据，将 OSU-03012 作为 GBM 治疗药物推向临床。