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（由适用提供）：多形胶质母细胞瘤（GBM）是最致命的恶性肿瘤之一，部分原因是其高度侵入性的性质，并且由于GBM细胞具有完全响应放射性或化学治疗的相对耐药性。一系列化合物源自NSAID塞来氧化的化学主链，这些链氧化酶的化合物不具有COX2抑制活性，但具有高度生物可用性，可以越过血脑屏障，并且比父母药物相比，在抑制肿瘤细胞生存能力方面的潜力更大。我们已经表明，最有效的铅化合物OSU-03012在体外已建立和原代的人类GBM细胞中引起强诱导细胞死亡，但在未转化的原发性星形胶质细胞或原发性肝细胞的培养物中并不引起浓度，在1-5波中的浓度低于1-20范围的plassma plossma consma consma的浓度。 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 primary via in the induction of a toxic endoplasmic网状（ER）应力 /自噬信号。在体内，我们在一个GBM模型中指出，OSU-03012可以增强动物的存活并与放射疗法相互作用，以进一步延长生存率。我们已经发表了OSU-03012的致死性，通过抑制HSP90或暴露于电离辐射来放大。我们假设：通过ROS和神经酰胺产生的Geldanamycin HSP90激动剂引起CD95激活，并平行于OSU -03012诱导的有毒自噬，这是GBM细胞杀死的协同作用。我们假设这是：通过促进神经酰胺合酶基因的表达/激活来增强OSU-03012诱导的有毒自噬来增强OSU-03012的电离辐射增强。具体目标1：将确定通过暴露于HSP90拮抗剂（Geldanamycins）17AAG / 17DMAG，促进原代人GBM细胞中OSU-03012毒性的分子机制。具体目标2：将确定OSU-03012无线电敏化原代人GBM细胞的分子机制，其特定于神经酰胺合酶基因的调节作用。特定目标3：将使用原代人GBM细胞的原位异种移植模型确定OSU-03012是在体内增强电离radiotion还是17AAG的结核效应。该提案中研究的目的是提供详细的机械证据，以将OSU-03012作为GBM从长凳上移至诊所的治疗方法。 公共卫生相关性：OSU-03012于2008年获得了一家生物技术公司（ARNO）的许可，部分基于我们在三个手稿中发表的数据，并以该药物为单一药物的I期试验将于2009年开始以各种恶性肿瘤开始，但在GBM患者中没有任何可能的恶性肿瘤。该提案中研究的目的是使用原代人GBM细胞确定OSU-03012作为单个药物的作用机理，并与电离辐射结合使用。并与Geldanamycins结合抑制HSP90功能。我们的目标是提供详细的机械证据，以将OSU-03012作为GBM的疗法转移到诊所中。