Development of E1A Gene Therapy in Ovarian Cancer

卵巢癌E1A基因疗法的进展

基本信息

  • 批准号:
    7729373
  • 负责人:
  • 金额:
    $ 14.74万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-09-04 至 2010-08-31
  • 项目状态:
    已结题

项目摘要

During the previous funding period, we defined multiple antitumor activities associated with E1A gene expression and established an appropriate animal model to evaluate the anti-ovarian cancer activity of an E1Aliposome complex. A phase I study using ElA-liposome complex targeting of breast and ovarian cancers was completed and reported during the previous funding period (Appendix 1-J. Clin. Oncol. 19:3422-3433, 2001). Based on this experience, we initiated a phase II trial of intraperitoneal single-agent E1A gene therapy in patients with recurrent ovarian cancer in 2001. Because of the small number of patients who met the eligibility requirements, we terminated the phase II trial and initiated a new phase l/ll trial that combines chemotherapy with E1A gene therapy and that has more appropriate eligibility requirements. This phase l/ll trial has been opened and has begun to accrue patients. In the competitive renewal, we will continue both preclinical studies and clinical trials to ensure the development of an effective therapeutic approach for ovarian cancer that utilizes gene therapy. To achieve this goal, we propose the following three Specific Aims: Specific Aim 1: To complete the phase l/ll trial of E1A gene therapy combined with chemotherapy. Using a novel trial design, we will perform a randomized phase l/ll trial in which one arm receives weekly i.v. paclitaxel (to establish a concurrent control group for a heterogeneous group of patients) and the other arm receives weekly i.v. paclitaxel with i.p. liposomal E1A gene therapy at different does levels. This study will define the toxicity, maximum tolerated dose (MTD), clinical response rate, and progression-free survival of weekly paclitaxel plus E1A-\\p\d complex treatment. Biopsies will be obtained to monitor therapy at the cellular level. Specific Aim 2: To develop an ovarian cancer-specific gene delivery system and expression vector. Two approaches will be used to improve systemic i.v. targeting of E1A gene therapy to treat ovarian cancer xenografts: 1) development of ovarian cancer-specific promoter elements and 2) conjugation of liposomes with targeting peptides, folate ligand, and anti¿folate receptor antibodies. Specific Aim 3: To develop an effective combination of E1A gene therapy with other agents in a preclinical ovarian cancer model. Using ovarian cancer xenografts, we will test the efficacy and toxicity of E1A gene therapy in combination with cytotoxic drugs used to treat ovarian cancer patients as well as novel biologic agents (TNFa and TRAIL). Preliminary data suggest that these agents may exert synergistic antitumor activity at subtoxic doses. The clinical data from Aim 1 and preclinical insights from Aims 2 and 3 can be combined in the future to design novel and potentially even more effective therapeutic strategies.
在之前的资助期间,我们定义了与E1a基因相关的多种抗肿瘤活性 表达并建立了合适的动物模型以评价E1Aliposome的抗卵巢癌活性 很复杂。使用ELA-脂质体复合体靶向治疗乳腺癌和卵巢癌的I期研究 在上一个供资期间完成并报告(附录1-J。克莱恩。奥科尔。19:3422-3433,2001)。 基于这一经验,我们启动了腹膜腔内单剂E1a基因治疗的II期试验 2001年复发性卵巢癌患者的临床资料。因为符合条件的患者数量很少 要求,我们终止了II期试验,并启动了结合化疗的新的L/11期试验 E1a基因疗法,这有更合适的资格要求。这一阶段的L/11审判已经完成 开业并已开始招收病人。在竞争更新中,我们将继续进行两项临床前研究 和临床试验,以确保开发一种有效的卵巢癌治疗方法, 利用基因疗法。为了实现这一目标,我们提出了以下三个具体目标:具体目标1: 完成E1a基因治疗联合化疗的L/11期试验。使用一种新的试验 设计,我们将进行随机阶段的L/11试验,其中一组每周一次静脉注射。紫杉醇(至 为不同种类的患者组建立同时控制组),另一组每周接受 静脉注射。紫杉醇ip。不同剂量脂质体E1a基因治疗。这项研究将确定其毒性, 每周加用紫杉醇的最大耐受量(MTD)、临床缓解率和无进展生存期 E1a-p\d复合处理。将获得活组织检查,以监测细胞水平的治疗。特定目标 2.建立卵巢癌特异性基因递送系统及表达载体。两种方法 将被用来改善全身静脉注射。靶向E1a基因治疗卵巢癌移植瘤:1) 卵巢癌特异性启动子元件的开发及2)靶向性脂质体的偶联 多肽、叶酸配体和抗叶酸受体抗体。具体目标3:制定有效的 临床前卵巢癌模型中E1a基因治疗与其他药物的联合应用。vbl.使用 卵巢癌移植瘤,我们将测试E1a基因治疗联合 用于治疗卵巢癌患者的细胞毒药物以及新型生物制剂(TNFa和TRAIL)。 初步数据表明,这些药物可能在亚毒性剂量下发挥协同抗肿瘤活性。这个 来自目标1的临床数据和来自目标2和目标3的临床前洞察可以在未来结合起来设计 新的、甚至可能更有效的治疗策略。

项目成果

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MIEN-CHIE HUNG其他文献

MIEN-CHIE HUNG的其他文献

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{{ truncateString('MIEN-CHIE HUNG', 18)}}的其他基金

Training Grant in Cancer Biology
癌症生物学培训补助金
  • 批准号:
    9148291
  • 财政年份:
    2016
  • 资助金额:
    $ 14.74万
  • 项目类别:
Negative regulation of C-type lectin receptor signaling in response to fungal infection
C 型凝集素受体信号传导对真菌感染的负调控
  • 批准号:
    9180678
  • 财政年份:
    2015
  • 资助金额:
    $ 14.74万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    7962747
  • 财政年份:
    2010
  • 资助金额:
    $ 14.74万
  • 项目类别:
Tyrosine Kinase-Dependant and - Independent Pathways of EGFR in Breast Cancer Pro
乳腺癌中 EGFR 的酪氨酸激酶依赖性和非依赖性通路
  • 批准号:
    7962726
  • 财政年份:
    2010
  • 资助金额:
    $ 14.74万
  • 项目类别:
GROWTH FACTOR RECEPTOR SIGNALING IN BREAST CANCER
乳腺癌中的生长因子受体信号传导
  • 批准号:
    7909246
  • 财政年份:
    2009
  • 资助金额:
    $ 14.74万
  • 项目类别:
Targeting Breast Cancer Specific Gene Therapy
针对乳腺癌特异性基因治疗
  • 批准号:
    7737058
  • 财政年份:
    2008
  • 资助金额:
    $ 14.74万
  • 项目类别:
HER2 in Breast Tumor Progression and Metastasis
HER2 在乳腺肿瘤进展和转移中的作用
  • 批准号:
    7079425
  • 财政年份:
    2004
  • 资助金额:
    $ 14.74万
  • 项目类别:
HER2 in Breast Tumor Progression and Metastasis
HER2 在乳腺肿瘤进展和转移中的作用
  • 批准号:
    7231450
  • 财政年份:
    2004
  • 资助金额:
    $ 14.74万
  • 项目类别:
HER2 in Breast Tumor Progression and Metastasis
HER2 在乳腺肿瘤进展和转移中的作用
  • 批准号:
    6914929
  • 财政年份:
    2004
  • 资助金额:
    $ 14.74万
  • 项目类别:
HER2 in Breast Tumor Progression and Metastasis
HER2 在乳腺肿瘤进展和转移中的作用
  • 批准号:
    7425887
  • 财政年份:
    2004
  • 资助金额:
    $ 14.74万
  • 项目类别:

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