ADENOVIRUS E1A AS A THERAPEUTIC AGENT IN BREAST CANCER

描述(申请人的描述)： 职业目标：申请者的职业目标是成为一名成熟的 一家学术机构的内科医生兼科学家，研究的领域是 涉及分子生物学技术在医学肿瘤学中的应用。他 特别希望他能参与到转化型乳腺癌中来 血液和骨髓剂量强化化疗的相关研究 移植支持。他坚信，理解 乳腺癌的分子机制将导致长期的改善， 晚期乳腺癌患者的无病存活率。至 为了实现这一目标，他在加州大学攻读了博士学位 Mien指导下的德克萨斯生物医学研究生院 Chie Hung博士，现为 德克萨斯大学的血液和骨髓移植系。 D.安德森癌症中心。建议：乳腺癌是最常见的癌症之一 美国女性癌症死亡的常见原因。少校 乳腺癌患者术后治疗失败原因分析 剂量密集的化疗仍然是疾病复发的原因，推测是由于 残留乳腺癌细胞的化疗耐药性。的过度表达 HER-2/neu癌基因在30%的乳腺癌中出现，并已被认为与 预后不良。这可能是由于HER-2/neu诱导 对化疗药物的抗药性。腺病毒5型E1a基因 已知该产物在转录水平上抑制HER-2/neu的表达。 赞助商的实验室之前已经表明，HER-2/neu的表达可以 在HER-2/neu高表达乳腺癌细胞系中被抑制 腺病毒载体或阳离子脂质体作为E1a的递送系统 吉恩。最近，有报道称E1a基因S u抑制肿瘤发生。 除了转录抑制外，还通过多种机制抑制 HER-2/neu。申请者目前正在进行第一阶段的临床试验。 E1a基因治疗HER-2/neu过表达乳腺的研究进展 癌症。因此，这一提议的最终目标是扩大和 建立E1a基因对人乳腺的抗肿瘤活性 通过将其与化疗药物或p53基因结合来治疗癌症，并 阐明其细胞毒作用机制。拟议中的实验旨在 将基础研究的发现转化为临床有用的 治疗剂。他们希望这种新的方法将被应用于 E1a基因治疗和提高疗效的II期研究 血液和骨髓剂量强化化疗的远期疗效 联合E1A基因治疗乳腺癌的移植治疗。

DESCRIPTION (Applicant's Description): Career Goal: The applicant's career goal is to become an established physician-scientist at an academic institution in a field of therapy that relates to the use of molecular biology techniques in medical oncology. He especially hopes that he can be involved in translational breast cancer research related to dose-intensive chemotherapy with blood and marrow transplantation support. He firmly believes that understanding the molecular mechanisms of breast cancer will result in improved long-term, disease-free survival rate among patients with advanced breast cancer. To achieve this goal, he has enrolled in a Ph.D. program at The University of Texas Graduate School of Biomedical Sciences under the supervision of Mien Chie Hung, Ph.D. and is providing patient care as a staff member in the Department of Blood and Marrow Transplantation at The University of Texas M. D. Anderson Cancer Center. Proposal: Breast cancer is one of the most common causes of cancer mortality for women in the United States. The major cause of treatment failure in patients with breast cancer after dose-intensive chemotherapy still remains disease relapse, presumably due to the chemoresistance of residual breast cancer cells. Overexpression of the HER-2/neu oncogene occurs in 30% of breast cancers and has been associated with poor prognosis. This may be due to the fact that HER-2/neu induces resistance to chemotherapeutic agents. The adenovirus type 5 E1A gene product is known to repress HER-2/neu expression at a transcription level. The sponsor's laboratory has previously shown that HER-2/neu expression can be repressed in HER-2/neu overexpressing breast cancer cell lines using adenoviral vector or cationic liposome as a delivery system for the E1A gene. Recently, it has been reported that E1A s u ppresses tumorigenicity by a variety of mechanisms in addition to transcriptional repression of HER-2/neu. The applicants are currently conducting a phase I clinical trial of E1A gene therapy for patients with HER-2/neu-overexpressing breast cancer. Therefore, the ultimate goal of this proposal is to expand and establish the anti-oncogenic activity of the E1A gene against human breast cancer by combining it with chemotherapeutic agents or the p53 gene, and to elucidate their cytotoxic mechanism. The proposed experiments are aimed at translating the findings from basic research into clinically useful therapeutic agents. They hope that this novel approach will be applied to the phase II study of E1A gene therapy and improve the efficacy and the long-term outcome of dose-intensive chemotherapy with blood and marrow transplantation in breast cancer by combining them with E1A gene therapy.