LIPOSOMAL BCL-2 ANTISENSE THERAPY FOR SOLID TUMORS

用于实体瘤的脂质体 BCL-2 反义疗法

• 批准号: 6173570
• 负责人: FRANCISCO J ESTEVA
• 金额: $ 13.61万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-04 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6173570
• 关键词: BCL2 gene /protein; MCF7 cell; SCID mouse; antisense nucleic acid; athymic mouse; biopsy; breast neoplasms; circulating neoplastic cell; clinical research; clinical trial phase I; combination cancer therapy; combination chemotherapy; gene therapy; human subject; human therapy evaluation; immunocytochemistry; liposomes; metastasis; neoplasm /cancer chemotherapy; paclitaxel; western blottings

The objective of this career development award is to provide the candidate, Dr. Francisco J. Esteva, the experience and knowledge necessary to direct an independent patient-oriented research program. Dr. Esteva is a medical oncologist with five years of clinical training and two years of basic research training, including experience with animal models of human breast cancer. He currently devotes 20 percent of his effort to research and 80 percent to clinical activities. This award would enable the candidate to increase his research effort to 75 percent. The specific aim of this proposal are: (1) to determine the pharmacokinetics, dose-limiting toxicity, maximum tolerated dose (MTD), or biologically active dose (BAD) of liposomal antisense to Bcl-2 (L-Bc1-2 AS) for patients with solid tumors; (2) to determine the efficacy of L-Bcl-2 AS in combination with docetaxel for patients with breast cancer resistant to paclitaxel; and (3) to investigate the efficacy of docetaxel, paclitaxel and doxorubicin in combination with L-Bcl-2 AS in animal models of human breast cancer. Research design and methods. Dr. Esteva will conduct a phase I trial of L-Bcl-2 AS in patients with metastatic solid tumors. The MTD is defined as the dose at which two of six patients experience grade 3 or higher toxicity. BAD is defined as the dose associated with a 50 percent reduction in Bcl-2 expression in circulating lymphoma cells (flow cytometry) or a 50 percent reduction in Bcl-2 expression in tumor biopsies (immunohistochemistry or western blot). It is anticipated that this study will accrue 21-24 patients in approximately 24 months. The second aim will be addressed by a phase I/II clinical trial. Efficacy will be measured by the rate of response. The trial will be conducted in two stages. Thirteen patients will be entered in the first stage and 30 in the second stage, for a total of 43 patients. It is anticipated this study will take approximately three years. The trial design assumes type I and type II error rates of 5 percent and 20 percent, respectively. Human breast cancer MCF-7 xenografts will also be developed in nude mice and Severe Combined Immunodeficiency (SCID) mice. MCF-7 cells overexpressess Bcl-2 and grow readily as xenografts in mice. The Candidate will be supervised by Dr. Gabriel Hortobagyi (Department of Breast Medical Oncology) and Dr. Gabriel Lopez-Berestein (Department of Bioimmunotherapy). M. D. Anderson Cancer Center has the patients and resources necessary for Dr. Esteva to successfully complete this research project.

该职业发展奖项的目的是为候选人Francisco J. Esteva博士提供指导独立的以患者为导向的研究项目所需的经验和知识。她是一名医学肿瘤学家，有五年的临床培训和两年的基础研究培训，包括人类乳腺癌动物模型的经验。目前，他将20%的精力用于研究，80%用于临床活动。该奖项将使候选人能够将他的研究努力增加到75%。本提案的具体目的是：(1)确定实体肿瘤患者Bcl-2 （l- Bcl-2 AS）脂质体反义的药代动力学、剂量限制性毒性、最大耐受剂量（MTD）或生物活性剂量（BAD）；(2)确定L-Bcl-2 AS联合多西紫杉醇治疗紫杉醇耐药乳腺癌患者的疗效；(3)探讨多西紫杉醇、紫杉醇、阿霉素联合L-Bcl-2 AS治疗人乳腺癌动物模型的疗效。研究设计和方法。Esteva博士将在转移性实体瘤患者中进行L-Bcl-2 AS的I期试验。MTD定义为6名患者中有2名出现3级或更高毒性的剂量。BAD被定义为与循环淋巴瘤细胞中Bcl-2表达降低50%（流式细胞术）或肿瘤活检中Bcl-2表达降低50%（免疫组织化学或western blot）相关的剂量。预计这项研究将在大约24个月内累积21-24例患者。第二个目标将通过I/II期临床试验来解决。疗效将由反应率来衡量。试验将分两个阶段进行。第一阶段有13名患者，第二阶段有30名患者，共43名患者。预计这项研究大约需要三年时间。试验设计假设第一类和第二类错误率分别为5%和20%。人类乳腺癌MCF-7异种移植物也将在裸鼠和严重联合免疫缺陷（SCID）小鼠中开发。MCF-7细胞过表达Bcl-2，在小鼠体内容易作为异种移植物生长。候选人将由Gabriel Hortobagyi博士（乳腺肿瘤内科）和Gabriel Lopez-Berestein博士（生物免疫治疗科）指导。安德森癌症中心拥有Esteva博士成功完成这项研究项目所需的患者和资源。