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: 6377286
• 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/6377286
• 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.

这一职业发展奖的目的是为候选人Francisco J.Esteva博士提供必要的经验和知识，以指导以患者为导向的独立研究计划。埃斯特瓦博士是一名内科肿瘤学家，接受过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。他目前将20%的精力投入到研究中，80%投入到临床活动中。这一奖项将使候选人能够将他的研究努力增加到75%。本建议的具体目的是：(1)测定实体瘤患者应用反义Bcl2脂质体(L-Bc1-2AS)的药代动力学、剂量限制毒性、最大耐受量(MTD)或生物活性剂量(BAD)；(2)确定L-Bcl2 AS联合多西紫杉醇治疗紫杉醇耐药乳腺癌的疗效；(3)观察多西紫杉醇、紫杉醇、阿霉素联合L-Bcl2 AS治疗乳腺癌的疗效。研究设计与方法。埃斯特瓦博士将在转移性实体肿瘤患者中进行L-Bcl2 AS的I期试验。MTD的定义是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Bcl2表达减少50%(流式细胞术)或肿瘤活检组织中Bcl2表达减少50%(免疫组织化学或Western印迹)相关的剂量。预计这项研究将在大约24个月内增加21-24名患者。第二个目标将通过I/II期临床试验来实现。疗效将通过应答率来衡量。审判将分两个阶段进行。第一阶段进入13名患者，第二阶段进入30名患者，共43名患者。预计这项研究将需要大约三年时间。试验设计假设第一类和第二类错误率分别为5%和20%。人乳腺癌MCF-7移植瘤也将在裸鼠和严重联合免疫缺陷(SCID)小鼠身上进行移植。Mcf-7细胞过度表达Bcl2，在小鼠体内容易作为异种移植生长。候选人将由加布里埃尔·霍托巴吉博士(乳腺内科肿瘤科)和加布里埃尔·洛佩斯-贝雷斯坦博士(生物免疫治疗系)监督。安德森癌症中心拥有埃斯特瓦博士成功完成这一研究项目所需的病人和资源。