LIPOSOMAL BCL-2 ANTISENSE THERAPY FOR SOLID TUMORS

该职业发展奖的目的是为候选人弗朗西斯科·J·埃斯特瓦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。 Esteva博士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。他目前将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其研究工作提高到75%。 本研究的主要目的是：（1）确定Bcl-2反义脂质体的药代动力学、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联合多西他赛治疗对紫杉醇耐药的乳腺癌患者的疗效;（3）研究多西紫杉醇、紫杉醇、阿霉素联合L-Bcl-2 AS对人乳腺癌动物模型的治疗作用。 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定义为与循环淋巴瘤细胞中Bcl-2表达减少50%（流式细胞术）或肿瘤活检中Bcl-2表达减少50%（免疫组织化学或蛋白质印迹）相关的剂量。 预计本研究将在约24个月内招募21-24例患者。 第二个目标将通过I/II期临床试验来实现。 疗效将通过缓解率来衡量。 试验将分两个阶段进行。 13名患者将进入第一阶段，30名进入第二阶段，共计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I型和II型错误率分别为5%和20%。 人乳腺癌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细胞过度表达Bcl-2，并在小鼠中作为异种移植物容易生长。 候选人将由Gabriel Horsagyi博士（乳腺医学肿瘤科）和Gabriel Lopez-Berestein博士（生物免疫治疗科）监督。 M. D.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必需的患者和资源。

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.