LIPOSOMAL BCL-2 ANTISENSE THERAPY FOR SOLID TUMORS

该职业发展奖的目的是为候选人 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。 Esteva 博士是一位肿瘤内科医生，接受过五年临床培训和两年基础研究培训，包括人类乳腺癌动物模型方面的经验。目前，他将 20% 的精力投入到研究中，80% 的精力投入到临床活动中。 该奖项将使候选人的研究工作量增加到 75%。 该提案的具体目的是：（1）确定Bcl-2反义脂质体（L-Bc1-2 AS）对实体瘤患者的药代动力学、剂量限制毒性、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、紫杉醇和阿霉素联合L-Bcl-2 AS在人乳腺癌动物模型中的疗效。 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 定义为六名患者中的两名出现 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。 预计这项研究将在大约 24 个月内招募 21-24 名患者。 第二个目标将通过 I/II 期临床试验来实现。 功效将通过反应率来衡量。 审判将分两个阶段进行。 第一阶段将有13名患者进入，第二阶段将有30名患者进入，总共43名患者。 预计这项研究将需要大约三年的时间。 试验设计假设 I 类和 II 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) 小鼠中进行开发。 MCF-7 细胞过度表达 Bcl-2，并且很容易在小鼠体内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）监督。 M.D. 安德森癌症中心拥有 Esteva 博士成功完成该研究项目所需的患者和资源。

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.