Radioimmunotherapy for Prostate Cancer

描述(申请人提供)：前列腺癌是美国男性癌症相关死亡的第二大常见原因。晚期疾病患者无法使用标准方法治愈，并遭受骨转移疾病的影响，骨转移是远处扩散的主要部位。到目前为止，这位候选人的研究是基于这样一种方法，即前列腺癌可以通过靶向独特的生物学特征来治疗，这些特征表征了前列腺癌自然病史的每种临床状态。这笔赠款的具体假设是，鉴于抵抗疾病的主要宿主是骨髓，应用于血液肿瘤的技术，如放射免疫疗法(RIT)，也可以应用于前列腺癌。建议的靶点是前列腺特异性膜抗原(PSMA)，它存在于疾病的所有阶段，在非前列腺组织中表达最低，并且可以调节。确定未标记和Y-90标记的抗PSMA抗体的性质的初步研究，如huJ591，现在正在完成。为了实施这项研究，为候选人提出了一个全面的职业发展计划，该计划利用了MSKCC和赞助商的资源和专业知识。计划开设为期三年的临床试验设计和核医学教学课程。该计划纳入了该领域专家的指导，如发起人(GU肿瘤科主任Scher博士)、Larson博士(核医学首席)以及放射学、放射化学、病理学和生物统计学的成员。参加国家/国际会议将使人们能够接触到其他专家，并了解将审判推向国家阶段的过程。通过这次培训，将执行基于以下三个目标的研究计划：(1)检验重复剂量RIT可以诱导与肿瘤吸收剂量相关的抗肿瘤效应的假设。在I阶段试验中，Y-86-huJ591(正电子发射体)将与重复剂量的Y-90-huJ591(纯Beta发射体)一起使用，以确定Y-86-huJ591的有效性、剂量学和生物分布(2)，以测试可以通过上调靶基因表达和/或增强肿瘤放射敏感性来优化RIT的假设。在1/11期试验中，钇结合物将与PSMA调制相结合，以及(3)在III期试验中将RIT与标准化疗进行比较。这些技能的获得与研究计划的完成相结合，将使应聘者能够独立从事此类研究。

DESCRIPTION (provided by applicant): Prostate cancer is the second most common cause of cancer-related deaths in American men. Patients with advanced disease are not curable using standard approaches and suffer the effects of metastatic disease to bone, the primary site of distant spread. The candidate's research to date is based on the approach that prostate cancer can be treated by targeting the unique biologic features that characterize the tumor in each clinical state of the disease's natural history. The specific hypothesis of this grant is that techniques applied to hematologic tumors, such as radioimmunotherapy (RIT), can also be applied to prostate cancer, given that the main reservoir of resistant disease is the bone marrow. The proposed target is prostate specific membrane antigen (PSMA), which is present at all phases of the disease, is minimally expressed in non-prostate tissue, and can be modulated. Preliminary studies to define the properties of unlabeled and yttrium-90 labeled anti-PSMA antibodies, such as huJ591, are now being completed. To implement this research, a comprehensive career development plan for the candidate is proposed, that capitalizes on MSKCC's and the Sponsor's resources and expertise. Three years of didactic courses in clinical trial design and nuclear medicine are planned. Mentoring by experts in the field, such as the Sponsor (Dr. Scher, Chief of GU Oncology), Dr. Larson (Chief, Nuclear Medicine), and members of Radiology, Radiochemistry, Pathology, and Biostatistics are incorporated into the plan. Participation in national/international conferences will allow exposure to other experts and to understand the process of bringing trials to a national stage. Through this training, a research plan based on the following three aims will be executed: (1) To test the hypothesis that repetitively dosed RIT can induce antitumor effects that correlate with tumor absorbed dose. In a phase I trial Y-86-huJ591 (a positron emitter) will be administered with repetitively dosed Y-90-huJ591 (a pure beta emitter) to establish the efficacy, dosimetry, and biodistribution of the yttrium conjugate (2) To test the hypothesis that RIT can be optimized by upregulating target expression and/or enhancing tumor radiosensitivity. In a phase 1/11trial, the yttrium conjugate will be combined with PSMA modulation, and (3) to compare RIT with standard chemotherapy in a phase III trial. The acquisition of these skills combined with the completion of the research plan will allow the candidate to pursue such research independently.