Radioimmunotherapy for Prostate Cancer

描述（由申请人提供）：前列腺癌是美国男性癌症相关死亡的第二大常见原因。晚期患者无法使用标准方法治愈，并遭受疾病转移到骨骼的影响，这是远处扩散的主要部位。该候选人迄今为止的研究是基于前列腺癌的治疗方法，该方法可以通过靶向在疾病自然史的每个临床状态中表征肿瘤的独特生物学特征来治疗。这项资助的具体假设是，考虑到耐药疾病的主要储存库是骨髓，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。建议的目标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。确定未标记和钇-90标记抗psma抗体（如huJ591）性质的初步研究目前正在完成。为了实施这项研究，我们为候选人提出了一个综合的职业发展计划，该计划利用MSKCC和赞助商的资源和专业知识。计划三年临床试验设计和核医学教学课程。该计划包括该领域专家的指导，如发起人（Dr. Scher， GU肿瘤学主任）、Dr. Larson（核医学主任）以及放射学、放射化学、病理学和生物统计学成员。参加国家/国际会议将有助于接触其他专家，并了解将试验推向国家阶段的过程。通过本次培训，将实施基于以下三个目标的研究计划：(1)验证重复给药RIT可诱导与肿瘤吸收剂量相关的抗肿瘤作用的假设。在一项I期试验中，Y-86-huJ591（一种正电子发射器）将与Y-90-huJ591（一种纯β发射器）一起重复给药，以确定钇偶联物的疗效、剂量学和生物分布(2)，以验证RIT可以通过上调靶表达和/或增强肿瘤放射敏感性来优化的假设。在1/11期试验中，钇缀合物将与PSMA调制联合使用，并且(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，将使候选人能够独立地进行此类研究。

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.