PET imaging of carcinoid tumors to guide individualized chemotherapy

描述（由申请人提供）：本提案的总体目标是开发临床PET方法来定量治疗过程中未占据的生长抑素受体（SSTR）部分，以优化小肠类癌患者治疗中生长抑素类似物的剂量。生长抑素类似物，包括奥曲肽LAR，以前仅用于功能活动性类癌患者的症状缓解，而不是用于预防疾病进展。最近，一项在晚期类癌患者中进行的对照良好的多中心试验表明，奥曲肽LAR治疗使肿瘤进展时间延长了一倍以上。这些数据导致了治疗指南和临床实践的改变；生长抑素类似物现在被用作这种疾病的抗肿瘤治疗。然而，在单药治疗研究中，所有患者都接受了任意的、未经优化的、固定的每月一次剂量的奥曲肽LAR 30mg。该剂量是否为控制肿瘤生长的最佳剂量尚不清楚；事实上，关于奥曲肽和其他生长抑素类似物控制肿瘤生长的最佳剂量的数据很少。此外，已知患者肿瘤之间的可变性表明，个体优化剂量的方法可能有助于改善治疗结果。使用受体成像提供了一种直接评估生长抑素受体占用的方法，因此可能是优化患者生长抑素类似物的选择和剂量的理想技术。为了支持这项研究，我们优化了68Ga-DOTATOC放射合成，开发了人类使用的配方，自动化合成，测量了str介导的细胞摄取，并展示了使用动态PET成像定量测量部分和完全受体阻断，定量评估了增殖变化，进行了临床前放射配体摄取的动力学建模，并自动确定了人类68Ga-DOTATOC扫描的总肿瘤体积。在我们提出的工作中，我们将进一步在临床前小鼠系统中开发定量参数成像方法，并使用这些技术基于奥曲肽LAR条件下峰值和低谷时68Ga-DOTATOC的摄入来模拟游离和总SSTR密度。我们将扩展这一研究，通过评估上游受体阻滞和下游增殖变化来评估临床前增加的预测。我们将把经过验证的技术转化为一项临床试验，纳入小肠类癌患者群体，并将早期计算的成像参数与随后的肿瘤进展联系起来。如果成功，我们的方法将提供生长抑素受体占用与临床结果之间相关性的数据，并为类癌患者的个体化化疗剂量提供分子成像指导。这项技术有进一步扩展到其他靶向药物治疗的潜力，用于治疗各种癌症。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop clinical PET methods to quantitate unoccupied somatostatin receptor (SSTR) fraction during therapy to allow optimization of the dose of somatostatin analogs in the treatment of patients with small bowel carcinoid tumors. Somatostatin analogs, including octreotide LAR, have previously been used only for symptom relief in patients with functionally active carcinoid tumors, but not to prevent disease progression. Recently, a well-controlled multicenter trial in patients with advanced carcinoid tumors demonstrated that treatment with octreotide LAR more than doubled the time to tumor progression. This data has led to a change in both treatment guidelines and clinical practice; somatostatin analogs are now used as an antineoplastic therapy for this disease. However, all patients in the monotherapy study received an arbitrary, non-optimized, fixed once monthly dose of octreotide LAR 30 mg. Whether this dose was optimal for controlling tumor growth is unknown; indeed, there is little data regarding the optimal dose of octreotide and other somatostatin analogs for tumor growth control. Furthermore, known variability between patients' tumors suggests that methods to individually optimize dose could be helpful to improve treatment outcomes. The use of receptor imaging provides a method to directly assess somatostatin receptor occupancy, and therefore could be an ideal technique to optimize the choice and dose of somatostatin analogs in patients. To support this research we have optimized 68Ga-DOTATOC radiosynthesis, developed human-use formulation, automated the synthesis, measured SSTR-mediated cellular uptake and demonstrated quantitative measurement of partial and complete receptor block using dynamic PET imaging, quantitatively evaluated proliferation changes, performed kinetic modeling of radioligand uptake preclinically, and automated total tumor volume determination for human 68Ga-DOTATOC scans. In the proposed work, we will further develop quantitative parametric imaging methods in preclinical murine systems and use these techniques to model free and total SSTR density, based on 68Ga-DOTATOC uptake at peak and trough octreotide LAR conditions. We will expand this to evaluate preclinically the increased prediction provided by evaluating upstream receptor block and downstream proliferation changes. We will translate the validated techniques to a clinical trial enrolling a small bowel carcinoid patient population, and correlate the early calculated imaging parameters with subsequent tumor progression. If successful, our approach will provide data on the correlation between somatostatin receptor occupancy and clinical outcomes, and introduce molecular imaging guidance for individualized chemotherapy dosing in patients with carcinoid tumors. This technique has the further potential to be expanded to other targeted drug therapies used to treat a broad range of cancers.