PET imaging of carcinoid tumors to guide individualized chemotherapy

描述(由申请人提供)：这项建议的总体目标是开发临床PET方法来量化治疗过程中未被占用的生长抑素受体(SSTR)部分，以便优化生长抑素类似物在治疗小肠类癌患者中的剂量。生长抑素类似物，包括奥曲肽LAR，以前只用于缓解功能性活动性类癌肿瘤患者的症状，但不用于防止疾病进展。最近，一项在晚期类癌患者中进行的受控良好的多中心试验表明，奥曲肽LAR的治疗使肿瘤进展时间增加了一倍以上。这些数据导致了治疗指南和临床实践的变化；生长抑素类似物现在被用作这种疾病的抗肿瘤治疗。然而，单一疗法研究中的所有患者都接受了每月一次的随机、非优化、固定剂量的奥曲肽LAR 30 mg。这个剂量是否是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，已知的患者肿瘤之间的差异表明，个性化优化剂量的方法可能有助于改善治疗结果。受体成像的使用提供了一种直接评估生长抑素受体占位的方法，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的放射合成，开发了人类使用的配方，自动化了合成，测量了SSTR介导的细胞摄取，并使用动态PET成像演示了部分和全部受体阻断的定量测量，定量评估了增殖变化，临床前进行了放射性配基摄取的动力学模拟，并自动确定了人类68Ga-DOTATOC扫描的总肿瘤体积。在拟议的工作中，我们将进一步开发临床前小鼠系统中的定量参数成像方法，并使用这些技术来模拟自由和总的SSTR密度，基于68Ga-DOTATOC在峰值和谷值摄取奥曲肽LAR的条件。我们将通过评估上游受体阻断和下游增殖变化，将其扩展到临床前评估增加的预测。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相关联。如果成功，我们的方法将提供生长抑素受体占有率和临床结果之间的相关性的数据，并为类癌患者的个体化化疗剂量提供分子成像指导。这项技术有可能进一步扩展到其他靶向药物疗法，用于治疗广泛的癌症。

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.