PET imaging of carcinoid tumors to guide individualized chemotherapy

类癌肿瘤 PET 成像指导个体化化疗

基本信息

批准号：
8641330
负责人：
Umar Mahmood
金额：
$ 34.74万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8641330
关键词：
Anatomy Antineoplastic Agents Biological Models Blood Carcinoid Tumor Clinical Clinical Practice Guideline Clinical Research Clinical Trials Data Disease Disease Progression Dose Drug Formulations Enrollment Frequencies Future Goals Human Image Imaging Techniques Kinetics Malignant Neoplasms Measurement Measures Mediating Methods Modeling Molecular Multicenter Trials Mus Octreotide Outcome Patients Peptides Pharmacotherapy Positron-Emission Tomography Pre-Clinical Model Progression-Free Survivals Receptor Inhibition Research Research Support S-Phase Fraction Sampling Scanning Small Intestinal Carcinoid Tumor Small Intestines Somatostatin Somatostatin Receptor Survival Rate Symptoms System Techniques Testing Time Tissues Translating Treatment outcome Tumor Volume Variant Work base chemotherapy drug metabolism imaging modality improved in vivo indexing molecular imaging neoplastic neoplastic cell patient population pre-clinical prevent protein expression public health relevance radioligand receptor receptor density receptor expression somatostatin analog standard measure tumor tumor growth tumor progression uptake

项目摘要

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.

描述（由申请人提供）：该提案的总体目标是开发临床PET方法，以在治疗过程中定量未占用的生长抑素受体（SSTR）部分，以优化小肠类癌肿瘤患者的生长抑素类似物的剂量。生长抑素类似物（包括奥曲肽LAR）以前仅用于减轻功能活性类癌肿瘤患者的症状，但不能预防疾病进展。最近，对晚期类癌肿瘤患者进行的良好控制的多中心试验表明，用Ocrototide LAR治疗的时间使肿瘤进展的时间翻了一番。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用作该疾病的抗肿瘤疗法。但是，单一疗法研究中的所有患者均接受任意，不优化的固定固定剂，一次每月剂量的Octreotide lar 30 mg。这种剂量是否最适合控制肿瘤生长。实际上，关于肿瘤生长控制的奥曲肽和其他生长抑素类似物的最佳剂量的数据很少。此外，患者肿瘤之间已知的差异表明，单独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用率的方法，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，我们已经优化了68GA-DOTATOC放射性合成，开发了人性化的配方，自动化了合成，测量的SSTR介导的细胞摄取，并使用动态PET成像进行定量测量了部分和完整的受体块，并进行了定量评估，进行了定量评估，进行了Kinetictictictictientic ofertientic ofer。放射性物体吸收的建模，并对人类68GA-DOTATOC扫描的自动化总肿瘤数量测定。在拟议的工作中，我们将基于68GA-DOTATOC在峰值和谷龙环肽的条件下的68GA-DOTATOC摄取，进一步开发临床前鼠系统中的定量参数成像方法，并使用这些技术对自由和总SSTR密度进行建模。我们将扩展这一点，以评估通过评估上游受体阻滞和下游增殖变化提供的增加预测。我们将将经过验证的技术转换为临床试验，该试验招收了小肠癌患者人群，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，我们的方法将提供有关生长抑素受体占用率和临床结果之间相关性的数据，并在类癌肿瘤患者的个性化化学疗法给药中引入分子成像指南。该技术具有进一步的潜力，可以扩展到用于治疗广泛癌症的其他靶向药物疗法。