MDACC-PREDICT

项目摘要 本申请提出了一个新的U24肿瘤学联合临床影像资源，名为VU-Forecast 范德比尔特大学--增强个体化癌症治疗的PET成像资源)。 精准癌症医学，寻求利用人类独特的细胞、分子和基因特征 个别肿瘤的优化治疗，仍然是一个严重未得到满足的需求。尽管生物标记物取得了进展 产生高质量细胞和基因组数据的技术，关键差距仍然需要一致匹配 癌症患者和理想的治疗方法。而基于RNA和DNA的“预测性”基因组分析现在是 通常，目前的方法大多忽略了通过定量成像可以区分的肿瘤表型。这个 VU-Forecast的总体愿景是一套有助于发现新奇的定量成像工具， 预测成像衍生的基因表达签名；这种签名可以由更大的 肿瘤学社区提高癌症治疗的个性化。VU-Forecast的关键是 正电子发射断层扫描(PET)成像。PET的敏感性和定量性质，加上 生产具有生物活性的PET示踪剂的能力，使PET具有独特的检测肿瘤和 描述他们的特定特征。作为基因组方法的补充，PET成像提供了一种定量的、 肿瘤表型的功能测量，以及当结合活检方法时，可以提供显著的 生物学特征的更大广度。 VU-Predicate以晚期结直肠癌患者的平行联合临床试验为中心 以及人在鼠PDX(病人来源的异种移植)模型。结直肠癌是癌症相关疾病的主要原因之一。 世界各地的死亡人数。表皮生长因子受体(EGFR)中和单抗(mAbs； 西妥昔单抗、帕尼图单抗)被批准用于治疗晚期野生型(WT)RAS CRC。然而， 仅有12-17%的患者对抗EGFR单抗有持久反应。VU-Forecast将利用 范德比尔特联合谷氨酰胺酶(GLS1)抑制剂(CB-839，Calithera)的I/II期临床试验开始， EGFR单抗联合伊立替康治疗晚期难治性WTRAS结直肠癌它是 预期CB-839与EGFR单抗联合治疗将使患有Gln的难治性CRC患者重新敏感。 热衷于肿瘤对EGFR的阻断。VU-Forecast将允许我们开发定量PET成像 在这项试验和相关的临床前研究中采取的措施，可以确定患者可能对 GLS1/EGFR联合抑制作用。我们有四个具体目标：(1)优化临床前PET定量 谷氨酰胺代谢的成像方案；实施定量18F-FSPG PET(2)，11C-醋酸酯PET(3)，以及 双示踪剂11C-乙酸酯/18F-FSPG PET(4)，以发现预测性、成像衍生的基因表达特征。

Project Summary This application proposes a new U24 Oncology Co-Clinical Imaging Resource entitled VU-PREDICT (Vanderbilt University-PET imaging Resource to Enhance Delivery of Individualized Cancer Therapeutics). Precision cancer medicine, which seeks to exploit unique cellular, molecular and genetic characteristics of individual tumors to optimize treatment, remains a critically unmet need. Despite advances in biomarker technologies that yield high-quality cellular and genomic data, critical gaps remain to consistently match patients with cancer and ideal therapies. While `predictive' genomic assays based on RNA and DNA are now commonplace, current methods largely ignore tumor phenotypes differentiable by quantitative imaging. The overarching vision for VU-PREDICT is a suite of quantitative imaging tools that facilitate the discovery of novel, predictive imaging-derived gene expression signatures; such signatures can be deployed by the greater oncology community to improve the personalization of cancer treatment. The linchpin of VU-PREDICT will be positron emission tomography (PET) imaging. The sensitive and quantitative nature of PET, coupled with the ability to produce biologically active PET tracers, renders PET uniquely capable of both detecting tumors and profiling their specific features. Complementary to genomic approaches, PET imaging provides a quantitative, functional measure of tumor phenotype, and when coupled biopsy approaches, can provide a significantly greater breadth of biological characterization. VU-PREDICT centers on a parallel co-clinical trial of patients with advanced colorectal cancer (CRC) and human-in-mouse PDX (patient-derived xenograft) models. CRC is a leading cause of cancer-related deaths worldwide. Epidermal growth factor receptor (EGFR) neutralizing monoclonal antibodies (mAbs; cetuximab, panitumumab) are approved for treatment of advanced wild-type (WT) RAS CRC. However, durable responses to anti-EGFR mAbs occur in only 12–17% of patients. VU-PREDICT will capitalize upon a Phase I/II clinical trial opening at Vanderbilt combining a glutaminase (GLS1) inhibitor (CB-839, Calithera), EGFR mAb therapy (panitumumab) and irinotecan in patients with advanced and refractory WT RAS CRC. It is anticipated that combining CB-839 with EGFR mAb therapy will resensitize refractory CRC patients with Gln- avid tumors to EGFR blockade. VU-PREDICT will allow our development of quantitative PET imaging measures within this trial and in related preclinical studies that may identify patients likely to respond to combined GLS1/EGFR inhibition. We have four Specific Aims: (1) Optimize quantitative preclinical PET imaging protocols for Gln metabolism; Implement quantitative 18F-FSPG PET (2), 11C-Acetate PET (3), and dual-tracer 11C-Acetate/18F-FSPG PET (4) to discover predictive, imaging-derived gene expression signatures.