MDACC-PREDICT

项目摘要 本申请提出了一种名为VU-PREDICT的新U24肿瘤学协同临床成像资源 （范德比尔特大学-PET成像资源，以加强个性化癌症治疗的交付）。 精确的癌症医学，旨在利用独特的细胞，分子和遗传特征， 个体肿瘤以优化治疗仍然是一个严重未满足的需求。尽管生物标志物的研究取得了进展 技术，产生高质量的细胞和基因组数据，关键的差距仍然是一致的匹配 癌症患者和理想的治疗方法。虽然基于RNA和DNA的“预测性”基因组分析现在 常见的是，目前的方法在很大程度上忽略了通过定量成像可区分的肿瘤表型。的 VU-PREDICT的总体愿景是一套定量成像工具， 预测成像衍生的基因表达签名;这样的签名可以由更大的 肿瘤学社区，以提高癌症治疗的个性化。VU-PREDICT的关键是 正电子发射断层扫描（PET）成像。PET的灵敏性和定量性，加上 产生生物活性PET示踪剂的能力，使得PET独特地能够检测肿瘤， 描绘他们的具体特征。作为基因组方法的补充，PET成像提供了定量， 肿瘤表型的功能测量，当结合活检方法时，可以提供显著的 更广泛的生物学特性。 VU-PREDICT中心对晚期结直肠癌（CRC）患者进行平行联合临床试验 和人鼠PDX（患者来源的异种移植物）模型。CRC是癌症相关疾病的主要原因。 全球死亡。表皮生长因子受体（EGFR）中和单克隆抗体（mAb; 西妥昔单抗、帕尼单抗）被批准用于治疗晚期野生型（WT）RAS CRC。然而，在这方面， 抗EGFR单克隆抗体的持久应答仅发生在12-17%的患者中。VU-PREDICT将利用 在范德比尔特开始的I/II期临床试验结合了谷氨酰胺酶（GLS 1）抑制剂（CB-839，Calithera）， EGFR mAb治疗（帕尼单抗）和伊立替康治疗晚期和难治性WT RAS CRC患者。是 预期CB-839与EGFR mAb治疗的组合将使患有Gln的难治性CRC患者重新敏感。 肿瘤对EGFR阻断的敏感性。VU-PREDICT将允许我们开发定量PET成像 本试验和相关临床前研究中可能识别可能对 联合GLS 1/EGFR抑制。我们有四个具体目标：（1）优化定量临床前PET 谷氨酰胺代谢成像方案;实施定量18F-FSPG PET（2），11 C-乙酸PET（3），和 双示踪剂11 C-Acetate/18F-FSPG PET（4），以发现预测性的、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.