PET Imaging-guided Personalized Therapy in Pancreatic Cancer

PET 成像引导的胰腺癌个性化治疗

• 批准号: 9535203
• 负责人: JOHANNES CZERNIN
• 金额: $ 58.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-18 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9535203
• 关键词: Abraxane; Address; Biological Assay; Biological Markers; Blood Vessels; Clinical; Clinical Research; Companions; Cytosine; Deoxycytidine Kinase; Dose; Drug Delivery Systems; Excision; Face; Genetic Models; Human; Hyaluronidase; Interdisciplinary Study; Lead; Left; Liquid Chromatography; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Measures; Metabolism; Modeling; Mus; Oncologist; Operative Surgical Procedures; Outcome; Pancreatic Ductal Adenocarcinoma; Patients; Perfusion; Pharmaceutical Preparations; Positron-Emission Tomography; Pre-Clinical Model; Prodrugs; Proteins; Regimen; Research Personnel; Resected; Scanning; Schedule; Survival Rate; Testing; Therapeutic; Time; Translational Research; Tumor Tissue; Xenograft procedure; analog; cancer therapy; chemotherapeutic agent; companion diagnostics; cytotoxic; gemcitabine; image guided; improved; molecular imaging; neoplastic cell; oncology; patient stratification; personalized approach; personalized medicine; pre-clinical; public health relevance; resistance mechanism; tandem mass spectrometry; therapy outcome; treatment response; tumor; uptake

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a dismal therapeutic outcome. This interdisciplinary study aims to develop a new Positron Emission Tomography (PET) assay for patient stratification, which could lead to more efficacious and better tolerated personalized therapies for PDAC. Therapeutic responses to gemcitabine (GEM), the most frequently used chemotherapeutic agent in PDAC, are observed in less than 10% of patients. Amongst proposed reasons for GEM's suboptimal efficacy in PDAC two suggested mechanisms have emerged as leading candidates: (i) suboptimal drug delivery to PDAC tumor cells because of a poorly vascularized and dense tumor-associated stroma and (ii) inefficient uptake and/or conversion of the prodrug GEM to its active, cytotoxic metabolites by the PDAC tumor cells. In support of the former mechanism, new stromal depleting (SD) therapies, such as Abraxane and pegylated hyaluronidase improve GEM delivery to tumor cells, extending survival in preclinical models, and, in the case of Abraxane, in patients. GEM could be used more effectively for PDAC therapy if companion diagnostics are developed to measure if the addition of a SD agent enhances intratumoral GEM delivery and its conversion to therapeutically active metabolites in tumor cells. This proposal will test the hypothesis that a new GEM analog PET probe 1-L-(2-Deoxy-2,-18Fluoro-Arabinofuranosyl) Cytosine (18F-L-FAC) developed by UCLA investigators can be used to determine (1) the shortest schedule of SD agents required to increase GEM delivery to tumor cells, and (2) the efficiency both of intratumoral GEM accumulation and activation by tumor cells in PDAC patients. In Aim 1, PET will be used to determine, in preclinical models, the shortest schedule of stromal depleting therapy required to induce detectable changes in tumor probe (18F-L-FAC) and drug (GEM) delivery. Aim 2 proposes study to determine the accuracy of 18F-L-FAC PET measures of intra-tumoral GEM delivery and metabolism in PDAC patients treated with SD therapies. The expected outcome is a new PET assay to identify PDAC patients who are likely responders to GEM administered in combination with SD therapies. This assay will address a currently unmet clinical need in pancreatic cancer management since alternatives to GEM/Abraxane, albeit considerably more toxic for patients, are now available.

描述（由申请人提供）：胰腺导管腺癌（PDAC）是一种治疗效果不佳的恶性肿瘤。这项跨学科研究旨在开发一种新的正电子发射断层扫描 (PET) 检测方法，用于患者分层，从而为 PDAC 提供更有效、耐受性更好的个性化治疗。不到 10% 的患者观察到对 PDAC 最常用化疗药物吉西他滨 (GEM) 的治疗反应。 GEM 在 PDAC 中疗效不佳的原因中，有两个机制已成为主要候选机制：(i) 由于血管化不良且致密的肿瘤相关基质，导致 PDAC 肿瘤细胞的药物输送不理想；(ii) 药物的低效摄取和/或转化。 PDAC 肿瘤细胞将前药 GEM 转化为其活性细胞毒性代谢物。为了支持前一种机制，新的基质消耗 (SD) 疗法，例如 Abraxane 和聚乙二醇化透明质酸酶，可改善 GEM 向肿瘤细胞的递送，延长临床前模型中的生存​​期，并且就 Abraxane 而言， 患者。如果开发出伴随诊断来测量添加 SD 剂是否增强瘤内 GEM 递送及其在肿瘤细胞中转化为治疗活性代谢物，GEM 可以更有效地用于 PDAC 治疗。该提案将测试以下假设：加州大学洛杉矶分校研究人员开发的新型 GEM 模拟 PET 探针 1-L-(2-Deoxy-2,-18Fluoro-Arabinofuranosyl) 胞嘧啶 (18F-L-FAC) 可用于确定 (1)增加 GEM 向肿瘤细胞的递送所需的 SD 药物的最短时间表，以及 (2) PDAC 患者肿瘤内 GEM 积累和肿瘤细胞激活的效率。在目标 1 中，PET 将用于在临床前模型中确定诱导肿瘤探针 (18F-L-FAC) 和药物 (GEM) 递送发生可检测变化所需的最短基质消耗治疗方案。目标 2 提出研究以确定 18F-L-FAC PET 测量对接受 SD 疗法治疗的 PDAC 患者瘤内 GEM 递送和代谢的准确性。预期结果是一种新的 PET 检测，用于识别可能对 GEM 与 SD 疗法联合治疗有反应的 PDAC 患者。该测定将解决目前胰腺癌治疗中未满足的临床需求，因为现在可以使用 GEM/Abraxane 的替代品，尽管对患者的毒性要大得多。

项目成果

CA19-9 Normalization During Pre-operative Treatment Predicts Longer Survival for Patients with Locally Progressed Pancreatic Cancer.

术前治疗期间 CA19-9 正常化可预测局部进展性胰腺癌患者的更长生存期。

• 发表时间: 2016-07
• 作者: Williams, Jennifer L;Kadera, Brian E;Nguyen, Andrew H;Muthusamy, V Raman;Wainberg, Zev A;Hines, O Joe;Reber, Howard A;Donahue, Timothy R
• 通讯作者: Donahue, Timothy R

Establishing 177Lu-PSMA-617 Radioligand Therapy in a Syngeneic Model of Murine Prostate Cancer.

在小鼠前列腺癌同基因模型中建立 177Lu-PSMA-617 放射性配体疗法。

• 发表时间: 2017
• 作者: Fendler, Wolfgang P;Stuparu, Andreea D;Evans;Lückerath, Katharina;Wei, Liu;Kim, Woosuk;Poddar, Soumya;Said, Jonathan;Radu, Caius G;Eiber, Matthias;Czernin, Johannes;Slavik, Roger;Herrmann, Ken
• 通讯作者: Herrmann, Ken

Histone deacetylase inhibitors provoke a tumor supportive phenotype in pancreatic cancer associated fibroblasts.

组蛋白脱乙酰酶抑制剂在胰腺癌相关成纤维细胞中激发肿瘤支持表型。

• 发表时间: 2017-03-21
• 作者: Nguyen, Andrew H;Elliott, Irmina A;Wu, Nanping;Matsumura, Cynthia;Vogelauer, Maria;Attar, Narsis;Dann, Amanda;Ghukasyan, Razmik;Toste, Paul A;Patel, Sanjeet G;Williams, Jennifer L;Li, Luyi;Dawson, David W;Radu, Caius;Kurdistani, Siavash K;D
• 通讯作者: D

Isoquinoline thiosemicarbazone displays potent anticancer activity with in vivo efficacy against aggressive leukemias.

异喹啉缩氨基硫脲显示出有效的抗癌活性，并具有体内对抗侵袭性白血病的功效。

• 发表时间: 2020-03-01
• 影响因子: 4.1
• 作者: Sun, Daniel L;Poddar, Soumya;Pan, Roy D;Rosser, Ethan W;Abt, Evan R;Van Valkenburgh, Juno;Le, Thuc M;Lok, Vincent;Hernandez, Selena P;Song, Janet;Li, Joanna;Turlik, Aneta;Chen, Xiaohong;Cheng, Chi;Chen, Wei;Mona, Christine E;Stuparu, An
• 通讯作者: Stuparu, An

Preoperative Treatment With FOLFIRINOX and Successful Resection for a Patient With Mixed Acinar-Endocrine Carcinoma of the Pancreas.

使用 FOLFIRINOX 进行术前治疗并成功切除胰腺混合性腺泡内分泌癌患者。

• 发表时间: 2017-04
• 影响因子: 2.9
• 作者: Sugimoto, Motokazu;Hines, O Joe;Dawson, David W;Muthusamy, V Raman;Reber, Howard A;Donahue, Timothy R
• 通讯作者: Donahue, Timothy R