Co-targeting PDAC tumor cells and the microenvironment to succeed in EGFR/ErbB2-targeted therapy

共同靶向 PDAC 肿瘤细胞和微环境以成功实现 EGFR/ErbB2 靶向治疗

• 批准号: 9438639
• 负责人: Dihua Yu
• 金额: $ 20.88万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9438639
• 关键词: Adenocarcinoma Cell; Adjuvant; Biological Models; CXCL5 gene; Cells; Clinic; Clinical Trials; Coculture Techniques; Communication; Data; Disease; ERBB2 gene; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Exhibits; FDA approved; Fibroblasts; Future; Genetically Engineered Mouse; Goals; Growth; HGF gene; High Pressure Liquid Chromatography; Immunotherapy; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Mediator of activation protein; Pancreatic Ductal Adenocarcinoma; Patients; Phenotype; Play; Proteins; Receptor Activation; Regimen; Research; Resistance; Signal Transduction; Survival Rate; Testing; Translating; Treatment Efficacy; Tyrosine Kinase Inhibitor; Xenograft procedure; base; cancer type; cell growth; design; effective therapy; experience; gemcitabine; glycogen synthase kinase 3 beta; improved; in vitro Model; in vivo; inhibitor/antagonist; innovation; lapatinib; mouse model; neoplastic cell; novel; novel strategies; outcome forecast; overexpression; pancreas xenograft; phenotypic data; prevent; resistance mechanism; responders and non-responders; response; targeted treatment; therapeutic evaluation; therapeutic target; treatment response; treatment strategy; tumor; tumor microenvironment

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types with a devastating 7% five- year survival rate. At present, no effective treatment exists for PDAC patients. Gemcitabine, the first-line adjuvant chemo-therapy for advanced PDAC, only yields a mild therapeutic response in 6-11% of PDAC patients. Targeted- and immuno-therapies have also showed very limited efficacy in PDAC. EGFR is frequently activated in PDAC. Although an EGFR tyrosine kinase inhibitor (TKI), erlotinib, in combination with gemcitabine, has been approved by FDA for PDAC treatment, the combination only slightly improved PDAC patients’ survival compared to gemcitabine alone (one year survival: 23% vs. 17%). It has been puzzling why EGFR/ErbB2 targeted therapies only had very limited benefits despite of frequent EGFR/ErbB2 activations in PDAC. Recently, we found that 14-3-3? overexpressing (14-3-3?+++) PDAC cells increase EGFR/ErbB2 activation and their growth were effectively inhibited by an EGFR/ErbB2 dual TKI (lapatinib) when cultured alone. However, the same 14-3-3?+++ and EGFR/ErbB2 activated PDAC cells were not inhibited by lapatinib when co-cultured with fibroblasts. The data phenotypically copy the low response to EGFR/ErbB2 TKIs in PDAC patients and suggested that the fibrotic tumor microenvironment (TME) may render PDAC tumor cells resistant to EGFR/ErbB2 TKIs. PDAC tumor cells and its fibrotic TME reciprocally communicate to co-evolve creating a vicious cycle. Indeed, we found that the 14-3-3?+++ PDAC cells secrete more CXCL5 which activates the PI3K-Akt-GSK3β signaling axis in fibroblasts. PI3K-Akt-GSK3β axis functions to promote fibroblast activation and is involved in multiple fibrotic diseases. Our data suggest that 14-3-3?+++ in PDAC tumor cells activates the PI3K-Akt-GSK-3β axis in fibroblasts which reciprocally confers PDAC tumor cell resistance to EGFR/ErbB2 TKIs. We then tested if targeting PI3K/Akt could prevent fibroblast activation and, thereby, sensitize PDAC tumor cells to EGFR/ErbB2 TKIs. Although targeting PI3K/Akt by an inhibitor (BKM120) had no significant effect on PDAC cell growth on its own, co-targeting PI3K/Akt function in fibroblasts by BKM120 and EGFR/ErbB2 activation in PDAC cells by lapatinib effectively inhibited PDAC cell growth in co-culture with fibroblasts. Therefore, we hypothesize that the vicious cycle created by the PDAC tumor cells and their fibrotic TME promotes PDAC resistance to EGFR/ErbB2 TKIs; whereas co-targeting EGFR/ErbB2 activation in the PDAC tumor cells and PI3K-Akt in fibrotic TME confers PDAC sensitivity to EGFR/ErbB2 targeted therapies. The major goals of this proposal are 1) to systematically test the therapeutic efficacy of co-targeting EGFR/ErbB2 activation in PDAC cells and PI3K-Akt signaling in fibrotic TME in various PDAC models in vitro and in vivo; and 2) to identify fibroblast-derived molecules that promote PDAC tumor cell resistance to EGFR/ErbB2 targeted therapies. The successful completion of these studies will guide the design of effective targeted therapies that can then be translated into the clinic to treat PDAC patients.

项目摘要/摘要 胰腺导管腺癌(PDAC)是最致命的癌症类型之一，其致命性高达7%。 一年存活率。目前，PDAC患者尚无有效的治疗方法。吉西他滨，一线 晚期PDAC的辅助化疗仅在6-11%的PDAC中产生轻微的治疗反应 病人。靶向治疗和免疫治疗在PDAC中的疗效也非常有限。EGFR经常出现在 在PDAC中激活。尽管EGFR酪氨酸激酶抑制剂(TKI)erlotinib与 吉西他滨已被FDA批准用于PDAC治疗，联合应用仅略有改善PDAC 患者的存活率与单独使用吉西他滨相比(一年存活率：23%比17%)。一直令人费解的是为什么 EGFR/ErbB2靶向治疗的益处非常有限，尽管在 PDAC。最近，我们发现14-3-3？过表达(14-3-3？+)PDAC细胞增加EGFR/ErbB2 EGFR/ErbB2双TKI(雷帕替尼)能有效地抑制细胞的激活和生长 独自一人。但相同的14-3-3？+和EGFR/ErbB2激活的PDAC细胞不被拉帕替尼抑制 当与成纤维细胞共培养时。数据典型地将对EGFR/ErbB2 TKIS的低响应复制到 提示纤维化的肿瘤微环境(TME)可能使PDAC肿瘤细胞 对EGFR/ErbB2 TKIs耐药。PDAC肿瘤细胞及其纤维化的TME相互沟通共同进化 造成了恶性循环。事实上，我们发现14-3-3？+PDAC细胞分泌更多的CXCL5，其中 激活成纤维细胞中的PI3K-Akt-GSK3β信号轴。PI3K-AKT-GSK3β轴功能提升 成纤维细胞被激活，并参与多种纤维化疾病。我们的数据表明PDAC中的14-3-3？+ 肿瘤细胞激活成纤维细胞中PI3K-Akt-GSK-3β轴，从而相互赋予PDAC肿瘤细胞 对EGFR/ErbB2 TKIs耐药。然后我们测试了靶向PI3K/Akt是否可以阻止成纤维细胞的激活， 从而使PDAC肿瘤细胞对EGFR/ErbB2TKI增敏。尽管以PI3K/Akt为靶点的抑制剂 (BKM120)单独对PDAC细胞生长无显著影响，共靶向PI3K/Akt功能。 BKM120诱导的成纤维细胞和雷帕替尼激活的EGFR/ErbB2对PDAC细胞的有效抑制 与成纤维细胞共培养生长。因此，我们假设PDAC造成的恶性循环 肿瘤细胞及其纤维化的TME促进PDAC对EGFR/ErbB2 TKIs的抵抗；而共靶向 PDAC肿瘤细胞中EGFR/ErbB2的激活和纤维化TME中的PI3K-Akt使PDAC对 EGFR/ErbB2靶向治疗。这项建议的主要目标是1)系统地测试治疗 联合靶向EGFR/ErbB2活化和PI3K-Akt信号通路在不同类型纤维化TME中的作用 体外和体内的PDAC模型；2)鉴定促进PDAC肿瘤细胞生长的成纤维细胞来源的分子 对EGFR/ErbB2靶向治疗耐药。这些研究的成功完成将指导设计 有效的靶向治疗，然后可以转化到临床上治疗PDAC患者。