Normalizing PDAC stroma with PCBP2 siRNA nanoparticles to improve the antitumor activity of chemotherapy and immunotherapy

使用 PCBP2 siRNA 纳米颗粒使 PDAC 基质正常化以提高化疗和免疫治疗的抗肿瘤活性

• 批准号: 10606872
• 负责人: Kun Cheng
• 金额: $ 36.86万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606872
• 关键词: Affinity; Animals; Apoptotic; Binding; Binding Proteins; Biodistribution; Biological Assay; Cancer Etiology; Cells; Characteristics; Cholesterol; Clinical Trials; Collagen Type I; Combined Modality Therapy; Deposition; Desmoplastic; Drug Kinetics; Exhibits; Extracellular Matrix; Fibroblasts; Functional disorder; Genes; Genetic Transcription; Goals; Hepatic Stellate Cell; Human; Immune Evasion; Immunotherapy; Implant; In Vitro; Integrins; Intercellular Fluid; Link; Morphology; Mus; Myofibroblast; NIH 3T3 Cells; Neoplasm Metastasis; Nude Mice; PD-1/PD-L1; Pancreatic Ductal Adenocarcinoma; Patients; Penetration; Peptides; Pharmaceutical Preparations; Phenotype; Play; Production; Proliferating; Proteins; Role; Safety; Serum; Small Interfering RNA; Solid; Solubility; Specificity; Stress; Structure-Activity Relationship; Survival Rate; Therapeutic Index; Tissues; Toxicology; Vertebral column; X-Ray Crystallography; Xenograft procedure; angiogenesis; anti-PD-L1; cell transformation; chemotherapy; crosslink; effector T cell; gemcitabine; improved; in vitro activity; in vivo; migration; mortality; mouse model; nanoparticle; neoplastic cell; novel; pancreatic ductal adenocarcinoma cell; pancreatic stellate cell; plectin; pressure; programmed cell death ligand 1; restraint; tumor; tumor growth; tumorigenesis; uptake

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality in the world. Desmoplasia is the most prominent characteristic of PDAC and comprises up to 80% of the tumor mass. Desmoplasia plays important roles in tumorigenesis and aggressiveness by promoting the proliferation and metastasis of tumor cells, enhancing angiogenesis, impeding drug penetration, and contributing to immune evasion. However, clinical trials employing strategies to deplete PDAC stroma have failed. The stroma acts not only as a barrier to the penetration of drug and effector T cells, but also as a barrier to restrain the metastasis of PDAC tumors. Complete depletion of the stroma, therefore, leads to a more aggressive tumor and a poor survival rate. By contrast, normalization, instead of depletion, of the stroma in combination with chemotherapy or immunotherapy to kill tumor cells within the stromal microenvironment is a promising strategy for PDAC therapy. In the stromal microenvironment, activated pancreatic stellate cells (PSCs) transform from a quiescent state into a myofibroblast-like phenotype and express a large amount of extracellular matrix (ECM). Type I collagen proteins are the main component of the ECM and are responsible for the major desmoplastic reaction. High levels of type I collagen are associated with a low survival rate for patients with PDAC. Type I collagen promotes the proliferation and migration of PDAC cells and inhibits apoptotic cells by binding to integrin. We discovered that silencing the poly(rC)-binding protein 2 (CP2) with siRNA reverses the accumulation of type I collagen in activated PSCs. Our central hypothesis is that silencing CP2 modulates the PDAC stroma, thus improving the therapeutic index of chemotherapy and immunotherapy. The long-term goal of the project is to develop a combination therapy strategy to treat PDAC.

胰腺导管腺癌（PDAC）是癌症相关性胰腺癌的主要原因之一。 死亡率在世界上。结缔组织增生是PDAC最突出的特征，包括 肿瘤的80%。结缔组织增生在肿瘤发生中起重要作用， 通过促进肿瘤细胞的增殖和转移， 血管生成、阻碍药物渗透并导致免疫逃避。但临床 采用消耗PDAC基质的策略的试验失败了。基质不仅作为 屏障药物和效应T细胞的渗透，但也作为一个障碍，以抑制 PDAC肿瘤的转移。因此，基质的完全耗尽导致更大的 恶性肿瘤和低生存率。相比之下，正常化，而不是耗尽， 与化疗或免疫疗法组合以杀死基质内的肿瘤细胞 微环境是PDAC治疗的一个有前途的策略。 在间质微环境中，活化的胰腺星状细胞（PSC）从一个小细胞转化为一个小细胞。 静止状态转化为肌纤维母细胞样表型，并表达大量的细胞外 矩阵（ECM）。I型胶原蛋白是ECM的主要成分， 主要的促纤维增生反应高水平的I型胶原蛋白与低水平的 PDAC患者的生存率。I型胶原蛋白促进细胞增殖和迁移， PDAC细胞，并通过结合整合素抑制凋亡细胞。 我们发现，用siRNA沉默poly（rC）-binding protein 2（siRNA CP 2）可以逆转 I型胶原在活化的PSC中的积累。我们的中心假设是， 调节PDAC基质，从而提高化疗的治疗指数， 免疫疗法。该项目的长期目标是开发一种联合治疗策略， 治疗PDAC。