Combination Therapy for Pancreatic Cancer

胰腺癌的联合治疗

• 批准号: 10581174
• 负责人: Song Li
• 金额: $ 47.26万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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/10581174
• 关键词: Abraxane; Adjuvant Therapy; Albumins; Binding; Biodistribution; Biological; Biological Availability; Biophysics; Blood; Blood Circulation; Breast Cancer Model; CCL2 gene; CCL7 gene; CD8-Positive T-Lymphocytes; Cancer Etiology; Cells; Cessation of life; Circulation; Clinic; Colon Carcinoma; Combined Modality Therapy; Complex; Cytidine Deaminase; Data; Deaminase; Development; Diagnosis; Doxorubicin; Doxorubicin Hydrochloride Liposome; Drug vehicle; Early Diagnosis; Extravasation; Human; Hydrophobicity; Immune; In Vitro; Incidence; Malignant Neoplasms; Malignant neoplasm of pancreas; Metabolic; Modeling; Mus; Myeloid-derived suppressor cells; Names; Neoadjuvant Therapy; Neoplasm Metastasis; Paclitaxel; Particle Size; Patients; Penetration; Pharmaceutical Preparations; Polymers; Probability; Prodrugs; Property; Recurrence; Regimen; Resectable; Survival Rate; T cell response; Time; Toxic effect; Treatment Efficacy; Tumor Cell Invasion; Tumor Promotion; Tumor Tissue; United States; Up-Regulation; antagonist; anti-PD1 therapy; cancer type; chemotherapy; design; effective therapy; gemcitabine; hydrophilicity; improved; in vivo; mortality; nanocarrier; nanomedicine; nanoparticle; nanosized; neoplastic cell; new combination therapies; novel therapeutics; pancreatic cancer model; pancreatic ductal adenocarcinoma model; patient derived xenograft model; preclinical study; recruit; tumor; tumor-immune system interactions

ABSTRACT: Pancreatic cancer (PCa) is one of the deadliest forms of cancers and the fourth leading cause of cancer deaths in the United States. Combination of gemcitabine (GEM) and paclitaxel (PTX) or Nab-paclitaxel (nanoparticle (NP) albumin-bound PTX, Abraxane®) is one of the first-line treatments for locally recurrent or metastatic PCa. However, only limited benefits have been shown in clinic. In addition, this treatment is associated with significant toxicity. PCa is characterized by the presence of dense stroma that may limit effective penetration of relatively large-sized NPs. On the other hand, free GEM is rapidly eliminated from the blood circulation and is also subjected to rapid inactivation by deaminase. Therefore, there is an urgent need to develop small NPs that are capable of protecting the drugs and are effective in tumor accumulation and penetration. We have recently shown that conjugation of GEM to POEG-co-PVD polymer led to a significant decrease in the particle size from 160 to 13 nm. The resulting nanocarrier, named PGEM, was highly effective in tumor accumulation and penetration. As a GEM prodrug, PGEM showed significantly improved antitumor activity in vivo. In addition, PGEM is highly effective in codelivery of GEM and another hydrophobic drug such as PF-04136309 (PF), a CCR2 antagonist. Flow study showed that PGEM treatment also led to increased CD8+ T cell response. However, we also observed increased numbers of myeloid-derived suppressor cells (MDSCs). Mechanistic study showed upregulation of CCL2 and CCL7 following treatment with PGEM. CCL2 and CCL7 are known to act on CCR2 on tumor cells and immune cells and promote tumor invasion and metastasis through both direct impact on tumor cells and recruitment of immunosuppressive cells. Our preliminary data showed that incorporation of PF into PGEM NPs led to significant improvement in PANC02 model. More importantly this treatment resulted in a drastic improvement in tumor immune microenvironment, which boded well with combination with anti-PD-1 treatment. This application is focused on further improvement and characterization of PF/PGEM-based therapy. An improved PGEM (PGEMi) will also be developed to improve the bioavailability of both PF and PGEM in tumor tissues. Three specific aims will be pursued in this application: Aim 1 will develop and characterize PGEMi and PF/PGEMi with respect to biophysical and in vitro biological properties. Aim 2 will define the tumor penetration efficiency of PGEMi, and the PK and biodistribution of PF/PGEMi in murine and human PCa models including PDX model.Aim 3 will investigate the toxicity profile and the therapeutic efficacy of PF/PGEMi in various PCa models. Completion of this study may lead to the development of a new and improved combination therapy that will advance the treatment of PCa.

抽象的： 胰腺癌 (PCa) 是最致命的癌症之一，也是癌症死亡的第四大原因 在美国。吉西他滨 (GEM) 和紫杉​​醇 (PTX) 的组合或 Nab-紫杉醇（纳米颗粒 (NP) 白蛋白结合 PTX（Abraxane®）是局部复发或转移性 PCa 的一线治疗方法之一。 然而，临床上仅显示出有限的益处。此外，这种治疗与显着相关 毒性。 PCa 的特点是存在致密基质，可能会限制相对有效的渗透。 大尺寸纳米粒子。另一方面，游离的GEM迅速从血液循环中消除，也被 经脱氨酶快速失活。因此，迫切需要开发小型纳米粒子 能够保护药物并有效抑制肿瘤的积累和渗透。我们最近展示了 GEM 与 POEG-co-PVD 聚合物的结合导致颗粒尺寸从 160 显着减小到 13纳米。由此产生的纳米载体被命名为 PGEM，在肿瘤积累和渗透方面非常有效。 作为 GEM 前药，PGEM 显示出显着改善的体内抗肿瘤活性。此外，PGEM 具有很高的 可有效同时递送 GEM 和另一种疏水性药物，例如 PF-04136309 (PF)（一种 CCR2 拮抗剂）。 Flow 研究表明 PGEM 治疗还导致 CD8+ T 细胞反应增强。然而我们也观察到 骨髓源性抑制细胞（MDSC）数量增加。机制研究表明上调 PGEM 治疗后的 CCL2 和 CCL7。已知 CCL2 和 CCL7 作用于肿瘤细胞上的 CCR2， 免疫细胞通过直接影响肿瘤细胞和促进肿瘤侵袭和转移 免疫抑制细胞的募集。我们的初步数据表明，将 PF 掺入 PGEM NP 中 导致 PANC02 模型的显着改进。更重要的是，这种治疗导致了剧烈的 肿瘤免疫微环境的改善，这与抗PD-1治疗相结合是个好兆头。 该应用的重点是进一步改进和表征基于 PF/PGEM 的疗法。一个 还将开发改进的 PGEM (PGEMi)，以提高 PF 和 PGEM 在肿瘤中的生物利用度 组织。该应用将追求三个具体目标： 目标 1 将开发并表征 PGEMi 和 PF/PGEMi 的生物物理和体外生物学特性。目标 2 将定义肿瘤渗透 PGEMi 的效率，以及 PF/PGEMi 在小鼠和人类 PCa 模型中的 PK 和生物分布，包括 PDX模型。目标3将研究PF/PGEMi在各种PCa中的毒性特征和治疗效果 模型。这项研究的完成可能会导致开发出一种新的、改进的联合疗法， 将推进PCa的治疗。