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.

摘要： 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）或Nab-紫杉醇（纳米颗粒）的组合 (NP)白蛋白结合的PTX，Abraxane®）是局部复发性或转移性PCa的一线治疗之一。 然而，在临床上仅显示出有限的益处。此外，这种治疗与显著的 毒性PCa的特征在于存在致密的基质，这可能限制相对低分子量的PCa的有效渗透。 大尺寸NP。另一方面，免费创业板迅速从血液循环中被淘汰， 通过脱氨酶快速灭活。因此，迫切需要开发小型NP， 能够保护药物，并有效地促进肿瘤的蓄积和渗透。我们最近的研究表明 GEM与POEG-共-PVD聚合物的缀合导致粒度从160显著降低到100。 13纳米。由此产生的纳米载体，命名为PGEM，在肿瘤积累和渗透方面非常有效。 作为GEM前体药物，PGEM在体内表现出显著的抗肿瘤活性。此外，PGEM高度 在GEM和另一种疏水性药物如PF-04136309（PF）（一种CCR 2拮抗剂）的共递送中有效。 流式细胞术显示PGEM处理也导致CD 8 + T细胞应答增加。然而，我们也观察到， 骨髓来源的抑制细胞（MDSC）数量增加。机制研究显示， PGEM治疗后的CCL 2和CCL 7。已知CCL 2和CCL 7作用于肿瘤细胞上的CCR 2， 免疫细胞和促进肿瘤的侵袭和转移，通过直接影响肿瘤细胞， 免疫抑制细胞的募集。我们的初步数据表明，PF掺入PGEM纳米粒 导致PANC 02模型显著改进。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，这预示着与抗PD-1治疗的组合。 本申请的重点是进一步改进和表征PF/PGEM为基础的治疗。一个 还将开发改良的PGEM（PGEMi）以提高PF和PGEM在肿瘤中的生物利用度 组织中本申请将追求三个具体目标：目标1将开发和表征PGEMi， PF/PGEMi的生物物理和体外生物学特性。目标2将定义肿瘤穿透 PGEMi的有效性，以及PF/PGEMi在小鼠和人PCa模型中的PK和生物分布，包括 目的3研究PF/PGEMi对不同PCa的毒性和治疗效果。 模型这项研究的完成可能会导致开发一种新的和改进的联合治疗， 将促进前列腺癌的治疗。