Exosomal Contents Guided Amino Acids Treatment for Pancreatic Cancer

外泌体内容物引导氨基酸治疗胰腺癌

• 批准号: 10434501
• 负责人: Dali Sun
• 金额: $ 16.95万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-02 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434501
• 关键词: Acids; Amino Acids; Breathing; Cell Death; Cell Survival; Cell secretion; Cells; Cellular Assay; Clinical Trials; Disease; Disease Progression; Distant; Distant Metastasis; Endocytosis; Epithelial; Excision; Exocytosis; Human; Impairment; In Vitro; Incidence; Investigation; Lead; Length; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Monitor; Neoplasm Metastasis; Non-Malignant; Normal tissue morphology; Operative Surgical Procedures; Outcome; Pancreas; Pancreatic Adenocarcinoma; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology; Proteins; Proteome; Proteomics; Quality of life; Scheme; Side; Solid; Survival Rate; Therapeutic; Therapeutic Effect; Treatment Cost; Work; advanced disease; cell type; chemoradiation; chemotherapy; comparative; dietary supplements; effective therapy; efficacy study; exosome; improved; in vivo; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; preclinical study; side effect; stressor; tumor; tumor progression; tumor xenograft

PROJECT SUMMARY/ABSTRACT With a 5-year survival rate of less than 5%, Pancreatic adenocarcinoma (PDAC) is a lethal condition with poor outcomes and an increasing incidence. Surgical resection is the only treatment that offers a potential cure, but was limited to the early stage cases without distant metastasis. Currently, there are scarce effective treatments for advanced disease. Chemoradiation and systemic chemotherapy are the mainstay of treatment to slow disease progression at advanced stages. But these therapies cause various side effects, which is one major barrier to the efficacy of anti-tumor therapeutics. There are no known medications that can selectively protect normal tissues from these side effects, and thus an urgent need for novel treatment selectively targeting only tumor cells to improve patient outcomes. Exosomes secreted by tumor cells actively participate in tumor progression and metastasis and contain multiple biomolecules reflecting the status of their parental tumor cells. Investigation of the exosomal contents may lead to a therapeutic inspiration for cancer. We conducted comparative proteomics studies over the malignant and nonmalignant cells at both the cellular and exosomal level. Significant different proteome sets have been identified between the malignant and nonmalignant cells at all levels. Since amino acids are the formation unit of the protein primary sequence, we furthered the proteomics results by studying the distribution of the amino acids statistically between the malignant and nonmalignant cells at both cellular and exosomal level. We found a significant imbalanced amino acid distribution between the tumor cells and exosomes, which is not found between nonmalignant cells and exosomes. This indicates that tumor cells selectively flux certain amino acids out of cells through exosomes, which inspired us to use these amino acids as stressors to tumor cells. The cell viability of the tumor cells treated by these amino acids was significantly decreased, but not that of nonmalignant cells. This exosome-guided observation potentiates a new therapeutic intervention selectively targeting tumor cells. In order to develop the finding into a therapeutic choice for pancreatic cancer, we propose to preclinically validate the treatment in vivo and study the mechanism in vitro.

项目总结/摘要 胰腺癌（PDAC）的5年生存率低于5%，是一种致命疾病，生存率低。 结果和增加的发病率。手术切除是唯一可能治愈的治疗方法，但 仅限于无远处转移的早期病例。目前，缺乏有效的治疗方法， 治疗晚期疾病放化疗和全身化疗是治疗的主要手段， 疾病进展到晚期。但这些疗法会引起各种副作用，这是一个主要的 抗肿瘤治疗剂的功效的障碍。没有已知的药物可以选择性地保护 正常组织免受这些副作用的影响，因此迫切需要选择性靶向仅 肿瘤细胞，以改善患者的预后。 由肿瘤细胞分泌的外泌体积极参与肿瘤进展和转移，并含有多种 反映其亲本肿瘤细胞状态的生物分子。外泌体内容物的研究可能导致 癌症治疗的灵感。我们对恶性和恶性肿瘤进行了比较蛋白质组学研究， 非恶性细胞在细胞和外泌体水平。显著不同的蛋白质组集已经被 恶性和非恶性细胞之间的所有水平。由于氨基酸是形成单位 蛋白质一级序列的氨基酸分布，进一步研究了蛋白质组学结果， 在细胞水平和外泌体水平上，恶性和非恶性细胞之间的酸统计学差异。我们发现 肿瘤细胞和外泌体之间的氨基酸分布显著不平衡，未发现 非恶性细胞和外来体之间的联系这表明肿瘤细胞选择性地将某些氨基酸 这启发了我们使用这些氨基酸作为肿瘤细胞的应激源。细胞 用这些氨基酸处理的肿瘤细胞的存活率显著降低，但非恶性肿瘤细胞的存活率没有降低。 细胞这种外泌体引导的观察增强了选择性靶向肿瘤的新治疗干预 细胞为了将这一发现发展为胰腺癌的治疗选择，我们建议在临床前 在体内验证治疗效果，并在体外研究其作用机制。