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Application of Mucolytic Therapy in Patient-Derived Models of Pseudomyxoma Peritonei

粘液溶解疗法在腹膜假粘液瘤患者来源模型中的应用

基本信息

批准号：
9808331
负责人：
Mohammad Haroon Asif Choudry
金额：
$ 17.02万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9808331
关键词：
Acetylcysteine Appendiceal Neoplasms Biological Models Bromelains Characteristics Clinical Colorectal Cancer Computer Simulation Cytotoxic agent Dimensions Disease Dose Drug Combinations Drug Targeting Environment Functional disorder Gel Goals Granulocyte-Macrophage Colony-Stimulating Factor Human In Vitro Incidence Institution Interleukin-3 International Intra-abdominal Longevity Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Modeling Molecular Morbidity - disease rate Mucin-2 Staining Method Mucinous Mucinous Neoplasm Mucolytics Mucous body substance Mus Nature Neoplasm Metastasis Non obese Operative Surgical Procedures Organ Organoids Outcome Pathway interactions Patients Peritoneal Pharmaceutical Preparations Polymers Production Proteins Pseudomyxoma Peritonei Rare Diseases Research Role Safety Severe Combined Immunodeficiency Stem Cell Factor Therapeutic Therapeutic Intervention Transgenic Organisms Transplant Recipients Tumor Burden Tumor Tissue Xenograft procedure biomedical referral center cancer cell chemotherapy clinically relevant combinatorial cytotoxic cytotoxicity diabetic efficacy testing extracellular humanized mouse improved in vivo in vivo Model intraperitoneal neoplastic cell novel preclinical efficacy preclinical study tumor growth tumor xenograft

项目摘要

Abstract Pseudomyxoma peritonei (PMP), an insidious but lethal malignancy, refers to peritoneal metastases from mucinous appendix neoplasms (MAN). PMP is poorly responsive to systemic chemotherapy and frequently recurs despite aggressive and morbid locoregional surgical therapy. For low-grade PMP (LG-PMP), nearly all of the deleterious clinical consequences are related to compressive organ dysfunction from excessive production and intra-abdominal accumulation of paucicellular mucus (predominantly composed of mucin 2 [MUC2] protein). Conversely, high-grade PMP (HG-PMP) is more cellular and invasive, and the abundant extracellular mucus provides a protective environment for cancer cells to thrive. We hypothesize that reducing extracellular mucus accumulation will minimize compressive organ dysfunction by decreasing the mucinous tumor burden of PMP (especially LG-PMP) and improve the efficacy of chemotherapeutic or targeted drugs by removing the protective mucus barrier surrounding neoplastic cells (especially HG-PMP). In this proposal, we will test the efficacy of combinatorial mucolytic therapy, using bromelain (BR) + N-acetylcysteine (NAC), to dissolve extracellular mucus in clinically relevant in vitro and in vivo patient-derived models of LG- and HG-MAN/PMP. Successful outcome of the proposed studies will overcome a major hurdle for treating PMP, which is the mass-effect and cytoprotective-effect of abundant extracellular mucus. In addition, our proposed research provides a novel treatment dimension for PMP that may be applied to mucinous colorectal, pancreatic and ovarian cancers. Our proposal is feasible since we are a major referral center for the management of patients with PMP, the proposed drug combination effectively dissolves mucus in-silico, and we have developed in vitro and in vivo patient-derived models of MAN/PMP that are representative of the clinical disease.

抽象的腹膜假粘液瘤（PMP）是一种隐匿但致命的恶性肿瘤，是指腹膜转移瘤粘液性阑尾肿瘤（MAN）。 PMP 对全身化疗反应较差，并且经常尽管进行了积极且病态的局部手术治疗，但仍会复发。对于低档PMP（LG-PMP），几乎所有有害的临床后果与过度生产导致的压迫器官功能障碍有关腹腔内积聚少量细胞粘液（主要由粘蛋白 2 [MUC2] 蛋白组成）。相反，高级别 PMP (HG-PMP) 更具细胞性和侵袭性，且细胞外粘液丰富为癌细胞的生长提供保护环境。我们假设减少细胞外粘液积累将通过减少 PMP 的粘液肿瘤负担来最大程度地减少压迫性器官功能障碍（特别是LG-PMP）并通过去除保护性来提高化疗或靶向药物的疗效肿瘤细胞周围的粘液屏障（尤其是 HG-PMP）。在这个提案中，我们将测试以下功能的有效性：组合粘液溶解疗法，使用菠萝蛋白酶 (BR) + N-乙酰半胱氨酸 (NAC) 溶解细胞外粘液在 LG- 和 HG-MAN/PMP 的临床相关体外和体内患者衍生模型中。成功的结果拟议的研究将克服治疗 PMP 的一个主要障碍，即质量效应和丰富的细胞外粘液的细胞保护作用。此外，我们提出的研究提供了一种新颖的 PMP 的治疗维度可应用于粘液性结直肠癌、胰腺癌和卵巢癌。我们的该提议是可行的，因为我们是管理 PMP 患者的主要转诊中心，提议的药物组合可以有效地在计算机中溶解粘液，我们已经在体外和体内开发了源自患者的代表临床疾病的 MAN/PMP 模型。