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:
- 金额:$ 17.02万
- 依托单位:
- 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:
- 关键词:AcetylcysteineAppendiceal NeoplasmsBiological ModelsBromelainsCharacteristicsClinicalColorectal CancerComputer SimulationCytotoxic agentDimensionsDiseaseDoseDrug CombinationsDrug TargetingEnvironmentFunctional disorderGelGoalsGranulocyte-Macrophage Colony-Stimulating FactorHumanIn VitroIncidenceInstitutionInterleukin-3InternationalIntra-abdominalLongevityMalignant NeoplasmsMalignant neoplasm of ovaryMalignant neoplasm of pancreasModelingMolecularMorbidity - disease rateMucin-2 Staining MethodMucinousMucinous NeoplasmMucolyticsMucous body substanceMusNatureNeoplasm MetastasisNon obeseOperative Surgical ProceduresOrganOrganoidsOutcomePathway interactionsPatientsPeritonealPharmaceutical PreparationsPolymersProductionProteinsPseudomyxoma PeritoneiRare DiseasesResearchRoleSafetySevere Combined ImmunodeficiencyStem Cell FactorTherapeuticTherapeutic InterventionTransgenic OrganismsTransplant RecipientsTumor BurdenTumor TissueXenograft procedurebiomedical referral centercancer cellchemotherapyclinically relevantcombinatorialcytotoxiccytotoxicitydiabeticefficacy testingextracellularhumanized mouseimprovedin vivoin vivo Modelintraperitonealneoplastic cellnovelpreclinical efficacypreclinical studytumor growthtumor 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.
摘要
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,
粘液性阑尾肿瘤(MAN)。PMP对全身化疗反应差,
尽管进行了积极的和病态的局部手术治疗,但仍会复发。对于低级PMP(LG-PMP),几乎所有的
有害的临床后果与过量产生的压迫性器官功能障碍有关
和腹腔内积聚少细胞粘液(主要由粘蛋白2 [MUC 2]蛋白组成)。
相反,高级别PMP(HG-PMP)更具细胞性和侵袭性,并且丰富的细胞外粘液
为癌细胞的生长提供了一个保护性的环境。我们假设减少细胞外粘液
通过降低PMP的粘液性肿瘤负荷,
(特别是LG-PMP),并通过去除保护性的药物来提高化疗或靶向药物的疗效。
粘液屏障包围肿瘤细胞(尤其是HG-PMP)。在本提案中,我们将测试
使用菠萝蛋白酶(BR)+N-乙酰半胱氨酸(NAC)的组合粘液溶解疗法,以溶解细胞外粘液
在LG-和HG-MAN/PMP的临床相关体外和体内患者衍生模型中。成功结果
这些研究将克服治疗PMP的一个主要障碍,即质量效应,
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
建议是可行的,因为我们是一个主要的转诊中心的管理患者的PMP,建议
药物组合有效地溶解粘液在硅片上,我们已经开发了体外和体内患者源性
代表临床疾病的MAN/PMP模型。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Mohammad Haroon Asif Choudry其他文献
Mohammad Haroon Asif Choudry的其他文献
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{{ truncateString('Mohammad Haroon Asif Choudry', 18)}}的其他基金
Application of mucus modulating multipurpose trypsin nanoparticles to overcome the mucus barrier and deliver mitochondria-targeted anticancer drugs in mucinous carcinoma peritonei
应用粘液调节多用途胰蛋白酶纳米颗粒克服粘液屏障并在腹膜粘液癌中递送线粒体靶向抗癌药物
- 批准号:
10510536 - 财政年份:2022
- 资助金额:
$ 17.02万 - 项目类别:
Application of mucus modulating multipurpose trypsin nanoparticles to overcome the mucus barrier and deliver mitochondria-targeted anticancer drugs in mucinous carcinoma peritonei
应用粘液调节多用途胰蛋白酶纳米颗粒克服粘液屏障并在腹膜粘液癌中递送线粒体靶向抗癌药物
- 批准号:
10693942 - 财政年份:2022
- 资助金额:
$ 17.02万 - 项目类别:
Application of mucus modulating multipurpose bromelain nanoparticles to overcome the mucus barrier in appendiceal pseudomyxoma peritonei
应用粘液调节多用途菠萝蛋白酶纳米颗粒克服阑尾腹膜假粘液瘤粘液屏障
- 批准号:
10290386 - 财政年份:2021
- 资助金额:
$ 17.02万 - 项目类别:
Application of mucus modulating multipurpose bromelain nanoparticles to overcome the mucus barrier in appendiceal pseudomyxoma peritonei
应用粘液调节多用途菠萝蛋白酶纳米颗粒克服阑尾腹膜假粘液瘤粘液屏障
- 批准号:
10457440 - 财政年份:2021
- 资助金额:
$ 17.02万 - 项目类别: