Sleeping Beauty-Mediated microRNA Therapeutics for Metastatic Colorectal Cancer
睡美人介导的 microRNA 治疗转移性结直肠癌
基本信息
- 批准号:8689231
- 负责人:
- 金额:$ 16.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-04-01 至 2016-03-31
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAddressAffectAngiogenesis InhibitorsAnimal Cancer ModelAnimal ModelBindingCaenorhabditis elegansCancer EtiologyCancer cell lineCanis familiarisCathetersCellsCessation of lifeClinical TrialsColorectal CancerColorectal NeoplasmsCultured CellsCyclophosphamideDNA deliveryDataDevelopmentDiagnosisDiffusionDiseaseEffectivenessEuropeExcisionFirefly LuciferasesFluorouracilFunctional RNAGap JunctionsGene DeliveryGene ExpressionGene TargetingGene TransferGenerationsGrowthHCT116 CellsHepaticHepatocyteHigh Density LipoproteinsHumanIndiumIndividualLengthLinkLiverLuciferasesMalignant NeoplasmsMediatingMediator of activation proteinMessenger RNAMetastatic Neoplasm to the LiverMetastatic toMicroRNAsMolecularMusNeoplasm MetastasisNormal CellNormal tissue morphologyNucleotidesNude MiceOncogenicOperative Surgical ProceduresPathway interactionsPatientsPatternPenetrationPlayPositioning AttributeProteinsReporterReporter GenesResearch Project GrantsRoleSiteSleeping BeautyStromal NeoplasmSystemTechniquesTestingTherapeuticTimeTissuesTranslationsTreatment ProtocolsTumor SuppressionTumor Suppressor ProteinsUnited StatesXenograft Model Antitumor Assaysadvanced diseasebasebioluminescence imagingcancer therapycancer typechemotherapygain of functionin vivoin vivo Modelintercellular communicationmetastatic colorectalmouse modelneoplastic cellnovel therapeutic interventionoutcome forecastoverexpressionpre-clinicalpublic health relevancesuccesstherapeutic genetumortumor xenografttumorigenesisvector
项目摘要
DESCRIPTION (provided by applicant): Colorectal cancer is one of the leading causes of cancer death worldwide, with the liver being the most common and critical site for development of colorectal cancer metastases. Surgical resection remains the only curative hope for patients with disease that is metastatic to the liver. However, 85% of these patients are ineligible for resection, with the 5-year survival for inoperative patients ranging from 0-5%. MicroRNAs (miRNAs) are non-coding RNAs approximately 20 nucleotides in length that exert their regulatory effects by binding to imperfect complementary sites predominantly located within the 3'UTR of their mRNA targets. Their causal role in promoting tumorigenesis, invasion and metastases has only recently come to light. Almost all cancer types show aberrant expression of miRNAs, with patterns of overexpression or, more commonly, underexpression in tumor cells. We hypothesize that these miRNAs constitute valid targets for the development of molecular therapies against metastatic disease. Here we propose to use the Sleeping Beauty transposon system to achieve extended and high level liver-directed expression of both tumor suppressor miRNAs as well as antimiRs against oncogenic miRNAs in the treatment of human colorectal cancer metastatic to the liver. Although it is well established that miRNAs can be transferred horizontally by a number of different mechanisms, in vivo data demonstrating exogenous miRNA transfer from normal cells to tumor cells in an animal model of cancer are lacking. In Aim 1, we have devised an approach to quantitatively evaluate intercellular transfer of miRNA from normal liver tissue into human tumor xenografts, assaying for miRNA delivery to an mRNA target by the effect on luciferase reporter gene expression in tumors. In Aim 2 we will test the effectiveness of tumor suppressive miRNAs (miR-34a, miR-9) as well as targeting an oncogenic miRNA (miR-21) both singly and in combination against human colorectal tumor xenografts in nude mice. Results from these studies will provide fundamental experimental support for therapeutic microRNA transfer from normal tissues into tumor cells in an in vivo model of metastatic disease. They will also provide preclinical support for an miRNA-based antitumor strategy against metastatic colorectal cancer that is potentially applicable to the treatment of an cancer that is metastatic to the liver.
描述(申请人提供):结直肠癌是全球癌症死亡的主要原因之一,肝脏是结直肠癌转移最常见和最关键的部位。对于转移到肝脏的患者,手术切除仍然是唯一的治疗希望。然而,这些患者中有85%不适合切除,未手术患者的5年生存率为0-5%。MicroRNAs (miRNAs)是一种长度约为20个核苷酸的非编码rna,通过结合主要位于其mRNA靶标3'UTR内的不完美互补位点来发挥调节作用。它们在促进肿瘤发生、侵袭和转移中的因果作用直到最近才被发现。几乎所有类型的癌症都表现出mirna的异常表达,在肿瘤细胞中表现为过表达或更常见的低表达模式。我们假设这些mirna构成了开发针对转移性疾病的分子疗法的有效靶点。在这里,我们建议使用睡美人转座系统来实现肿瘤抑制mirna和抗肿瘤mirna的扩展和高水平肝脏定向表达,以治疗人类结肠直肠癌转移到肝脏。虽然已经确定miRNA可以通过多种不同的机制水平转移,但在癌症动物模型中,缺乏证明外源miRNA从正常细胞转移到肿瘤细胞的体内数据。在Aim 1中,我们设计了一种方法来定量评估miRNA从正常肝组织向人类肿瘤异种移植物的细胞间转移,通过对肿瘤中荧光素酶报告基因表达的影响来检测miRNA向mRNA靶点的传递。在Aim 2中,我们将在裸鼠中测试肿瘤抑制miRNA (miR-34a, miR-9)以及靶向致癌miRNA (miR-21)单独和联合对人类结直肠癌异种移植物的有效性。这些研究结果将为在体内转移性疾病模型中将治疗性microRNA从正常组织转移到肿瘤细胞提供基础实验支持。他们还将为针对转移性结直肠癌的基于mirna的抗肿瘤策略提供临床前支持,该策略可能适用于转移到肝脏的癌症的治疗。
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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R. Scott McIvor其他文献
strongIdentification of inflammatory cells in dilated ascending aortas of IDUA-deficient (MPS I) mice/strong
在扩张的IDUA缺陷(MPS I)小鼠的升高主动脉中炎性细胞的强鉴定/强
- DOI:
10.1016/j.ymgme.2023.107774 - 发表时间:
2024-02-01 - 期刊:
- 影响因子:3.500
- 作者:
Bryce Binstadt;Davis Seelig;Jennifer Auger;Andrea Karlen;Michael Evans;R. Scott McIvor;Elizabeth Braunlin - 通讯作者:
Elizabeth Braunlin
strongFirst-in-human clinical trial of genetically engineered B cells: Application to the treatment of mucopolysaccharidosis type I/strong
基因工程B细胞的强烈狂热临床试验:应用I/强的粘多糖含糖治疗
- DOI:
10.1016/j.ymgme.2023.107957 - 发表时间:
2024-02-01 - 期刊:
- 影响因子:3.500
- 作者:
R. Scott McIvor;Christiane S. Hampe;Glen Grandea;Erik R. Olson;Kole D. Meeker;Cassidy Papia;Joell Solan;Robert Hayes;Sean Ainsworth;Paul J. Orchard;Jacob Wesley;Robert Sikorski - 通讯作者:
Robert Sikorski
Recovery of neurologic function in mucopolysaccharidosis type I mice with existing neurocognitive dysfunction by treatment with AAV9-IDUA vector
- DOI:
10.1016/j.ymgme.2016.11.038 - 发表时间:
2017-01-01 - 期刊:
- 影响因子:
- 作者:
Lalitha Belur;Kelly M Podetz-Pedersen;Walter C Low;R. Scott McIvor - 通讯作者:
R. Scott McIvor
<strong>Intranasal gene delivery of AAV9 iduronidase: A non-invasive and effective gene therapy approach for prevention of neurologic disease in a murine model of mucopolysaccharidosis type I</strong>
- DOI:
10.1016/j.ymgme.2015.12.195 - 发表时间:
2016-02-01 - 期刊:
- 影响因子:
- 作者:
Lalitha Belur;Megan Buckvold;Kelly M. Podetz-Pedersen;Maureen Riedl;Lucy Vulchanova;Leah R. Hanson;Carolyn Fairbanks;Karen Kozarsky;William H. Frey;Walter C. Low;R. Scott McIvor - 通讯作者:
R. Scott McIvor
<strong>Ex vivo lentiviral transduction of hematopoietic stem cells in mucopolysaccharidosis type II (MPS II) mice achieves high levels of systemic iduronate-2-sulfatase (IDS) enzyme activity and normalization of glycosaminoglycans (GAGs)</strong>
- DOI:
10.1016/j.ymgme.2020.12.247 - 发表时间:
2021-02-01 - 期刊:
- 影响因子:
- 作者:
Miles C. Smith;Lalitha Belur;Olivia Erlanson;Kelly Podetz-Pedersen;Andrea Karlen;Jessica McKenzie;Jenn Detellis;Khatuna Gagnidze;Geoff Parsons;Nick Robinson;Shelby Labarre;Gina Scarglia;Saumil Shah;Hsing-Chen Tsai;R. Scott McIvor;Melissa Bonner - 通讯作者:
Melissa Bonner
R. Scott McIvor的其他文献
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{{ truncateString('R. Scott McIvor', 18)}}的其他基金
Sleeping Beauty-Mediated microRNA Therapeutics for Metastatic Colorectal Cancer
睡美人介导的 microRNA 治疗转移性结直肠癌
- 批准号:
8810227 - 财政年份:2014
- 资助金额:
$ 16.53万 - 项目类别:
Lentiviral gene therapy for mucopolysaccharidosis
粘多糖贮积症的慢病毒基因治疗
- 批准号:
7805078 - 财政年份:2010
- 资助金额:
$ 16.53万 - 项目类别:
Transposon Mediated Gene Therapy for Colorectal Cancer
转座子介导的结直肠癌基因治疗
- 批准号:
8053301 - 财政年份:2007
- 资助金额:
$ 16.53万 - 项目类别:
Transposon Mediated Gene Therapy for Colorectal Cancer
转座子介导的结直肠癌基因治疗
- 批准号:
7458085 - 财政年份:2007
- 资助金额:
$ 16.53万 - 项目类别:
Transposon Mediated Gene Therapy for Colorectal Cancer
转座子介导的结直肠癌基因治疗
- 批准号:
7197886 - 财政年份:2007
- 资助金额:
$ 16.53万 - 项目类别:
Transposon Mediated Gene Therapy for Colorectal Cancer
转座子介导的结直肠癌基因治疗
- 批准号:
7619606 - 财政年份:2007
- 资助金额:
$ 16.53万 - 项目类别:
Transposon Mediated Gene Therapy for Colorectal Cancer
转座子介导的结直肠癌基因治疗
- 批准号:
7802899 - 财政年份:2007
- 资助金额:
$ 16.53万 - 项目类别:
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