Integrating Anti-invasive and Anti-growth Therapies Targeting Cancer Metastasis

针对癌症转移的整合抗侵袭和抗生长疗法

• 批准号: 9062389
• 负责人: NICOLE S SAMPSON
• 金额: $ 32.58万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-02 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9062389
• 关键词: Area; Behavior; Binding; Biochemical; Biological; Biological Assay; Cancer Model; Cell Death; Cell Line; Cell surface; Cells; Cessation of life; Clinical; Cytotoxic agent; Data; Development; Dialysis procedure; Dissociation; Drug Kinetics; Encapsulated; Endocytosis; Environment; Epithelial; Equilibrium; Future; Goals; Growth; Heat-Shock Proteins 90; Homing; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; Incidence; Knowledge; Liposomes; MMP14 gene; Malignant Neoplasms; Metastatic to; MicroRNAs; Mission; Modeling; Molecular; Neoplasm Metastasis; Outcome; Oxygen; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Play; Process; Property; Public Health; Publishing; Reagent; Reporting; Research; Resistance; Risk; Role; Solid Neoplasm; Specificity; Testing; Time; Treatment Failure; Tumor Cell Invasion; Work; base; cancer cell; cancer invasiveness; cancer prevention; cancer recurrence; cancer stem cell; cancer therapy; cell killing; chemotherapy; cytotoxic; drug discovery; effective therapy; epithelial to mesenchymal transition; improved; improved outcome; in vivo; innovation; metastasis prevention; metastatic process; novel; novel strategies; peptide drug; pre-clinical; pressure; prevent; stem; success; targeted treatment; therapeutic target; tool; tool development; treatment strategy; tumor; tumor growth

DESCRIPTION (provided by applicant): There is an unmet need to develop novel chemotherapeutics that enhance selectivity and specificity for targeting chemo-resistant tumors. In particular, new strategies that attack chemotherapy-insensitive cancer stem cells/tumor initiating cells (TICs) are lacking. The goal of this proposal is to understand the interplay between TICs and their microenvironment during the transition to invasion and metastasis, as well as to develop a novel treatment reagent to specifically induce invasive TIC death in a preclinical setting. Our central hypothesis is that a cell surface-anchored protease, matrix metalloproteinase-14 (MMP-14), is a key molecule capable of executing the switch in epithelial TICs from quiescent to invasive cells, thereby controlling metastasis. Development of reagents to selectively and specifically target invasive TICs utilizing an MMP-14 binding peptide will facilitate prevention of cancer dissemination. The rationale for this project is that the development of a specific tumor-homing vehicle that carries inhibitory peptide and cytotoxic drug will allow us to not only block cancer invasion but to also induce cancer cell death. Furthermore, this study will advance our understanding of how the microenvironment influences quiescent TICs to give rise to metastases. We plan to test our hypothesis by pursuing the following three specific aims:1) Elucidate the role and mechanism of MMP-14 in conversion of quiescent TICs to invasive cells under hypoxic conditions; 2) Define the mechanism of action of an MMP-14 homing peptide; and 3) Develop a bi-functional reagent that specifically targets cancer invasiveness and induces cancer cell death. With respect to the expected outcomes, the work proposed in this application will potentially result in development of a bi-functional reagent capable of delivering a potent chemotherapeutic drug to invasive TICs. This project is innovative because it utilizes novel peptides specific for MMP-14 to selectively target invasive TICs. The proposed research will have significant future implications because it is expected to vertically advance our understanding of how quiescent TICs become reprogrammed into invasive TICs in a hypoxic environment. The developed bi-functional reagent will have a positive impact on future cancer prevention/treatment and could eventually improve the outcome of patients with cancer.

描述（由申请人提供）：不需要开发新型的化学治疗剂，从而提高了靶向化学耐药性肿瘤的选择性和特异性。特别是，缺乏攻击化学疗法的癌症干细胞/肿瘤引发细胞（TICS）的新策略。该提议的目的是了解在过渡到入侵和转移期间抽动与它们的微环境之间的相互作用，以及开发一种新型的治疗试剂，以在临时性环境中特异性诱导侵入性的TIC死亡。我们的中心假设是，细胞表面锚定的蛋白酶基质金属蛋白酶-14（MMP-14）是一个关键分子，能够从静止细胞到浸润细胞执行上皮细胞中的开关，从而控制转移。开发利用MMP-14结合肽的有选择性，特异性靶向侵入性抽动的试剂将有助于预防癌症传播。该项目的基本原理是，携带抑制性肽和细胞毒性药物的特定肿瘤动力汽车的发展将使我们不仅可以阻止癌症侵袭，还可以诱导癌细胞死亡。此外，这项研究将促进我们对微环境如何影响静态抽动产生转移的理解。我们计划通过追求以下三个特定目的来检验我们的假设：1）阐明MMP-14在低氧条件下静态细胞转化为入侵细胞中的作用和机制； 2）定义MMP-14归巢肽的作用机理； 3）开发一种双功能试剂，该试剂专门针对癌症的侵入性并诱导癌细胞死亡。关于预期的结果，本应用中提出的工作可能会导致双功能试剂的发展 能够将有效的化学治疗药物输送到侵入性抽搐中。该项目具有创新性，因为它利用了针对MMP-14的新型肽来选择性地靶向侵入性抽搐。拟议的研究将具有未来的重大影响，因为预计将在低氧环境中垂直促进我们对静态抽动如何重新编程为侵入性抽动的理解。开发的双功能试剂将对未来的癌症预防/治疗产生积极影响，并最终可以改善癌症患者的结果。