Engineered HGF-NK1 antagonists for Met-targeted cancer imaging and therapy

用于 Met 靶向癌症成像和治疗的工程化 HGF-NK1 拮抗剂

基本信息

  • 批准号:
    8657879
  • 负责人:
  • 金额:
    $ 31.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-07-01 至 2017-04-30
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Dysregulation of cell signaling pathways that mediate proliferation, survival, and migration are an underlying cause of cancer, and result in invasion and metastasis of many human tumors. In particular, dysregulation and over-expression of the Met tyrosine kinase receptor correlates to poor prognosis in many human tumors, making it an attractive target for therapeutic intervention. There are currently no FDA-approved therapeutics targeting the Met receptor; however, a few candidate molecules have recently entered early stage clinical trials. Therefore, molecules that potently inhibit Met receptor activation would have a significant clinical impact on cancer therapy. In addition, studies to develop Met-targeted molecular imaging agents for non- invasive visualization of Met expression in vivo have been extremely limited. The availability of such imaging agents would aid in cancer diagnosis, staging, and disease management, as well as help identify patients who would be good candidates for Met-targeted therapies. To develop robust Met-targeting agents we used the N- terminal and first Kringle domain (NK1) of the natural Met activating ligand, hepatocyte growth factor (HGF), as a basis for engineering potent Met receptor antagonists. Using directed evolution, we engineered NK1 mutants with significant improvements in Met binding affinity and thermal stability compared to wild-type NK1. Rationally-designed, site-directed mutations introduced into these NK1 proteins transformed them into Met receptor antagonists. In Aim 1 of the proposal, we will perform pre-clinical studies on fluorescently-labeled and radiolabeled NK1 mutants to test their ability to non-invasively image Met expression in living subjects, with the goal of developing them as in vivo molecular imaging agents. In Aim 2, we will perform pre-clinical studies to measure the effects of NK1 mutants on tumor growth, metastasis, and angiogenesis in several mouse tumor models. During the course of treatment, non-invasive imaging will be used to monitor growth and progression of the primary tumor and metastases, and to monitor changes in Met expression and metabolism at the tumor site. In Aim 3, we will fully characterize the binding of a larger panel of engineered NK1 mutants to Met-expressing tumor cells, and will determine their ability to dimerize and subsequently inhibit Met receptor activation. In Aim 4, we will use these engineered NK1 proteins to probe sequence-structure-function relationships of ligand- receptor interactions in the Met receptor system, and provide biochemical and biophysical insight into their mechanism of action. In all four aims, results will be compared to wild-type NK1 to determine the effects of Met receptor binding affinity and protein stability on biological activity in cell culture and animal models. Upon completion of this proposal, we will have evaluated the potential of engineered NK1 proteins as molecular imaging and therapeutic agents in pre-clinical models, an important step on the path to clinical translation.
项目总结/摘要 介导增殖、存活和迁移的细胞信号传导途径的失调是一种免疫缺陷。 是癌症的潜在原因,并导致许多人类肿瘤的侵袭和转移。特别是, Met酪氨酸激酶受体的失调和过度表达与许多肿瘤的预后不良相关, 人类肿瘤,使其成为治疗干预的有吸引力的靶点。目前没有FDA批准的 靶向Met受体的治疗;然而,一些候选分子最近已进入早期阶段, 临床试验因此,有效抑制Met受体活化的分子将具有显著的临床意义。 对癌症治疗的影响此外,开发Met靶向分子成像剂用于非肿瘤的研究, 体内Met表达侵入性可视化非常有限。这种成像的可用性 药物将有助于癌症诊断、分期和疾病管理,并有助于识别 会是很好的二甲双胍靶向治疗的候选药物为了开发强大的Met靶向剂,我们使用N- 天然Met活化配体肝细胞生长因子(HGF)的末端和第一Kringle结构域(NK 1),如 一个基础工程有效的甲硫氨酸受体拮抗剂。利用定向进化,我们设计了NK 1突变体, 与野生型NK 1相比,Met结合亲和力和热稳定性显著改善。 将经过精心设计的定点突变引入这些NK 1蛋白质中, 受体拮抗剂 在提案的目标1中,我们将对荧光标记和放射性标记的NK 1进行临床前研究 突变体,以测试它们在活体受试者中非侵入性成像Met表达的能力,目的是 将其开发为体内分子成像剂。在目标2中,我们将进行临床前研究, 在几种小鼠肿瘤模型中,NK 1突变体对肿瘤生长、转移和血管生成的影响。 在治疗过程中,非侵入性成像将用于监测生长和进展的 原发性肿瘤和转移,并监测肿瘤部位Met表达和代谢的变化。在 目的3,我们将充分表征更大组的工程化NK 1突变体与表达Met的细胞的结合。 肿瘤细胞,并将决定其二聚化和随后抑制Met受体活化的能力。在Aim中 4,我们将使用这些工程化的NK 1蛋白来探测配体的序列-结构-功能关系, 受体相互作用的Met受体系统,并提供生物化学和生物物理学的见解, 作用机制。在所有四个目标中,将结果与野生型NK 1进行比较,以确定Met 受体结合亲和力和蛋白质稳定性对细胞培养物和动物模型中生物活性的影响。后 完成这一提议后,我们将评估工程化NK 1蛋白作为分子生物学的潜力。 临床前模型中的成像和治疗药物,这是临床转化道路上的重要一步。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Dual display of proteins on the yeast cell surface simplifies quantification of binding interactions and enzymatic bioconjugation reactions.
  • DOI:
    10.1002/biot.201600696
  • 发表时间:
    2017-05
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
    Lim S;Glasgow JE;Filsinger Interrante M;Storm EM;Cochran JR
  • 通讯作者:
    Cochran JR
Delivery of an engineered HGF fragment in an extracellular matrix-derived hydrogel prevents negative LV remodeling post-myocardial infarction.
  • DOI:
    10.1016/j.biomaterials.2014.12.021
  • 发表时间:
    2015-03
  • 期刊:
  • 影响因子:
    14
  • 作者:
    Sonnenberg, Sonya B.;Rane, Aboli A.;Liu, Cassie J.;Rao, Nikhil;Agmon, Gillie;Suarez, Sophia;Wang, Raymond;Munoz, Adam;Bajaj, Vaibhav;Zhang, Shirley;Braden, Rebecca;Schup-Magoffin, Pamela J.;Kwan, Oi Ling;De Maria, Anthony N.;Cochran, Jennifer R.;Christman, Karen L.
  • 通讯作者:
    Christman, Karen L.
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JENNIFER R COCHRAN其他文献

JENNIFER R COCHRAN的其他文献

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{{ truncateString('JENNIFER R COCHRAN', 18)}}的其他基金

Graduate Training Program in Biotechnology
生物技术研究生培训计划
  • 批准号:
    10621920
  • 财政年份:
    2021
  • 资助金额:
    $ 31.25万
  • 项目类别:
Graduate Training Program in Biotechnology
生物技术研究生培训计划
  • 批准号:
    10205604
  • 财政年份:
    2021
  • 资助金额:
    $ 31.25万
  • 项目类别:
Graduate Training Program in Biotechnology
生物技术研究生培训计划
  • 批准号:
    10413061
  • 财政年份:
    2021
  • 资助金额:
    $ 31.25万
  • 项目类别:
Engineering a multispecific receptor antagonist to inhibit cancer metastasis
设计多特异性受体拮抗剂来抑制癌症转移
  • 批准号:
    8749811
  • 财政年份:
    2014
  • 资助金额:
    $ 31.25万
  • 项目类别:
Engineered HGF-NK1 antagonists for Met-targeted cancer imaging and therapy
用于 Met 靶向癌症成像和治疗的工程化 HGF-NK1 拮抗剂
  • 批准号:
    8449727
  • 财政年份:
    2010
  • 资助金额:
    $ 31.25万
  • 项目类别:
Engineering high affinity tumor-targeting peptides against carbonic anhydrase IX
针对碳酸酐酶 IX 设计高亲和力肿瘤靶向肽
  • 批准号:
    7772227
  • 财政年份:
    2010
  • 资助金额:
    $ 31.25万
  • 项目类别:
Engineering high affinity tumor-targeting peptides against carbonic anhydrase IX
针对碳酸酐酶 IX 设计高亲和力肿瘤靶向肽
  • 批准号:
    8034243
  • 财政年份:
    2010
  • 资助金额:
    $ 31.25万
  • 项目类别:
Engineered HGF-NK1 antagonists for Met-targeted cancer imaging and therapy
用于 Met 靶向癌症成像和治疗的工程化 HGF-NK1 拮抗剂
  • 批准号:
    8100279
  • 财政年份:
    2010
  • 资助金额:
    $ 31.25万
  • 项目类别:
Engineered HGF-NK1 antagonists for Met-targeted cancer imaging and therapy
用于 Met 靶向癌症成像和治疗的工程化 HGF-NK1 拮抗剂
  • 批准号:
    8257561
  • 财政年份:
    2010
  • 资助金额:
    $ 31.25万
  • 项目类别:
Engineering the Met receptor: a potent antagonist of tumor growth and metastasis
改造 Met 受体:肿瘤生长和转移的有效拮抗剂
  • 批准号:
    7539905
  • 财政年份:
    2007
  • 资助金额:
    $ 31.25万
  • 项目类别:

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