Targeting of Doppel-axis to Control Lung Tumor Angiogenesis and Immunity

双轴靶向控制肺肿瘤血管生成和免疫

基本信息

  • 批准号:
    10674889
  • 负责人:
  • 金额:
    $ 34.22万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-08-01 至 2027-07-31
  • 项目状态:
    未结题

项目摘要

Project summary Tumors, just like normal tissues, require blood vessels to receive nutrients and oxygen and to eliminate wastes and carbon dioxide. To ensure this blood supply, tumors create their own vascular beds from established blood vessels by a process called angiogenesis. This process plays a major role in tumor growth, survival, and invasiveness. Currently, various monoclonal antibodies (mAb) and small-molecular-weight drugs are used to restrain angiogenesis and starve tumors of nutrients. Bevacizumab and ramucirumab, for example, are two mAbs that inhibit angiogenesis-bevacizumab by binding with vascular endothelial growth factors (VEGF) and ramucirumab by blocking VEGF receptors (VEGFR). When used alone or in combination with chemotherapy, anti-angiogenic drugs slow down metastasis, stop disease deterioration, and extend the overall survival time of cancer patients. However, angiogenesis not only drives the growth of blood vessels in tumors, it also performs many important physiological functions in the body. The ‘good’ (physiological) angiogenesis regulates the thrombotic process, maintains vascular tone, and speeds up wound healing. Unfortunately, current anti-angiogenic drugs indiscriminately inhibit both good and ‘bad’ (tumor-directed) angiogenesis, thus resulting in blood-coagulation disorders, hypertension, hypothyroidism, proteinuria, and bowel perforation. In principle, it should be possible to reduce or eliminate many of the side effects of current anti-angiogenic drugs by blocking signaling molecules that are expressed only in tumor endothelial cells (TECs) but not in normal endothelial cells (NECs). Recently, we discovered that a prion-like protein called doppel is expressed only in TECs but not in NECs. In preliminary study, we showed that (i) doppel is expressed in both human and animal cancers; (ii) increased doppel expression in TECs (Dplhi-TECs) is associated with increased blood vessel density in tumors; (iii) doppel erasure from TECs and from mice (i.e., doppel knockout) reduces the number of vessels in tumors; (iv) anti-doppel mAb slows tumor growth in mice; and (v) doppel-knockout mice shows higher ratio of intratumoral CD8 versus regulatory T cells. Thus, we posit that Dplhi-TECs promote neoangiogenesis and create an immunosuppressive TME, and targeting of Dplhi-TECs using novel monoclonal antibodies increase the efficacy of chemo- and immune-therapies. We will test this assumption under three major sets of experiments: (i) elucidate the molecular mechanisms by which doppel activates neoangiogenesis and tumor progression in a spontaneous model of non-small cell lung carcinoma (NSCLC); (ii) assess the pharmacokinetics, pharmacodynamic and antitumor efficacy of anti-Doppel mAbs in KrasLSL-G12D;p53Frt/FRT mice in combination with chemotherapeutics; and (iii) assess how Dplhi-TECs control lung tumor immune microenvironment. This project has both basic and translational applicability, because we will understand the biology of Dplhi-TECs in tumor microenvironment as well use construct new mAbs to block this novel molecular target that has no known roles in physiological angiogenesis.
项目总结 肿瘤,就像正常组织一样,需要血管接受营养和氧气,并清除废物和 二氧化碳。为了确保这种血液供应,肿瘤从已建立的血管中创建自己的血管床 通过一种叫做血管生成的过程。这一过程在肿瘤的生长、存活和侵袭性方面起着重要作用。 目前,各种单抗和小分子药物被用来抑制 血管生成和肿瘤营养匮乏。例如,贝伐单抗和Ramucirumab是两种抑制 血管生成-贝伐单抗通过与血管内皮生长因子和Ramucirumab结合 阻断血管内皮生长因子受体(VEGFR)单独使用或与化疗、抗血管生成药物联合使用时 延缓转移,阻止疾病恶化,延长癌症患者的总体生存时间。然而, 血管生成不仅推动肿瘤中血管的生长,还执行许多重要的生理功能 在身体中发挥作用。良好的(生理)血管生成调节血栓形成过程,维持血管 语气,并加速伤口愈合。不幸的是,目前的抗血管生成药物不分青红皂白地抑制了这两种好的 和‘坏’(肿瘤导向的)血管生成,从而导致凝血障碍、高血压、 甲状腺功能减退、蛋白尿和肠穿孔。原则上,应该有可能减少或消除许多 当前抗血管生成药物通过阻断仅在肿瘤中表达的信号分子的副作用 内皮细胞(TECs),而正常内皮细胞(NECs)不表达。最近,我们发现一种类似普里恩的蛋白质 仅在TEC中表达,而在NECs中不表达。在初步研究中,我们发现(I)多巴是 在人类和动物癌症中均有表达;(Ii)在TECs(Dplhi-TECs)中增加的多巴素表达与 肿瘤中血管密度增加;(Iii)TEC和小鼠的多巴波擦除(即多巴波敲除) 减少肿瘤中的血管数量;(Iv)抗多巴单抗减缓小鼠肿瘤的生长;以及(V)多巴胺基因敲除 小鼠肿瘤内CD8细胞的比例高于调节性T细胞。因此,我们假设Dplhi-TEC促进 新血管生成和构建免疫抑制的TME,以及利用新的单抗靶向Dplhi-TECs 抗体可提高化疗和免疫疗法的疗效。我们将在三个主要方面测试这一假设 系列实验:(I)阐明多巴胺激活新血管生成和肿瘤的分子机制 自发性非小细胞肺癌(NSCLC)模型的进展;(Ii)评估药代动力学, 抗多普勒单抗对KrasLSL-G12D;p53Frt/FRT小鼠的药效学和抗肿瘤作用 评估Dplhi-TECs如何控制肺肿瘤免疫微环境。这个项目有 基本的和翻译的适用性,因为我们将了解肿瘤中Dplhi-TECs的生物学 微环境也利用构建新的单抗来阻断这一未知作用的新的分子靶点 生理性血管生成。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Taslim A Al-Hilal其他文献

Taslim A Al-Hilal的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Taslim A Al-Hilal', 18)}}的其他基金

The role of tumor endothelium-specific prion-gene PRND in epithelial ovarian cancer
肿瘤内皮特异性朊病毒基因PRND在上皮性卵巢癌中的作用
  • 批准号:
    10529033
  • 财政年份:
    2022
  • 资助金额:
    $ 34.22万
  • 项目类别:
The role of tumor endothelium-specific prion-gene PRND in epithelial ovarian cancer
肿瘤内皮特异性朊病毒基因PRND在上皮性卵巢癌中的作用
  • 批准号:
    10687005
  • 财政年份:
    2022
  • 资助金额:
    $ 34.22万
  • 项目类别:
Targeting of Doppel-axis to Control Lung Tumor Angiogenesis and Immunity
双轴靶向控制肺肿瘤血管生成和免疫
  • 批准号:
    10522763
  • 财政年份:
    2022
  • 资助金额:
    $ 34.22万
  • 项目类别:
Priming pancreatic ductal adenocarcinoma using blood thinners to sensitize the efficacy of checkpoint immunotherapy
使用血液稀释剂引发胰腺导管腺癌以提高检查点免疫疗法的疗效
  • 批准号:
    10333749
  • 财政年份:
    2022
  • 资助金额:
    $ 34.22万
  • 项目类别:
Priming pancreatic ductal adenocarcinoma using blood thinners to sensitize the efficacy of checkpoint immunotherapy
使用血液稀释剂引发胰腺导管腺癌以提高检查点免疫疗法的疗效
  • 批准号:
    10659108
  • 财政年份:
    2022
  • 资助金额:
    $ 34.22万
  • 项目类别:

相似海外基金

Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
  • 批准号:
    MR/Z503605/1
  • 财政年份:
    2024
  • 资助金额:
    $ 34.22万
  • 项目类别:
    Research Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
  • 批准号:
    2402691
  • 财政年份:
    2024
  • 资助金额:
    $ 34.22万
  • 项目类别:
    Standard Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
  • 批准号:
    2336167
  • 财政年份:
    2024
  • 资助金额:
    $ 34.22万
  • 项目类别:
    Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
  • 批准号:
    24K12150
  • 财政年份:
    2024
  • 资助金额:
    $ 34.22万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
  • 批准号:
    2341428
  • 财政年份:
    2024
  • 资助金额:
    $ 34.22万
  • 项目类别:
    Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
  • 批准号:
    DE240100561
  • 财政年份:
    2024
  • 资助金额:
    $ 34.22万
  • 项目类别:
    Discovery Early Career Researcher Award
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
  • 批准号:
    10065645
  • 财政年份:
    2023
  • 资助金额:
    $ 34.22万
  • 项目类别:
    Collaborative R&D
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
  • 批准号:
    23K09542
  • 财政年份:
    2023
  • 资助金额:
    $ 34.22万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
  • 批准号:
    23K07552
  • 财政年份:
    2023
  • 资助金额:
    $ 34.22万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
  • 批准号:
    23K07559
  • 财政年份:
    2023
  • 资助金额:
    $ 34.22万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了