Targeting p38 gamma signaling to advance Cutaneous T Cell Lymphoma Therapy

靶向 p38 γ 信号传导以推进皮肤 T 细胞淋巴瘤治疗

基本信息

项目摘要

Cutaneous T cell lymphoma (CTCL) is a disfiguring, incurable cancer. For patients with advanced disease, current therapies are inadequate, and outcome is poor. An incomplete understanding of CTCL molecular regulators has limited development of effective targeted therapies. One candidate regulator is p38γ, the gene expression of which is selectively increased in CTCL cell lines and patient samples, but not healthy T cells. We demonstrate that inhibition or silencing of p38γ inhibits proliferation and induces CTCL cell death. The NF-κB pathway is constitutively active in CTCL, provides a complementary T cell signaling pathway to p38γ, and can be inhibited by histone deacetylase inhibitors (HDACi). HDACi, which are currently the most effective clinically approved cytotoxic compounds against CTCL, demonstrate synergistic killing when combined with p38γ Inhibition. Our objective is to understand and exploit the p38γ pathway in CTCL, using a combination of molecular, chemical, and genetic approaches. Our first Aim is to determine the mechanisms by which p38γ inhibition induces cell death in CTCL. We will define the kinase cascade involved in p38γ inhibition-induced CTCL cell killing and identify phosphorylation targets of p38γ signaling; use a synthetic lethal RNAi screen to identify signaling components that cause cell death upon depletion in the presence of p38γ inhibition; and determine the extent to which combined inhibition of p38γ and complementary pathways, including HDACs, induce synergistic therapeutic effects. We will validate identified proteins for the ability to affect downstream signaling and cellular responses in vitro and in vivo, using CTCL cell line xenograft and patient-derived xenograft (PDX) models. Our second Aim is to develop novel p38γ inhibitors for potential therapeutic application. Using high throughput screening and molecular modeling, we identified the multi-kinase inhibitor F7 (also known as PIK75), and showed it is an ATP-competitive p38γ inhibitor with nanomolar cytotoxic efficacy against CTCL cells. To develop a more selective p38γ inhibitor, we will combine ligand- and structure-based computational methods with organic synthesis; using F7 as a scaffold molecule, we will identify F7 analogs and derivatize F7 to have higher a binding affinity for p38γ than other kinases. In addition, we will use CRISPR-based screening to identify novel functional domains and non-conserved sites for developing allosteric next-generation therapeutics. We will synthesize the various analogs and validate hits for CTCL cytotoxicity and p38γ-specific kinase inhibition in vitro and in vivo, using CTCL xenograft and PDX models. We expect that successful completion of this proposal will yield mechanistic information about the unique biological and clinical relevance of p38γ signaling and complementary pathways in CTCL. Importantly, validation of a specific p38γ inhibitor with efficacy in CTCL animal models will have immediate relevance for CTCL therapy.
皮肤T细胞淋巴瘤(CTCL)是一种毁容,无法治愈的癌症。对于疾病晚期的患者,

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 }}

STEVEN Terry ROSEN其他文献

STEVEN Terry ROSEN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('STEVEN Terry ROSEN', 18)}}的其他基金

Novel targeted therapies for HPV-associated Non-AIDS-defining cancers (Biospecimens/Biocohort)
针对 HPV 相关非艾滋病定义癌症的新型靶向疗法(生物样本/生物队列)
  • 批准号:
    10620083
  • 财政年份:
    2022
  • 资助金额:
    $ 67.8万
  • 项目类别:
Genomic and Microenvironment Analysis of HIV-Associated Diffuse Large B-cell Lymphoma (Immuno/Microenvironment)
HIV 相关弥漫性大 B 细胞淋巴瘤的基因组和微环境分析(免疫/微环境)
  • 批准号:
    10620074
  • 财政年份:
    2022
  • 资助金额:
    $ 67.8万
  • 项目类别:
Caribbean Investigation of Cancer Stigma and its effect on Cervical Cancer Screening and HPV Vaccination
加勒比癌症耻辱调查及其对宫颈癌筛查和 HPV 疫苗接种的影响
  • 批准号:
    10406126
  • 财政年份:
    2021
  • 资助金额:
    $ 67.8万
  • 项目类别:
Creating an Efficient Clinical Trial Build System Via the Clinical Trials Rapid Activation Consortium (CTRAC)
通过临床试验快速激活联盟 (CTRAC) 创建高效的临床试验构建系统
  • 批准号:
    10227589
  • 财政年份:
    2020
  • 资助金额:
    $ 67.8万
  • 项目类别:
Targeting p38 gamma signaling to advance Cutaneous T Cell Lymphoma Therapy
靶向 p38 γ 信号传导以推进皮肤 T 细胞淋巴瘤治疗
  • 批准号:
    10525229
  • 财政年份:
    2018
  • 资助金额:
    $ 67.8万
  • 项目类别:
Targeting p38 gamma signaling to advance Cutaneous T Cell Lymphoma Therapy
靶向 p38 γ 信号传导以推进皮肤 T 细胞淋巴瘤治疗
  • 批准号:
    10057371
  • 财政年份:
    2018
  • 资助金额:
    $ 67.8万
  • 项目类别:
Novel RNA-Directed Therapy for the Treatment of Acute Myeloid Leukemia
治疗急性髓系白血病的新型 RNA 导向疗法
  • 批准号:
    9243226
  • 财政年份:
    2016
  • 资助金额:
    $ 67.8万
  • 项目类别:
Novel RNA-Directed Therapy for the Treatment of Acute Myeloid Leukemia
治疗急性髓系白血病的新型 RNA 导向疗法
  • 批准号:
    9107212
  • 财政年份:
    2016
  • 资助金额:
    $ 67.8万
  • 项目类别:
Novel RNA-Directed Therapy for the Treatment of Acute Myeloid Leukemia
治疗急性髓系白血病的新型 RNA 导向疗法
  • 批准号:
    9900748
  • 财政年份:
    2016
  • 资助金额:
    $ 67.8万
  • 项目类别:
Novel RNA-Directed Therapy for the Treatment of Acute Myeloid Leukemia
治疗急性髓系白血病的新型 RNA 导向疗法
  • 批准号:
    9458707
  • 财政年份:
    2016
  • 资助金额:
    $ 67.8万
  • 项目类别:

相似海外基金

Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
  • 批准号:
    23H01982
  • 财政年份:
    2023
  • 资助金额:
    $ 67.8万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
  • 批准号:
    23KJ0116
  • 财政年份:
    2023
  • 资助金额:
    $ 67.8万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
  • 批准号:
    10682794
  • 财政年份:
    2023
  • 资助金额:
    $ 67.8万
  • 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
  • 批准号:
    10598276
  • 财政年份:
    2023
  • 资助金额:
    $ 67.8万
  • 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
  • 批准号:
    2233343
  • 财政年份:
    2023
  • 资助金额:
    $ 67.8万
  • 项目类别:
    Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
  • 批准号:
    2233342
  • 财政年份:
    2023
  • 资助金额:
    $ 67.8万
  • 项目类别:
    Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
  • 批准号:
    479363
  • 财政年份:
    2023
  • 资助金额:
    $ 67.8万
  • 项目类别:
    Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
  • 批准号:
    10681989
  • 财政年份:
    2023
  • 资助金额:
    $ 67.8万
  • 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
  • 批准号:
    2237240
  • 财政年份:
    2023
  • 资助金额:
    $ 67.8万
  • 项目类别:
    Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
  • 批准号:
    2305592
  • 财政年份:
    2023
  • 资助金额:
    $ 67.8万
  • 项目类别:
    Continuing Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了