A NOVEL EPIGENETIC IMMUNOTHERAPY FOR OVARIAN CANCER TREATMENT

一种治疗卵巢癌的新型表观遗传免疫疗法

基本信息

  • 批准号:
    9917757
  • 负责人:
  • 金额:
    $ 7.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-06-01 至 2021-05-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Ovarian cancer is the leading cause of deaths due to gynecological malignancies in women and will accounts for over 14,000 deaths in the United States this year alone. However, current therapies do not provide meaningful long-term clinical benefits to ovarian cancer patients. Therefore, new and more effective therapies for ovarian cancer treatment are urgently needed. We found that ovarian cancer cells epigenetically downregulate the Natural Killer Group 2 D (NKG2D) ligands that are necessary for Natural Killer (NK) cells of innate immune system to eradicate cancer cells. Based on these findings, we rationalized that an approach that will allow re-expression of NKG2D ligands will enhance NK cell-mediated eradication of ovarian cancer cells and will be of therapeutic value. To identify such epigenetic drug targets that when inhibited will increase the expression of NKG2D ligand in ovarian cancer cells, we performed a large-scale epigenome-wide shRNA screen and identified Disruptor of Telomeric Silencing 1-Like (DOT1L) as a regulator of NKG2D ligand ULBP1. We found that DOT1L inhibition by short-hairpin RNA (shRNA) or by a small-molecule inhibitor, EPZ-5676, significantly increased eradication of ovarian cancer cells by NK cells. Based on these results, we hypothesize that DOT1L by regulating the expression of NKG2D ligands regulates NK cell-mediated eradication of ovarian cancer cells. The overall objective is to rigorously determine the role of DOT1L as a driver of ovarian cancer tumor growth and progression that function in a NK cell-dependent manner and test the clinical value of pharmacologically inhibiting DOT1L for treating ovarian cancer. Aim 1 experiments will focus on determining the in vivo role of DOT1L as a driver of ovarian cancer growth and ascertain if this function of DOT1L is dependent on NK cells. To this end, based on our results in immunocompetent syngeneic mouse models, we will use a novel humanized mouse model with functional human immune system containing NK cells to test the DOT1L inhibition in a more human disease relevant pre-clinical mouse model setting. We will also determine the mechanism of DOT1L action. To this end, based on our preliminary results, we will test the role of NKG2D ligands and other potential mechanisms, such as regulation of ICAM1 by DOT1L, in regulating the ability of DOT1L on NK cell-mediated eradication of ovarian cancer. Aim 2 experiments will determine if pharmacological inhibition of DOT1L in vivo blocks ovarian cancer growth in a NK cell-dependent manner. To this end, we will determine if DOT1L inhibitor, EPZ-5676, inhibits ovarian tumor growth in a NK cell-dependent manner in humanized and in the pre-clinical patient-derived xenograft (PDX) models of ovarian cancer. Collectively, the results of our studies will identify a novel function of DOT1L in regulating NK cell activity against ovarian cancer cells in vivo and validate DOT1L small-molecule inhibitors to enhance NK cell function as a new therapeutic approach for treating ovarian cancer.!
项目摘要 卵巢癌是由于妇女妇女的妇科恶毒而导致死亡的主要原因,并将说明 仅今年在美国,超过14,000人死亡。但是,当前的疗法不提供 对卵巢癌患者的有意义的长期临床益处。因此,新的,更有效的疗法 迫切需要卵巢癌的治疗。我们发现卵巢癌细胞表观遗传 下调天然杀手2 D(NKG2D)配体是天然杀手(NK)细胞所必需的 先天免疫系统消除癌细胞。基于这些发现,我们合理化了一种方法 这将允许重新表达NKG2D配体将增强NK细胞介导的根除卵巢癌 细胞,将具有治疗价值。确定这样的表观遗传药物靶标,如果被抑制会增加 NKG2D配体在卵巢癌细胞中的表达,我们进行了大型表观基因组shRNA 屏幕并确定端粒沉默1类(DOT1L)的破坏者为NKG2D配体ULBP1的调节剂。 我们发现短发蛋白RNA(SHRNA)或小分子抑制剂EPZ-5676,dot1l抑制 NK细胞显着增加了卵巢癌细胞的根除。基于这些结果,我们假设 通过调节NKG2D配体的表达来调节NK细胞介导的根除卵巢的表达 癌细胞。总体目标是严格确定Dot1l作为卵巢癌驱动的作用 以NK细胞依赖性方式发挥作用的肿瘤生长和进展,并测试 药理学抑制DOT1L治疗卵巢癌。 AIM 1实验将专注于确定 DOT1L作为卵巢癌生长的驱动器的体内作用,并确定DOT1L的这种功能是否为 取决于NK细胞。为此,根据我们在免疫能力合成小鼠模型中的结果,我们 将使用具有NK细胞功能性人体免疫系统的新型人性化小鼠模型来测试 DOT1L抑制更为人类疾病相关的临床前小鼠模型设置。我们还将确定 DOT1L作用的机制。为此,根据我们的初步结果,我们将测试NKG2D的作用 配体和其他潜在机制,例如DOT1L对ICAM1的调节,在调节能力方面 NK细胞介导的根除卵巢癌的dot1l。 AIM 2实验将确定是否 DOT1L在体内的药理抑制作用以NK细胞依赖性方式阻断卵巢癌的生长。到 在此目的,我们将确定DOT1L抑制剂EPZ-5676是否抑制NK细胞依赖性的卵巢肿瘤生长 卵巢癌的人性化和临床前患者异种移植(PDX)模型中的方式。 总的来说,我们的研究结果将确定DOT1L在调节NK细胞活性中的新功能 在体内对卵巢癌细胞的抗性和验证点1L小分子抑制剂以增强NK细胞功能 作为治疗卵巢癌的一种新的治疗方法。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Changes in the Transcriptome and Chromatin Landscape in BRAFi-Resistant Melanoma Cells.
  • DOI:
    10.3389/fonc.2022.937831
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
    Reddi, Kiran Kumar;Guruvaiah, Praveen;Edwards, Yvonne J. K.;Gupta, Romi
  • 通讯作者:
    Gupta, Romi
The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis.
  • DOI:
    10.3390/cancers13215516
  • 发表时间:
    2021-11-03
  • 期刊:
  • 影响因子:
    5.2
  • 作者:
    Mason LD;Chava S;Reddi KK;Gupta R
  • 通讯作者:
    Gupta R
Disruptor of telomeric silencing 1-like promotes ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic pathways and blocking apoptosis.
  • DOI:
    10.1038/s41389-021-00339-6
  • 发表时间:
    2021-07-12
  • 期刊:
  • 影响因子:
    6.2
  • 作者:
    Chava S;Bugide S;Edwards YJK;Gupta R
  • 通讯作者:
    Gupta R
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Romi Gupta其他文献

Romi Gupta的其他文献

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{{ truncateString('Romi Gupta', 18)}}的其他基金

PRECISION METABOLIC THERAPY OF p53 MUTANT TRIPLE NEGATIVE BREAST CANCERS
p53 突变三阴性乳腺癌的精准代谢治疗
  • 批准号:
    10454390
  • 财政年份:
    2021
  • 资助金额:
    $ 7.43万
  • 项目类别:
PRECISION METABOLIC THERAPY OF p53 MUTANT TRIPLE NEGATIVE BREAST CANCERS
p53 突变三阴性乳腺癌的精准代谢治疗
  • 批准号:
    10294457
  • 财政年份:
    2021
  • 资助金额:
    $ 7.43万
  • 项目类别:
PRECISION METABOLIC THERAPY OF p53 MUTANT TRIPLE NEGATIVE BREAST CANCERS
p53 突变三阴性乳腺癌的精准代谢治疗
  • 批准号:
    10621315
  • 财政年份:
    2021
  • 资助金额:
    $ 7.43万
  • 项目类别:
A Novel Anoikis Effector that Drives Ovarian Cancer Metastasis
一种驱动卵巢癌转移的新型失巢效应器
  • 批准号:
    10117214
  • 财政年份:
    2020
  • 资助金额:
    $ 7.43万
  • 项目类别:
PERSONALIZED THERAPY FOR p16-DEFICIENT MELANOMA
p16 缺乏的黑色素瘤的个性化治疗
  • 批准号:
    9933633
  • 财政年份:
    2018
  • 资助金额:
    $ 7.43万
  • 项目类别:

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