Ligand-Directed KRAS G12V Mutant-Specific Therapeutics

配体导向的 KRAS G12V 突变特异性治疗

基本信息

  • 批准号:
    10757070
  • 负责人:
  • 金额:
    $ 27.56万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-05 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

Project Summary The proto-oncogene KRAS is one of the most critical genes in cancer, yet, as a drug target, it has proven to be among the most elusive. A remarkable 30% of lung adenocarcinomas, 45% of colon, and 98% of pancreatic cancers are driven by KRAS mutations. These cancers account for the top 3 causes of cancer-related deaths in the United States. Most cancer associated KRAS mutations result in a constitutively active protein, which drives aberrantly high downstream signaling of pro-proliferative and pro-survival effectors including the MAPK and PI3K pathways. Kinase inhibitors have revolutionized treatment of many cancers driven by other molecular aberrations, yet, unfortunately a lack of such success in KRAS-driven cancers has led to KRAS itself to be widely regarded as “undruggable”. EnFuego Therapeutics, Inc. (EFTX) was founded to address the growing number of “undruggable” targets in cancer using RNA interference (RNAi)-based therapeutics. RNAi is particularly attractive for KRAS targeting because it can be optimized to enable selective silencing of mutant transcripts while sparing wild type transcripts, which is important for maintaining normal function in nonmalignant tissue. Mutation-specific therapeutics against KRAS are under development by several companies such as Amgen and Mirati, and rely on small molecules (specific only to G12C mutations). Unlike prior RNAi strategies in cancer, the EFTX approach employs nucleotide modification and ligand conjugation chemistries to promote in vivo stability and affinity-based targeting in cancer cells. In particular, ligand conjugation represents a significant advantage over legacy delivery technologies such as lipid nanoparticles. We have shown that EnFuego siRNAs targeting mutant KRAS transcripts result in: 1) reduced oncogenic MAPK signaling, 2) reduced cancer cell proliferation, and 3) reduced tumor burden in murine cancer models. Based on these preliminary data, this Fast Track program will further develop EFTX siRNA technologies for targeting mutant KRAS in humans. During Phase I, we will focus on optimization of fully chemically modified (FM) siRNA compounds that potently and specifically silence mutant G12V transcripts, exhibit serum stability and immune stealth, and inhibit downstream cancer cell signaling. Two to three FM siRNAs will be selected as lead compound candidates for progression to Phase II studies. Phase II Specific Aims will focus on optimization of pharmacokinetics, tissue targeting, and efficacy in murine models of metastatic lung cancer. These data will inform the selection of a single candidate for scale up and a 4-week GLP safety assessment study. As such, this Fast Track program will accelerate progression of this novel therapeutic strategy toward filing an Investigational New Drug application for metastatic lung cancer therapy.
项目概要 原癌基因 KRAS 是癌症中最关键的基因之一,但作为药物靶点,它已被证明 成为最难以捉摸的人之一。高达 30% 的肺腺癌、45% 的结肠癌和 98% 的胰腺癌 癌症是由 KRAS 突变驱动的。这些癌症占癌症相关的前 3 位原因 美国的死亡人数。大多数癌症相关的 KRAS 突变都会产生一种组成型活性蛋白, 它驱动促增殖和促生存效应器的异常高的下游信号传导,包括 MAPK 和 PI3K 通路。激酶抑制剂彻底改变了许多由其他因素引起的癌症的治疗 分子畸变,然而,不幸的是,在 KRAS 驱动的癌症中缺乏这样的成功,导致 KRAS 其本身被广泛认为是“不可成药的”。 EnFuego Therapeutics, Inc. (EFTX) 的成立是为了解决 使用基于 RNA 干扰 (RNAi) 的疗法发现越来越多的癌症“不可成药”靶点。 RNAi 对于 KRAS 靶向特别有吸引力,因为它可以经过优化以实现突变体的选择性沉默 转录本,同时保留野生型转录本,这对于维持非恶性细胞的正常功能非常重要 组织。多家公司正在开发针对 KRAS 的突变特异性疗法,例如 Amgen 和 Mirati,并依赖小分子(仅针对 G12C 突变)。与之前的 RNAi 策略不同 在癌症中,EFTX 方法采用核苷酸修饰和配体缀合化学来促进 癌细胞中的体内稳定性和基于亲和力的靶向。特别地,配体缀合代表 与脂质纳米粒子等传统递送技术相比具有显着优势。我们已经证明 EnFuego siRNA 靶向突变 KRAS 转录物导致:1) 致癌 MAPK 信号传导减少,2) 减少 癌细胞增殖,3) 减少小鼠癌症模型中的肿瘤负荷。基于这些初步 数据显示,该快速通道计划将进一步开发 EFTX siRNA 技术,用于靶向突变 KRAS 人类。在第一阶段,我们将重点关注完全化学修饰 (FM) siRNA 化合物的优化,这些化合物 有效且特异性地沉默突变 G12V 转录本,表现出血清稳定性和免疫隐形性,并抑制 下游癌细胞信号传导。将选择两到三个 FM siRNA 作为先导化合物候选物 进展至 II 期研究。第二阶段的具体目标将侧重于药代动力学、组织的优化 转移性肺癌小鼠模型的靶向性和疗效。这些数据将告知单个的选择 扩大规模和为期 4 周的 GLP 安全评估研究的候选者。因此,该快速通道计划将 加速这一新治疗策略的进展,以提交研究性新药申请 用于转移性肺癌治疗。

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 }}

Chad V Pecot其他文献

Chad V Pecot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('Chad V Pecot', 18)}}的其他基金

Circle RNA Regulation of Lung Cancer Metastasis
Circle RNA对肺癌转移的调控
  • 批准号:
    10637900
  • 财政年份:
    2023
  • 资助金额:
    $ 27.56万
  • 项目类别:
Development of EFTX-001 to target KRAS mutations in cancer
开发 EFTX-001 以靶向癌症中的 KRAS 突变
  • 批准号:
    9906510
  • 财政年份:
    2020
  • 资助金额:
    $ 27.56万
  • 项目类别:
Immune Regulation of Lung Squamous Metastasis
肺鳞状细胞癌的免疫调节
  • 批准号:
    9770826
  • 财政年份:
    2017
  • 资助金额:
    $ 27.56万
  • 项目类别:
Immune Regulation of Lung Squamous Metastasis
肺鳞状细胞癌的免疫调节
  • 批准号:
    10237317
  • 财政年份:
    2017
  • 资助金额:
    $ 27.56万
  • 项目类别:
Immune Regulation of Lung Squamous Metastasis
肺鳞状细胞癌的免疫调节
  • 批准号:
    9445530
  • 财政年份:
    2017
  • 资助金额:
    $ 27.56万
  • 项目类别:

相似海外基金

SHINE: Origin and Evolution of Compressible Fluctuations in the Solar Wind and Their Role in Solar Wind Heating and Acceleration
SHINE:太阳风可压缩脉动的起源和演化及其在太阳风加热和加速中的作用
  • 批准号:
    2400967
  • 财政年份:
    2024
  • 资助金额:
    $ 27.56万
  • 项目类别:
    Standard Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
  • 批准号:
    2328975
  • 财政年份:
    2024
  • 资助金额:
    $ 27.56万
  • 项目类别:
    Continuing Grant
EXCESS: The role of excess topography and peak ground acceleration on earthquake-preconditioning of landslides
过量:过量地形和峰值地面加速度对滑坡地震预处理的作用
  • 批准号:
    NE/Y000080/1
  • 财政年份:
    2024
  • 资助金额:
    $ 27.56万
  • 项目类别:
    Research Grant
Market Entry Acceleration of the Murb Wind Turbine into Remote Telecoms Power
默布风力涡轮机加速进入远程电信电力市场
  • 批准号:
    10112700
  • 财政年份:
    2024
  • 资助金额:
    $ 27.56万
  • 项目类别:
    Collaborative R&D
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
  • 批准号:
    2328973
  • 财政年份:
    2024
  • 资助金额:
    $ 27.56万
  • 项目类别:
    Continuing Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
  • 批准号:
    2328972
  • 财政年份:
    2024
  • 资助金额:
    $ 27.56万
  • 项目类别:
    Continuing Grant
Collaborative Research: A new understanding of droplet breakup: hydrodynamic instability under complex acceleration
合作研究:对液滴破碎的新认识:复杂加速下的流体动力学不稳定性
  • 批准号:
    2332916
  • 财政年份:
    2024
  • 资助金额:
    $ 27.56万
  • 项目类别:
    Standard Grant
Collaborative Research: A new understanding of droplet breakup: hydrodynamic instability under complex acceleration
合作研究:对液滴破碎的新认识:复杂加速下的流体动力学不稳定性
  • 批准号:
    2332917
  • 财政年份:
    2024
  • 资助金额:
    $ 27.56万
  • 项目类别:
    Standard Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
  • 批准号:
    2328974
  • 财政年份:
    2024
  • 资助金额:
    $ 27.56万
  • 项目类别:
    Continuing Grant
Radiation GRMHD with Non-Thermal Particle Acceleration: Next-Generation Models of Black Hole Accretion Flows and Jets
具有非热粒子加速的辐射 GRMHD:黑洞吸积流和喷流的下一代模型
  • 批准号:
    2307983
  • 财政年份:
    2023
  • 资助金额:
    $ 27.56万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了