Targeting the detoxification function of the enzyme KDSR for cancer therapy

针对癌症治疗中 KDSR 酶的解毒功能

基本信息

  • 批准号:
    10595401
  • 负责人:
  • 金额:
    $ 38.88万
  • 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:
    2023-01-16 至 2027-12-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY It is increasingly recognized that certain metabolic enzymes are required in cells not for what they produce, but instead for processing and thus preventing the accumulation of their substrates which may have toxic properties. Such enzymes can be attractive therapeutic targets, as their inhibition can poison cancer cells with self-produced toxic metabolites in a manner that is highly dependent on production of the toxic metabolite. Here we investigate a new detoxifying enzyme, ketodehydrosphinganine reductase (KDSR), which is part of the de novo sphingolipid biosynthesis pathway. We find that KDSR is not required to provide sphingolipids, as cancer cells can readily salvage them from their environment, but instead is needed to prevent accumulation of its substrate 3-ketodehydrosphinganine (3KDS). Accumulation of 3KDS, either via KDSR KO or by direct treatment of 3KDS to cells, appears to disrupt the endoplasmic reticulum (ER) and cause an overload of misfolded proteins in cancer cells. This indicates KDSR as a potential cancer therapy target capable of impairing ER function and proteostasis in cancer cells, which we will explore in this proposal. In Aim 1, we will examine the upstream steps that drive 3KDS production, which we hypothesize are elevated in multiple cancer subtypes, and thus directly renders the cells dependent on KDSR for 3KDS detoxification. These will be further considered as possible biomarkers for tumors that would respond to KDSR targeting. In Aim 2, we will examine how 3KDS accumulation disrupts the ER and leads to death, and the responses mounted by cancer cells to counter 3KDS toxicity. In Aim 3, we will gauge the therapeutic potential of targeting KDSR by comparing 3KDS production capacity between tumor tissues and normal tissues from animal models and from deidentified patient tissues. In this manner we hope to provide a working blueprint for how to selectively target subtypes and subpopulation of cancer cells based on their 3KDS producing activities, provide biomarkers which predict whether a tumor will respond to such a therapy, and provide new insights into the endoplasmic reticulum- and proteostasis- related vulnerabilities of cancer cells.
项目总结

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 }}

Dohoon Kim其他文献

Dohoon Kim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('Dohoon Kim', 18)}}的其他基金

Selenoprotein-independent biological roles for selenium in selenium deficiency and excess
硒在硒缺乏和过量时的独立于硒蛋白的生物学作用
  • 批准号:
    10737250
  • 财政年份:
    2023
  • 资助金额:
    $ 38.88万
  • 项目类别:

相似海外基金

Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
  • 批准号:
    10590611
  • 财政年份:
    2022
  • 资助金额:
    $ 38.88万
  • 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中的骨-脂肪相互作用
  • 批准号:
    10706006
  • 财政年份:
    2022
  • 资助金额:
    $ 38.88万
  • 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
  • 批准号:
    10368975
  • 财政年份:
    2021
  • 资助金额:
    $ 38.88万
  • 项目类别:
BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Combined long-acting PTH and calcimimetics actions on skeletal anabolism
BCCMA:针对和抵抗不利于骨骼的条件的基础研究(遏制骨折):长效 PTH 和拟钙剂联合作用对骨骼合成代谢的作用
  • 批准号:
    10365254
  • 财政年份:
    2021
  • 资助金额:
    $ 38.88万
  • 项目类别:
Bone-Adipose Interactions During Skeletal Anabolism
骨骼合成代谢过程中骨-脂肪相互作用
  • 批准号:
    10202896
  • 财政年份:
    2021
  • 资助金额:
    $ 38.88万
  • 项目类别:
BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Combined long-acting PTH and calcimimetics actions on skeletal anabolism
BCCMA:针对和抵抗不利于骨骼的条件的基础研究(遏制骨折):长效 PTH 和拟钙剂联合作用对骨骼合成代谢的作用
  • 批准号:
    10531570
  • 财政年份:
    2021
  • 资助金额:
    $ 38.88万
  • 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
  • 批准号:
    10541847
  • 财政年份:
    2019
  • 资助金额:
    $ 38.88万
  • 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
  • 批准号:
    10319573
  • 财政年份:
    2019
  • 资助金额:
    $ 38.88万
  • 项目类别:
Dissecting molecular mechanisms implicated in age- and osteoarthritis-related decline in anabolism in articular cartilage
剖析与年龄和骨关节炎相关的关节软骨合成代谢下降有关的分子机制
  • 批准号:
    10062790
  • 财政年份:
    2019
  • 资助金额:
    $ 38.88万
  • 项目类别:
Promotion of NAD+ anabolism to promote lifespan
促进NAD合成代谢以延长寿命
  • 批准号:
    DE170100628
  • 财政年份:
    2017
  • 资助金额:
    $ 38.88万
  • 项目类别:
    Discovery Early Career Researcher Award
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了