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
- 来源:
- 关键词:AffectAnabolismAnimal ModelAwarenessBiological MarkersBreast Cancer CellCellsCessation of lifeColorectal CancerComplexCytoprotectionDependenceDistalDrug Metabolic DetoxicationEndoplasmic ReticulumEnvironmentEnzymesFoundationsFunctional disorderFutureGenetic EngineeringImpairmentMalignant NeoplasmsMembraneMetabolicModelingNormal CellNormal tissue morphologyOxidoreductasePalmitatesPalmitoyl Coenzyme APathway interactionsPatientsPlayPoisonPoisoningPredispositionProductionPropertyRoleSerineShockSphingolipidsTherapeuticTissuesToxic effectTumor MarkersTumor TissueUbiquitinWorkcancer cellcancer cell subtypecancer subtypescancer therapycancer typeendoplasmic reticulum stressinhibitorinsightketodihydrosphingosinemalignant breast neoplasmmisfolded proteinmulticatalytic endopeptidase complexnovelpatient derived xenograft modelpreventproteostasisresponseserine palmitoyltransferasetargeted cancer therapytherapeutic targettriple-negative invasive breast carcinomatumoruptake
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.
项目摘要
越来越多的人认识到,某些代谢酶在细胞中是必需的,而不是因为它们产生什么,
而是用于处理并因此防止其可能具有毒性的底物的积累
特性.这些酶可能是有吸引力的治疗靶点,因为它们的抑制可以毒害癌细胞
与自身产生的有毒代谢物,在某种程度上是高度依赖于生产的有毒
代谢物。在这里,我们研究了一种新的解毒酶,酮脱氢神经鞘氨醇还原酶(KDSR),
其是从头鞘脂生物合成途径的一部分。我们发现KDSR不需要
提供鞘脂,因为癌细胞可以很容易地将它们从环境中拯救出来,
需要防止其底物3-酮脱氢鞘氨醇(3 KDS)的积累。积累
3 KDS,无论是通过KDSR KO还是通过3 KDS对细胞的直接处理,似乎都破坏了细胞的内质网。
内质网(ER),并导致癌细胞中错误折叠的蛋白质过载。这表明KDSR是一个
能够损害癌细胞中ER功能和蛋白质稳态的潜在癌症治疗靶点,
我们会在这个建议中探讨。在目标1中,我们将研究驱动3 KDS生产的上游步骤,
我们假设它在多种癌症亚型中升高,因此直接使细胞
依赖KDSR进行3 KDS解毒。这些将进一步被认为是可能的生物标志物,
对KDSR靶向有反应的肿瘤。在目标2中,我们将研究3 KDS积累如何破坏
ER并导致死亡,以及癌细胞对抗3 KDS毒性的反应。在Aim中
3、我们将通过比较3 KDS的生产能力来评估靶向KDSR的治疗潜力
肿瘤组织和来自动物模型和来自去识别的患者组织的正常组织之间的差异。在
我们希望通过这种方式为如何选择性地靶向亚型提供工作蓝图,
基于其3 KDS产生活性的癌细胞亚群,提供了预测
肿瘤是否会对这种疗法产生反应,并为内质网提供新的见解-
和癌细胞蛋白质稳定相关的脆弱性。
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