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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：
Dohoon Kim
金额：
$ 38.88万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
https://reporter.nih.gov/project-details/10595401
关键词：
Affect Anabolism Animal Model Awareness Biological Markers Breast Cancer Cell Cells Cessation of life Colorectal Cancer Complex Cytoprotection Dependence Distal Drug Metabolic Detoxication Endoplasmic Reticulum Environment Enzymes Foundations Functional disorder Future Genetic Engineering Impairment Malignant Neoplasms Membrane Metabolic Modeling Normal Cell Normal tissue morphology Oxidoreductase Palmitates Palmitoyl Coenzyme A Pathway interactions Patients Play Poison Poisoning Predisposition Production Property Role Serine Shock Sphingolipids Therapeutic Tissues Toxic effect Tumor Markers Tumor Tissue Ubiquitin Work cancer cell cancer cell subtype cancer subtypes cancer therapy cancer type endoplasmic reticulum stress inhibitor insight ketodihydrosphingosine malignant breast neoplasm misfolded protein multicatalytic endopeptidase complex novel patient derived xenograft model prevent proteostasis response serine palmitoyltransferase targeted cancer therapy therapeutic target triple-negative invasive breast carcinoma tumor uptake

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。