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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.

项目总结