Ceramides for Breast Cancer Treatment

用于乳腺癌治疗的神经酰胺

基本信息

批准号：
9812698
负责人：
MARYAM FOROOZESH
金额：
$ 40.81万
依托单位：
XAVIER UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9812698
关键词：
Agreement American Animals Apoptosis Biological Assay Breast Cancer Patient Breast Cancer Treatment Cancer Patient Cancer cell line Cause of Death Cell Proliferation Cell Survival Cells Ceramidase Ceramide Signaling Pathway Ceramide glucosyltransferase Ceramides Clinical Development Dose Drug Kinetics Drug effect disorder Drug resistance Effectiveness Enzymes Fatty acid glycerol esters Flavones Fluorescence Fluorescence Microscopy Glucosylceramides Growth Histology Human Immunochemistry In Vitro Induction of Apoptosis Injections MCF7 cell Malignant Neoplasms Mammary gland Metastatic breast cancer Methods Multi-Drug Resistance Neoplasm Metastasis Nude Mice P-Glycoprotein P-Glycoproteins Participant Pathogenesis Pathway interactions Patients Play Procedures Process Publishing Quality of life Rattus Research Training Resistance Role Series Signal Pathway Sphingolipids Structure Students Survival Rate System Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Toxicology Training Programs Treatment Failure Woman analog anti-cancer anticancer activity base cancer cell cancer therapy chemotherapeutic agent clinical candidate fluorophore improved in vivo malignant breast neoplasm migration mortality novel novel therapeutics response senescence small molecule tool tumor undergraduate research

Agreement American Animals Apoptosis Biological Assay Breast Cancer Patient Breast Cancer Treatment Cancer Patient Cancer cell line Cause of Death Cell Proliferation Cell Survival Cells Ceramidase Ceramide Signaling Pathway Ceramide glucosyltransferase Ceramides Clinical Development Dose Drug Kinetics Drug effect disorder Drug resistance Effectiveness Enzymes Fatty acid glycerol esters Flavones Fluorescence Fluorescence Microscopy Glucosylceramides Growth Histology Human Immunochemistry In Vitro Induction of Apoptosis Injections MCF7 cell Malignant Neoplasms Mammary gland Metastatic breast cancer Methods Multi-Drug Resistance Neoplasm Metastasis Nude Mice P-Glycoprotein P-Glycoproteins Participant Pathogenesis Pathway interactions Patients Play Procedures Process Publishing Quality of life Rattus Research Training Resistance Role Series Signal Pathway Sphingolipids Structure Students Survival Rate System Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Toxicology Training Programs Treatment Failure Woman analog anti-cancer anticancer activity base cancer cell cancer therapy chemotherapeutic agent clinical candidate fluorophore improved in vivo malignant breast neoplasm migration mortality novel novel therapeutics response senescence small molecule tool tumor undergraduate research

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项目摘要

PROJECT SUMMARY/ABSTRACT Many studies have shown a correlation between the sphingolipid signaling pathway and cancer pathogenesis as well as drug-resistance. The central molecule in sphingolipid pathway, ceramide, is involved in the induction of apoptosis, senescence, and growth arrest in many human cancers including breast cancer. Recent studies have shown that certain ceramide analogs possess the capability of preferentially killing resistant cancer cells and/or inhibiting glucosylceramide synthase (GCS) activity, which is highly correlated to cancer multidrug-resistance. The main hypothesis of this project is that ceramide analogs can be developed as new therapeutic agents for the treatment of chemo-resistant and aggressive metastatic breast cancers influencing clinical cancer treatment concepts. Our Secondary hypothesis is that self-fluorescent ceramide analogs can be used to affirm known ceramide mechanisms of action, determine potential new mechanisms of action, and discover novel targets and interactions. Four specific aims are proposed for the Project: Specific Aim 1 - Development of highly potent selective agents for killing resistant cancer cells as candidates for clinical treatment of breast cancer multidrug-resistance and metastasis; Specific Aim 2 - Determination of the mechanistic factors leading to the apoptosis of resistant and metastatic cells, and investigating the relationship between preferential killing of resistant cancer cells and glucosylceramide synthase (GCS) and ceramidase inhibition by ceramide analogs; Specific Aim 3 - Using a novel experimental tool, self-fluorescent small molecules, for investigating the distribution and action of ceramides in cancer cells; and Specific Aim 4 - Determination of the in vivo effects of the most potent target ceramide analog(s). To achieve the Specific Aim 1, 40-45 self-fluorescent ceramide analogs will be synthesized with extended aromatic conjugated systems. To achieve the Specific Aim 2, general anticancer activity screenings will be performed to identify the effective and selective ceramide analogs. A series of mechanistic studies on the potent ceramide analogs will be performed to examine whether the analogs induce apoptosis, and if yes, through which pathway(s). A glucosylceramide level assay, GCS and P-gp level assays, resistance-reversal assays, and ceramidase inhibition assays will determine the effects of the target analogs on the activity and expression of GCS and P-gp and ceramidase. To achieve the Specific Aim 3, through fluorescence microscopy, distribution and actions of the target fluorescent ceramide analogs will be tracked in treated cells, validating the mechanisms of action. Finally, most potent analogs will be used in animal studies to achieve the Specific Aim 4. The long-term objective of this project is to improve the survival rate and quality of life of breast cancer patients by targeting the ceramide signaling pathway. Undergraduate research students, including participants in research training programs, will be involved in all aspects of the Project.

项目摘要/摘要许多研究表明，鞘脂信号通路与癌症之间存在相关性发病机理和耐药性。鞘脂途径中的中央分子涉及神经酰胺在包括乳腺癌在内的许多人类癌症中诱导凋亡，衰老和生长停滞。最近的研究表明，某些神经酰胺类似物具有优先杀死的能力抗性癌细胞和/或抑制葡萄糖基酶合酶（GCS）活性，该活性高度相关癌症多药。该项目的主要假设是可以开发神经酰胺类似物作为用于治疗化学耐化和侵略性转移性乳腺癌的新治疗剂影响临床癌症治疗概念。我们的次要假设是自荧光神经酰胺类似物可用于确认已知的神经酰胺作用机理，确定潜在的新机制动作并发现新颖的目标和互动。该项目提出了四个具体目标：具体目标1-开发高度有效的选择性剂来杀死抗性癌细胞作为候选者用于乳腺癌多药耐药和转移的临床治疗；具体目标2-确定导致抗性和转移性凋亡的机械因素细胞，并研究抗性癌细胞优先杀死的关系和通过神经酰胺类似物抑制葡萄糖基酶合酶（GCS）和神经酰胺酶抑制；特定的目标3-使用新型的实验工具，自荧光的小分子，用于研究神经酰胺在癌细胞中的分布和作用；和具体目标4-确定最有效的靶向神经酰胺类似物的体内效应。为了达到特定目标1，将与40-45个自荧光神经酰胺类似物合成扩展的芳族共轭系统。为了达到特定目标2，一般抗癌活性筛选将执行以识别有效和选择性的神经酰胺类似物。一系列关于将进行有效的神经酰胺类似物，以检查类似物是否诱导凋亡，如果是，则通过哪个路径。葡萄糖基酰胺水平测定法，GCS和P-GP水平测定，抗性 - 反转测定和神经酶抑制测定将确定靶类似物对活动的影响和 GCS和P-GP和神经酶的表达。通过荧光实现特定目标3 目标荧光神经酰胺类似物的显微镜，分布和作用将在处理的细胞中跟踪，验证作用机理。最后，大多数有效的类似物将用于动物研究中以实现具体目标4。该项目的长期目标是提高乳房的生存率和生活质量癌症患者通过靶向神经酰胺信号通路。本科生的学生，包括研究培训计划的参与者将参与该项目的各个方面。