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Targeting ATP-citrate lyase (ACLY) to overcome therapy resistance in breast cancer and melanoma

靶向 ATP-柠檬酸裂解酶 (ACLY) 以克服乳腺癌和黑色素瘤的治疗耐药性

基本信息

批准号：
10580197
负责人：
Nancy A Krucher
金额：
$ 40.02万
依托单位：
PACE UNIVERSITY NEW YORK
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-09 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580197
关键词：
ATP Citrate (pro-S)-Lyase Acetyl Coenzyme A Acids Aftercare Antineoplastic Agents Apoptosis Award BRAF gene Biological Assay Biological Models Breast Melanoma CDK4 gene Cancer Patient Cell Count Cell Culture Techniques Cell Proliferation Cell Survival Cell membrane Cell model Citrates Clinic Clinical Data Development Disease Drug Combinations ERBB2 gene Educational process of instructing Environment Enzymes Exhibits Experimental Designs FDA approved Friends Funding Future Goals Growth Immunofluorescence Immunologic Impairment Induction of Apoptosis Institution Invaded Link Lipids MAP Kinase Gene MEK inhibition MEKs Malignant Neoplasms Mediating Melanoma Cell Metabolic Metabolic Diseases Metabolism Microscopy Modeling Molecular Mutation Neoplasm Metastasis Oncogenic Pathway interactions Patient Care Patient-Focused Outcomes Pharmaceutical Preparations Phenotype Phosphatidylinositols Phosphorylation Phosphotransferases Play Production Proliferating Proto-Oncogene Proteins c-akt Research Research Personnel Resistance Retinoblastoma Protein Role Scientist Signal Pathway Students Talents Techniques Therapeutic Tumor Promotion Tumor Suppressor Genes United States National Institutes of Health Universities Western Blotting Zebrafish advanced breast cancer cancer cell cancer subtypes cancer therapy cell type clinically relevant design drug development efficacy evaluation epithelial to mesenchymal transition experimental study hormone receptor-positive hormone therapy improved in vivo in vivo Model inhibitor kinase inhibitor knock-down malignant breast neoplasm melanoma neoplastic cell novel strategies overexpression patient population patient response programs response small molecule small molecule inhibitor student participation targeted agent targeted treatment therapy resistant three dimensional cell culture treatment response tumor tumor metabolism tumor progression tumorigenesis undergraduate student

项目摘要

SUMMARY The use of small molecule kinase inhibitors that target specific enzymes overactive in cancer cells has revolutionized cancer patient treatment. To treat some types of breast cancer, CDK4/6 inhibitors have been developed that target the phosphorylation of the Rb tumor suppressor gene. These inhibitors have been approved by the FDA and are used in combination with hormonal therapies. Similarly, in melanoma, the recently approved BRAF and MEK inhibitors target the MAPK growth stimulatory pathway to impair cancer progression. While these therapies exhibit clear patient responses initially, the development of acquired resistance occurs when the cancer cells subvert the action of the kinase inhibitor by activating alternate pathways that stimulate tumorigenesis. For example, the AKT pro- survival signaling pathway is often activated in response to targeted therapy, and stimulates resistance to the initial treatment. AKT plays various roles in promoting cancer by stimulating growth, metastasis, and changes in metabolism that support rapid cell proliferation. In this project we will focus on AKT- mediated stimulation of ATP-citrate lyase (ACLY), an enzyme that links high glycolytic activity in cancer cells with increased lipid synthesis required for the production of cell membranes. ACLY expression and activity is abnormal in several types of tumors, and is a newly identified target in drug development. These studies will determine the efficacy of combining ACLY inhibition with CDK4/6 inhibition in breast cancer or BRAF/MEK inhibition in melanoma on tumorigenesis; namely with respect to cell proliferation, apoptosis and invasiveness. The project will be carried out by undergraduate researchers at Pace University and may yield useful information that could inform the development of future therapies aimed at the reduction of acquired resistance and improve patient care.

概括使用针对癌细胞中过度活跃的特定酶的小分子激酶抑制剂已彻底改变了癌症患者的治疗。为了治疗某些类型的乳腺癌，CDK4/6 抑制剂具有已开发出针对 Rb 肿瘤抑制基因磷酸化的药物。这些抑制剂具有已获得 FDA 批准，与激素疗法联合使用。同样，在黑色素瘤，最近批准的 BRAF 和 MEK 抑制剂针对 MAPK 生长刺激损害癌症进展的途径。虽然这些疗法最初表现出明显的患者反应，当癌细胞破坏激酶的作用时，就会产生获得性耐药性通过激活刺激肿瘤发生的替代途径来抑制剂。例如，AKT 亲生存信号通路经常因靶向治疗而被激活，并刺激抵抗力到初步治疗。 AKT 通过刺激生长、转移、以及支持细胞快速增殖的新陈代谢变化。在这个项目中，我们将重点关注 AKT- 介导的 ATP-柠檬酸裂解酶 (ACLY) 刺激，这是一种与癌症中高糖酵解活性相关的酶细胞膜生产所需的脂质合成增加。 ACLY 表达和活性在几种类型的肿瘤中是异常的，并且是药物开发中新确定的靶点。这些研究将确定 ACLY 抑制与 CDK4/6 抑制相结合的功效乳腺癌或黑色素瘤中 BRAF/MEK 抑制对肿瘤发生的影响；即相对于细胞增殖、凋亡和侵袭。该项目将由本科生研究人员进行佩斯大学，可能会产生有用的信息，为未来的发展提供信息旨在减少获得性耐药并改善患者护理的疗法。