GCDH Addiction in Melanoma

黑色素瘤中的 GCDH 成瘾

基本信息

批准号：
10656574
负责人：
Steven H Olson
金额：
$ 72.17万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
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：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656574
关键词：
Address Advanced Development Antibodies Apoptosis Apoptotic Attenuated Azoles Brain Neoplasms Breast Cancer Cell CASP3 gene Catabolism Cell Death Cell Death Signaling Process Cell Line Cell Survival Cessation of life Chemicals Chemoresistance Clinical Data Development Dissociation Effectiveness Enzymes Evaluation Foundations Genetic Genetic Transcription Growth Human Immune Immunotherapy In Vitro Induction of Apoptosis Knockout Mice Liver neoplasms Lysine Lysine Degradation Pathway Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of prostate Mammary Neoplasms Maps Mediating Melanoma Cell Mitochondria Modality Modeling Mole the mammal Molecular Weight Monitor Mus Neoplasm Metastasis Outcome Oxidoreductase Pathway interactions Patients Pharmaceutical Chemistry Phenocopy Phenotype Physiological Process Production Prostatic Neoplasms Proteins Regulation Resistance Resistance development Sampling Signal Pathway Signal Transduction Site Specimen Testing Transactivation Transcription Coactivator Transcriptional Activation Tumor Cell Line Xenograft procedure activating transcription factor 3 addiction anti-PD-1 cancer cell gene function genome-wide analysis glutaryl coA in vivo inhibitor liquid chromatography mass spectrometry malignant breast neoplasm melanocyte melanoma mouse model new therapeutic target novel novel therapeutics prostate cancer cell response small molecule small molecule inhibitor targeted treatment therapy resistant transcription factor treatment response tumor tumor growth tumor heterogeneity ubiquitin-protein ligase

项目摘要

Project Summary In this revised R01 application we propose to characterize a novel mechanism underlying the control of apoptosis by the mitochondrial enzyme GCDH, and to extend the development of small molecule GCDH inhibitors to treat melanoma. In our preliminary results we discovered that addiction to GCDH activity is critical for cell survival in melanoma, but not liver, breast or prostate tumor cells, a discovery that was confirmed in patient specimens where inverse correlation between GCDH expression and survival is seen in melanoma. Our studies reveal induction of apoptosis in melanoma cell lines following GCDH inhibition, a phenotype dependent on the upstream DHTKD1 enzyme. Key in mediating GCDH activities in melanoma is NRF2, which is subjected to glutarylation upon inhibition of GCDH. NRF2 glutarylation promotes its stability and transactivation of an apoptotic UPR signaling consisting of ATF4, ATF3, CHOP and CHAC1, the latter being components of the Unfolded Protein Response (UPR). Inhibition of GCDH effectively induces apoptotic UPR signaling in melanoma but not in liver or breast cancer cells, substantiating the selectivity of the pathway as mapped in cell lines and patient tumor samples. These observations provide the foundation for our hypothesis that GCDH-mediated regulation of NRF2-UPR signaling constitutes a novel pathway controlling melanoma cell survival. Our studies will (i) map the NRF2 glutarylation pathway in melanoma, generate antibodies specific to glutarylated NRF2, monitor NRF2 glutarylation in specimens from melanoma patients both responsive and non-responsive to therapy (ii) assess how GCDH impacts tumor development, progression and response to targeted and immuno therapy in genetic mouse models. YUMM1.7, MaRas, B16F10 lines will be modified to express inducible KD of GCDH before their inoculation into syngeneic WT or GCDH KO mouse models which will be monitored prior and following therapy (iii) advance development GCDH inhibitors as novel therapeutic modalities. SBI-0690564 was confirmed in vitro and in cultured melanoma cells, where it phenocopies genetic inactivation of GCDH and inhibits melanoma tumors in mice. We will characterize and further develop a novel class of inhibitors to target GCDH and determine their effectiveness in culture and in vivo using mouse models. Our studies will establish novel paradigm for GCDH signaling as we define mechanisms underlying GCDH control melanoma tumor fate. Understanding the addiction to GCDH in melanoma provides the foundation for the development and evaluation of novel GCDH inhibitors to selectively target these and possibly other select cancers.

项目摘要在此修订后的R01应用中，我们建议表征凋亡控制的新机制通过线粒体酶GCDH，并扩展小分子GCDH抑制剂的发展黑色素瘤。在我们的初步结果中，我们发现对GCDH活性成瘾对于细胞存活至关重要黑色素瘤，但不是肝脏，乳腺或前列腺肿瘤细胞，这是患者标本中证实的发现在黑色素瘤中可以看到GCDH表达与存活之间的反相关性。我们的研究揭示了 GCDH抑制后黑色素瘤细胞系凋亡诱导，这是一种取决于上游的表型 DHTKD1酶。 NRF2的介导GCDH活性的钥匙是经受麸质的作用抑制GCDH。 NRF2谷氨酸促进了凋亡UPR的稳定性和反式激活由ATF4，ATF3，CHOP和CHAC1组成的信号传导，后者是展开蛋白的组成部分响应（UPR）。 GCDH的抑制有效地诱导了黑色素瘤的凋亡UPR信号传导，而不是在肝脏中或乳腺癌细胞，证实途径在细胞系和患者肿瘤中的选择性样品。这些观察结果为我们的假设奠定了基础，即GCDH介导的调节 NRF2-UPR信号传导构成了一种控制黑色素瘤细胞存活的新途径。我们的研究将（i）在黑色素瘤中绘制NRF2谷胱甘肽途径，生成针对谷物化NRF2的抗体，监测来自黑色素瘤患者的标本中的NRF2谷氨酸对治疗反应性和无反应性（II）评估GCDH如何影响肿瘤的发展，进展和对靶向和免疫治疗的反应遗传小鼠模型。 Yumm1.7，Maras，B16F10线将被修改以表达诱导型gcdh 在接种合成元WT或GCDH KO小鼠模型之前，该模型将在先进之前进行监控和在治疗后（III）提高了GCDH抑制剂作为新型治疗方法。 SBI-0690564是在体外和培养的黑色素瘤细胞中得到了证实，在该细胞中，它的表观植物遗传失活并抑制小鼠黑色素瘤肿瘤。我们将表征并进一步开发一种新型的抑制剂来靶向GCDH 并使用小鼠模型确定它们在培养和体内的有效性。我们的研究将建立新颖当我们定义GCDH控制黑色素瘤肿瘤命运的机制时，GCDH信号传导的范例。了解黑色素瘤中GCDH的成瘾为开发和评估提供了基础新型的GCDH抑制剂有选择地靶向这些癌症以及其他选择的癌症。