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Principal Investigator: Bulent Ozpolat
Organization: METHODIST HOSPITAL RESEARCH INSTITUTE
Fiscal Year: 2022
Award: $377,538
Funding agency: National Cancer Institute
Project Summary
Triple negative breast cancer (TNBC) has the worst prognosis and survival in all breast cancer subtypes with
currently available standard therapies, representing an unmet therapeutic challenge. Significant heterogeneity
(with six genetically defined subgroups) and a lack of FDA-approved targeted therapeutics and are the major
reasons contributing to poor prognosis and high mortality rates and have prevented identification of common
molecular targets and development of targeted therapeutics. To meet this challenge, we extensively analyzed
breast cancer patient databases and discovered that expression of Eukaryotic Elongation Factor 2-Kinase
(EF2K) gene encoding an unusual alpha kinase has a dramatic effect on survival rates of TNBC patients.
Remarkably, TNBC patients with low EF2K expression had no mortality up to 10 years. More importantly, we
found that EF2K is highly overexpressed in the majority of TNBC patients and showed that it is an important
driver for TNBC tumorigenesis, invasion and progression; and validated it as a potential molecular target using
genetic silencing technology in multiple preclinical animal models. Based on our preliminary studies, we
hypothesize that EF2K represents an Achilles’ heel for targeting TNBC and if effectively targeted, it will have a
tremendous impact on patient survival. Considering that EF2K knock-out mice are healthy and have no signs of
toxicity, EF2K-targeted therapies are expected to be safe. However, currently there is no specific or potent
inhibitors for targeting EF2K. Thus, in collaboration with a team of investigators, including medicinal chemists
and computational chemists, we recently synthesized a serious of potential small molecule inhibitors of EF2K
based on computational modeling and identified a lead compound that significantly inhibits EF2K activity. Based
on the lead compound, we further designed and synthesized more than a hundred of second generation of novel
compounds and identified a more potent inhibitor that is effective in inhibiting EF2K at with nanomolar
concentrations and demonstrated remarkable in vivo efficacy in TNBC tumors when formulated in long-acting
single-lipid based nanoparticles, with no observed toxic effects. In this proposed project, we will characterize
and optimize the EF2K-inhibitor based therapy using clinically relevant TNBC models with the goal of developing
highly specific strategies for TNBC. Our long-term goal is to develop safe, highly effective therapies and translate
them to the clinic for TNBC patients, who lack targeted treatment options.
Terms: <ATP-protein phosphotransferase><Animal Model><Animal Models and Related Studies><Anthelone U><Anti-Estrogens><Antioncogene Protein p53><Assay><Basal Transcription Factor><Basal transcription factor genes><Binding><Bioassay><Biologic Assays><Biological Assay><Breast Cancer><Breast Cancer Cell><Breast Cancer Model><Breast Cancer Patient><Breast Neoplasms><Breast Tumor Patient><Breast Tumors><Breast tumor model><CAM kinase III><CCL2><CCL2 gene><CCND1 Protein><Cam PK III><Cancer Cell Growth><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cells><Cellular Proliferation><Cellular Tumor Antigen P53><Chemicals><Chemokine, CC Motif, Ligand 2><Clinic><Clinical Trials><Collaborations><Computer Models><Computerized Models><Corpus Luteum Hormone><Crystallization><Cyclin D1><Data Bases><Databases><Delta4-pregnene-3,20-dione><Development><Docking><Dose><Drug Kinetics><Drug or chemical Tissue Distribution><E-2 kinase><EEF2><EEF2 gene><EF-2 kinase><EF2><ERBB2><ERBB2 gene><Endocrine Gland Secretion><Epidermal Growth Factor><Epidermal Growth Factor-Urogastrone><Estrogen Antagonists><Estrogens><Evaluation><FADK><FAK><FAK1><FDA approved><FKHL16><FOXM1><FOXM1 gene><FOXM1B><Family><Forkhead Box M1><Forkhead Box M1B Transcription Factor><Forkhead, Drosophila, Homolog-Like 16><Foundations><Future><G1/S-Specific Cyclin D1><General Transcription Factor Gene><General Transcription Factors><Generations><Genes><Genetic><Goals><HER -2><HER-2><HER2><HER2 Genes><HER2/neu><HFH11><Half-Life><Heterogeneity><Homology Modeling><Hormones><Hydrophobicity><In Vitro><Intracellular Communication and Signaling><Investigators><KO mice><Kinase Family Gene><Kinases><Kinetics><Knock-out Mice><Knockout Mice><Lead><Light><MCAF><MCP-1><MCP1><Mammary Cancer><Mammary Neoplasms><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Mice><Mice Mammals><Modeling><Molecular><Molecular Fingerprinting><Molecular Interaction><Molecular Profiling><Molecular Target><Molecular Tumor Suppression><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Murine><Mus><Mutate><NEU Oncogene><NEU protein><Nature><Neoplasm Metastasis><Null Mouse><Oncogene ErbB2><Oncogenesis><Oncogenic><Oncoprotein p53><P53><PDX model><PRAD1 Protein><PTK2><PTK2 gene><Patient derived xenograft><Patients><Pb element><Pharmacodynamics><Pharmacokinetics><Pharmacology><Phenotype><Phosphoprotein P53><Phosphoprotein pp53><Phosphotransferase Gene><Phosphotransferases><Photoradiation><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Pre-Clinical Model><Preclinical Models><Pregn-4-ene-3,20-dione><Pregnenedione><Primary Neoplasm><Primary Tumor><Progesterone><Prognosis><Prognostic Marker><Protein Kinase><Protein TP53><Proto-Oncogene Proteins c-bcl-1><Quelling><RNA Interference><RNA Silencing><RNAi><Receptor Protein><Relapse><Research Personnel><Researchers><Resistance><SCYA2><Schedule><Secondary Neoplasm><Secondary Tumor><Sequence-Specific Posttranscriptional Gene Silencing><Short interfering RNA><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Small Inducible Cytokine A2><Small Interfering RNA><Structure><Subgroup><Survival Rate><System><TKR1><TNBC><TP53><TP53 gene><TRIDENT gene><TRIDENT protein><TRP53><Tamoxifen><Technology><Testing><Therapeutic><Therapeutic Estrogen><Therapeutic Hormone><Therapeutic Progesterone><Tissue Distribution><Toxic effect><Toxicities><Transcription Factor Proto-Oncogene><Transcription factor genes><Translating><Translations><Transphosphorylases><Treatment Efficacy><Treatment Failure><Tumor Protein p53><Tumor Protein p53 Gene><Tumor Suppression><Tumor-associated macrophages><Urogastrone><VEGF><VEGFs><Vascular Endothelial Growth Factors><advanced disease><advanced illness><antiestrogen><antiestrogenic><aptamer><base><bcl-1 Proto-Oncogene Products><bcl-1 Proto-Oncogene Proteins><bcl1 Proto-Oncogene Proteins><beta-Urogastrone><biological signal transduction><breast tumor cell><c myc><c-bcl-1 Proteins><c-erbB-2><c-erbB-2 Genes><c-erbB-2 Proto-Oncogenes><c-myc Genes><calmodulin-dependent protein kinase III><cancer metastasis><cancer microenvironment><cancer sub-types><cancer subtypes><chemotherapy><clinical relevance><clinical significance><clinically relevant><clinically significant><cmyc><computational modeling><computational models><computer based models><computerized modeling><cyclin D><data base><design><designing><developmental><eEF-2-specific Ca and calmodulin-dependent protein kinase III><effective therapy><effective treatment><elongation factor 2 kinase><erbB-2 Genes><estrogen inhibitor><glycogen synthase a kinase><heavy metal Pb><heavy metal lead><herstatin><hydroxyalkyl protein kinase><improved><in silico><in vivo><inhibitor><intervention efficacy><kinase inhibitor><lipid based nanoparticle><lipid nanoparticle><lung metastatic><malignant breast neoplasm><malignant breast tumor><mammary cancer model><mammary tumor><mammary tumor model><member><model of animal><model organism><molecular profile><molecular signature><mortality><nano particle delivery><nano-molar><nanomolar><nanoparticle delivered><nanoparticle delivery><neu Genes><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><overexpress><overexpression><p53 Antigen><p53 Genes><p53 Tumor Suppressor><patient derived xenograft model><phosphorylase b kinase kinase><potential biological marker><potential biomarker><pp125FAK><pre-clinical><pre-clinical evaluation><pre-clinical safety><pre-clinical study><preclinical><preclinical evaluation><preclinical safety><preclinical study><prevent><preventing><prognostic biomarker><protein kinase CPK3><protein p53><pulmonary metastatic><receptor><resistant><response><screening><siRNA><site targeted delivery><small molecule><small molecule inhibitor><targeted delivery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutic target><therapeutically effective><therapy efficacy><therapy failure><transcription factor><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumor growth><tumor microenvironment><tumorigenesis><v-myc Avian Myelocytomatosis Viral Oncogene Cellular Homolog>