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Principal Investigator: Besim Ogretmen
Organization: MEDICAL UNIVERSITY OF SOUTH CAROLINA
Fiscal Year: 2024
Award: $384,227
Funding agency: National Cancer Institute
SUMMARY
Non-small cell lung cancer (NSCLC) remains the deadliest cancer, and novel therapeutic strategies are
needed to improve treatment outcomes of patients with this disease. FTY720 (Fingolimod/Gilenya, Novartis) is
a sphingosine analog drug approved for the treatment of refractory multiple sclerosis due to its immune
suppressor function. Immune suppression by FTY720 requires its phosphorylation (P-FTY720) mainly by
sphingosine kinase 2 (SphK2). However, pro-drug FTY720, without its phosphorylation, exhibits anti-cancer
functions in various models, including NSCLC. Our published and unpublished preliminary studies
demonstrated that FTY720, and not P-FTY720, directly binds and targets cytoplasmic SET oncoprotein, which
is overexpressed in majority of NSCLC cells and tumors. Cytoplasmic SET is a known inhibitor of protein
phosphatase 2A (PP2A). FTY720-SET binding prevents inhibitory SET-PP2A association, leading to the
activation of tumor suppressor PP2A. Mechanistically, activation of PP2A by FTY720 induces necroptosis and
cell death in NSCLC cells in culture and in animal models through the formation of RIPK1-C16-ceramide-non-
muscle myosin IIA (NMIIA) enriched pores (we coined the name “ceramidosomes”) at the plasma membrane.
Thus, we designed this application to test the novel hypothesis that FTY720 and its functional mimetics
mediate NSCLC cell death and tumor suppression, at least in part, by directly binding and targeting SET
oncoprotein, resulting in the generation of plasma membrane pores and necroptosis. There are three Specific
Aims proposed in this application: Aim 1) Define the mechanism by which FTY720 mediates necroptosis via
induction of ceramidosomes. Aim 2) Identify how FTY720-induced ceramidosomes are activated by PP2A to
mediate necroptosis. Aim 3) Determine the therapeutic and clinical significance of targeting SET by FTY720
and its functional mimetics, like A7-2, to mediate PP2A-dependent ceramidosome activation and NSCLC tumor
suppression. These studies will help define how targeting SET induces necroptosis using molecular, genetic,
pharmacologic, and structural tools, including X-ray crystallography and cryo-EM. Moreover, data obtained
from this proposal will help predict which of the NSCLC patients are likely to benefit from the treatment with
FTY720 and its analog drugs. We will also utilize functional mimetics of FTY720, such as A7-2, which is a
recently developed analog that inhibits SET and induces necroptosis at nanomolar concentrations, in the
absence/presence of mutant (G12C)-K-Ras inhibitors, such as sotorasib or adagrasib, to suppress NSCLC
tumor growth/progression. Thus, these studies will provide first-in-class treatment options and precision
therapy for the treatment of patients with refractory NSCLC.
Terms: <4-Sphingenine><AKT><Akt protein><Animal Model><Animal Models and Related Studies><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Binding><Biological><Bradycardia><Breast Cancer><C(16)-ceramide><C-K-RAS><C-jun Amino-Terminal Kinase><C-jun Kinase-1><C-jun N-Terminal Kinase 1><C16-0(palmitoyl)ceramide><C16-ceramide><Cancer Drug><Cancer Patient><Cancer Treatment><Cancers><Cardiac Toxicity><Cardiotoxic><Cardiotoxicity><Cell Communication and Signaling><Cell Death><Cell Signaling><Cell membrane><Ceramides><Clinic><Clinical><Coin><Colon Cancer><Colon Carcinoma><Complex><Cryo-electron Microscopy><Cryoelectron Microscopy><Cytoplasm><Cytoplasmic Membrane><DNA Molecular Biology><Data><Dephosphorylation><Development><Disease><Disorder><Disseminated Sclerosis><Drug Precursors><Drugs><ERK 1><ERK1><ERK1 Kinase><Electron Cryomicroscopy><Exhibits><Extracellular Signal-Regulated Kinase 1><FADK><FAK><FAK1><Generalized Growth><Generations><Genetic><Goals><Growth><Immunosuppressants><Immunosuppression><Immunosuppression Effect><Immunosuppressive Agents><Immunosuppressive Effect><Immunosuppressive drug><Immunosuppressive treatment><Intracellular Communication and Signaling><JN Kinase><JNK><JNK Mitogen-Activated Protein Kinases><JNK1><JNK1 Kinase><JNK1 protein><JNK1A2><JNK21B1/2><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Lipids><Lung Neoplasms><Lung Tumor><MAP Kinase 3><MAP Kinase 8><MAP Kinase 8 Gene><MAPK3><MAPK3 Mitogen-Activated Protein Kinase><MAPK3 gene><MAPK8><MAPK8 Mitogen-Activated Protein Kinase><MAPK8 gene><Macromolecular Protein Complexes><Malignant Breast Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant Tumor of the Prostate><Malignant neoplasm of lung><Malignant neoplasm of prostate><Malignant prostatic tumor><Mediating><Medication><Membrane><Mitogen-Activated Protein Kinase 3><Mitogen-Activated Protein Kinase 3 Gene><Mitogen-Activated Protein Kinase 8><Modeling><Molecular><Molecular Biology><Molecular Interaction><Molecular Tumor Suppression><Multiple Sclerosis><Multiprotein Complexes><Myosin A><Myosin IIA><N-palmitoylsphingosine><NFA(C16)CER><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Names><Neoplastic Disease Chemotherapeutic Agents><Non-Muscle Myosin Type IIA><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Nonmuscle Myosin Type IIA><Nuclear Envelope><Nuclear Membrane><Oncogene K-Ras><Oncogene Products><Oncogene Proteins><Oncoproteins><P44ERK1><PRKM8><PSTkinase p44mpk><PTK2><PTK2 gene><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pharmaceutical Preparations><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoprotein Phosphatase><Phosphoprotein Phosphatase-2C><Phosphoprotein Phosphohydrolase><Phosphoric Monoester Hydrolases><Phosphorylation><Plasma Membrane><Precision therapeutics><Pro-Drugs><Prodrugs><Proliferating><Prostate CA><Prostate Cancer><Prostate malignancy><Prostatic Cancer><Protein Dephosphorylation><Protein Kinase B><Protein Phosphatase C><Protein Phosphatase Gene><Protein Phosphatase Inhibitor><Protein Phosphatase-1><Protein Phosphatase-2A><Protein Phosphorylation><Protein phosphatase><Proto-Oncogene Proteins c-akt><Publishing><Pulmonary Cancer><Pulmonary Neoplasms><Pulmonary malignant Neoplasm><RAC-PK protein><RASK2><RIP1><RIPK1><RIPK1 gene><Ras Inhibitor><Receptor-Interacting Serine/Threonine Kinase 1><Refractory><Reporting><Role><Rupture><SAP Kinase-1><SAPK/JNK><SAPK1 Mitogen-Activated Protein Kinase><SAPK1/JNK><Signal Transduction><Signal Transduction Systems><Signaling><Single Crystal Diffraction><Sphingolipids><Sphingosine><Stress-Activated Protein Kinase JNK1><Stress-Activated Protein Kinase gamma><Testing><Therapeutic><Tissue Growth><Treatment outcome><Tumor Suppression><Tumor Suppressor Proteins><Tumor-Specific Treatment Agents><United States><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><analog><anti-cancer><anti-cancer drug><anti-cancer therapy><biologic><biological signal transduction><c-akt protein><c-jun N-Terminal Kinase><cancer in the colon><cancer therapy><cancer-directed therapy><ceramide synthase><clinical significance><clinically significant><cryo-EM><cryoEM><cryogenic electron microscopy><design><designing><developmental><dihydroceramide desaturase><drug/agent><experiment><experimental research><experimental study><experiments><immune suppression><immune suppressive activity><immune suppressive agent><immune suppressive function><immune suppressor><immunosuppressive activity><immunosuppressive function><immunosuppressive response><immunosuppressive substance><immunosuppressor><improved><in vivo><inhibitor><insular sclerosis><jun-NH2-Terminal Kinase><leukemia><lung cancer><lung cancer cell><malignancy><malignant breast tumor><membrane structure><mimetics><model of animal><mutant><name><named><naming><nano-molar><nanomolar><necrocytosis><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><non-muscle myosin><nonmuscle myosin><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><ontogeny><overexpress><overexpression><p44 MAPK><patient oriented outcomes><pharmacologic><plasmalemma><pp125FAK><precision therapies><precision treatment><prevent><preventing><protein complex><proto-oncogene protein RAC><proto-oncogene protein akt><rac protein kinase><related to A and C-protein><social role><sphingosine kinase><stress-activated protein kinase 1><structural biology><tool><tumor><tumor growth><tumor suppressor><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog>