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PID2022-141955OB-I00

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DESPITE THE BREADTH OF CANCER CELL METABOLIC VULNERABILITIES NOW TARGETED WITH AN EVER-GROWING LIST OF DRUGS, THE DISCREPANCY BETWEEN BENCH FINDINGS AND BEDSIDE EFFECTS POSES SEVERAL CHALLENGES IN LEVERAGING METABOLIC INFORMATION... ver más

01/01/2022

FUNDACIO INSTITUT...

338K€

Presupuesto del proyecto: 338K€

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FUNDACIO INSTITUT D'INVESTIGACIO BIOMEDICA DE... Actividades auxiliares a la educación asociacion

TRL 4-5 | 100K€

Fecha límite participación Sin fecha límite de participación.

Financiación concedida El organismo AGENCIA ESTATAL DE INVESTIGACIÓN notifico la concesión del proyecto el día 2022-01-01 No tenemos la información de la convocatoria

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Este proyecto no cuenta con búsquedas de partenariado abiertas en este momento.

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1 Participantes

FUNDACIO INSTITUT D'INVESTIG...

337.50K€ | Lider

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FUNDACIO INSTITUT D'INVESTIGACIO BIOMEDICA DE... Actividades auxiliares a la educación asociacion

TRL 4-5 | 100K€

Presupuesto del proyecto 338K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto DESPITE THE BREADTH OF CANCER CELL METABOLIC VULNERABILITIES NOW TARGETED WITH AN EVER-GROWING LIST OF DRUGS, THE DISCREPANCY BETWEEN BENCH FINDINGS AND BEDSIDE EFFECTS POSES SEVERAL CHALLENGES IN LEVERAGING METABOLIC INFORMATION TO INFORM CANCER TREATMENT. USING FATTY ACID SYNTHASE (FASN) AS A METABOLIC TARGET OF INTENSE INTEREST FOR SEVERAL DECADES, THIS PROPOSAL WILL PROVIDE A NEW FRAMEWORK TO OVERCOME THE CURRENT LIMITATIONS IN BASIC RESEARCH AND DRUG DISCOVERY FOR TARGETING CANCER LIPOGENESIS, WHILE PROVIDING TRANSLATABLE INFORMATION TO GUIDE THE PERSONALIZED USE OF FASN-TARGETED METABOLIC THERAPIES. THIS PROPOSAL WILL ADDRESS THE MECHANISTIC WEAKNESSES AND THERAPEUTIC CONSTRAINTS OF FASN WITHIN A NEW PARADIGM OF FASN ACTIVITY AS AN INFORMATION-PROCESSING SYSTEM THAT RECEIVES, INTEGRATES, AND TRANSDUCES THE DIALOGUE BETWEEN INTRINSIC SIGNALS AND MICROENVIRONMENTAL CUES TO EXECUTE FATE-SPECIFIC RESPONSES THROUGHOUT CANCER INITIATION, THERAPEUTIC RESISTANCE, AND METASTATIC PROGRESSION. WE WILL DISSECT THE UNMAPPED FEATURES OF NON-CANONICAL AND CANONICAL FASN SIGNAL TRANSDUCTION IN UNLOCKING PHENOTYPIC PLASTICITY, MITOCHONDRIAL REGULATION OF CELL DEATH, IMMUNE-ESCAPE, AND ORGAN-SPECIFIC METASTATIC POTENTIAL. BASED ON THE IN-DEPTH KNOWLEDGE OF THESE EMERGING FASN HALLMARKS, WE WILL DEVELOP NEW CLINICO-THERAPEUTIC STRATEGIES TO OPTIMIZE FASN AS A METABOLIC TARGET FOR FUNCTIONAL PRECISION ONCOLOGY, INCLUDING: (1) RATIONAL DISCOVERY OF A FIRST-IN-CLASS FAMILY OF DRUG-LIKE MOLECULAR GLUES FOR CHEMICAL DEGRADATION OF FASN BY IMPLEMENTING A COMPUTATIONAL FRAMEWORK TO IN SILICO IDENTIFY MOLECULAR GLUE CANDIDATES PREDICTED TO STABILIZE THE INTERACTION BETWEEN FASN AND ONE OF ITS COGNATE E3 UBIQUITIN LIGASES. WE WILL THEN TEST THE CAPACITY OF FASN DEGRADERS TO SUPPRESS FASN-DEPENDENT EPIGENETIC REPROGRAMMING OF CANCER CELL IDENTITY IN RESPONSE TO BIOMECHANICAL, METABOLIC, AND ONCOGENIC STRESSES. (2) DEVELOPMENT OF FUNCTIONAL PREDICTORS OF RESPONSE TO FASN INHIBITORS AND ONE-TWO PUNCH TREATMENT STRATEGIES BASED ON THE ACQUIRED VULNERABILITIES OF THE FASN THERAPY-INDUCED SENESCENCE (FASTIS) STATE. WE WILL MAP THE MITOCHONDRIAL PRIMING STATUS BY BH3 PROFILING TO PREDICT CANCER CELL RESPONSES TO FASN INHIBITORS AND INFORM CANCER TYPE-CUSTOMIZED COMBINATIONS OF FASNIS WITH BH3 MIMETICS. WE WILL DESIGN AND EVALUATE SENOGENIC-SENOLYTIC STRATEGIES BASED ON THE DISTINCTIVE MITOCHONDRIAL, TRANSCRIPTIONAL, AND METABOLIC TRAITS OF THE FASTIS STATE. (3) EXAMINATION OF THE IMMUNOTHERAPEUTIC DIMENSIONS OF FASN SIGNALING INCLUDING: PRIMING OF IMMUNOLOGICALLY COLD CANCER CELLS TO T-CELLS CYTOLYSIS, MODIFICATION OF THE SURFACEOME LANDSCAPE OF FASTIS CANCER CELLS TO PROMOTE IMMUNE RESPONSE-MEDIATED SENOLYSIS, AND PALMITOYLATION-DEPENDENT FUNCTIONING OF THE PD-L1/PD-1 IMMUNE CHECKPOINTS. (4) EXPLORATION OF FASN AS A SYNTHETIC-LETHAL METABOLIC DEPENDENCY OF BRAIN METASTASIS-INITIATING CANCER CELLS WHEN COMBINED WITH: INHIBITORS OF CD36-DRIVEN LIPID UPTAKE, FATTY ACID FORMULATIONS MISMATCHING THE LIPIDOME OF FASN-INHIBITED CELLS, AND DIETARY/PHARMACOLOGICAL INDUCERS OF FERROPTOTIC CELL DEATH. UNDERSTANDING, PREDICTING, AND MANIPULATING TUMORAL FASN AS AN INFORMATION-PROCESSING SYSTEM WILL ENABLE US TO THERAPEUTICALLY GUIDE LIPOGENIC CANCER CELLS TOWARDS DESIRED HARMLESS OUTCOMES INCLUDING TERMINAL DIFFERENTIATION, APOPTOTIC CELL DEATH, SENOLYSIS, IMMUNE CLEARANCE, AND FERROPTOSIS. CANCER\FERROPTOSIS\METASTASIS\INMUNOTERAPIA\SENESCENCIA\APOPTOSIS MITOCONDRIAL\EPIGENETICA\PEGAMENTOS MOLECULARES\ACIDO GRASO SINTASA\METABOLISMO

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