PID2021-126325OB-I00
Financiado
POTENCIAL TRASLACIONAL DE INHIBIDORES DEL FACTOR DE TRANSCRIPCION HSF1 COMO DROG...
POTENCIAL TRASLACIONAL DE INHIBIDORES DEL FACTOR DE TRANSCRIPCION HSF1 COMO DROGAS ANTICANCERIGENAS
THE MASTER REGULATOR OF THE MAMMALIAN HEAT SHOCK RESPONSE (HSR), ALSO KNOWN AS THE STRESS RESPONSE, IS THE HEAT SHOCK TRANSCRIPTION FACTOR 1 (HSF1). BEYOND THE REGULATION OF TYPICAL HSR GENES SUCH AS HSP GENES, ACTIVATED HSF1 INFL...
THE MASTER REGULATOR OF THE MAMMALIAN HEAT SHOCK RESPONSE (HSR), ALSO KNOWN AS THE STRESS RESPONSE, IS THE HEAT SHOCK TRANSCRIPTION FACTOR 1 (HSF1). BEYOND THE REGULATION OF TYPICAL HSR GENES SUCH AS HSP GENES, ACTIVATED HSF1 INFLUENCES THE ACTIVITIES OF GENES RELATED TO BASIC CELLULAR PROCESSES. THIS HSF1-INDUCED PROGRAM MAY FACILITATE ONCOGENIC TRANSFORMATION AND MAINTENANCE OF THE MALIGNANT PHENOTYPE. USING A CELL-BASED ASSAY, WE HAVE IDENTIFIED INHIBITORS (IHSFS) CAPABLE OF INTERACTING DIRECTLY WITH THE DNA-BINDING DOMAIN OF HUMAN HSF1, INTERFERING WITH THE ASSEMBLY OF ATF1-CONTAINING TRANSCRIPTION COMPLEXES. IHSFS ARE CYTOTOXIC FOR A VARIETY OF HUMAN CANCER CELL LINES, MULTIPLE MYELOMA (MM) LINES CONSISTENTLY EXHIBITING HIGH SENSITIVITY. IN VITRO DATA WE HAVE COLLECTED DURING RECENT YEARS INDICATE THAT IHSFS INDUCE MASSIVE PROTEIN UNFOLDING AT CONCENTRATIONS AT WHICH THEY ARE CYTOTOXIC, BROUGHT ABOUT BY RELATIVELY INDISCRIMINATE COVALENT MODIFICATION OF CELLULAR PROTEINS, LEADING TO A PROTEOSTASIS CRISIS. THE MAIN HYPOTHESIS OF THIS PROJECT IS THAT IHSFS MIGHT AUGMENT THE ARMAMENTARIUM AVAILABLE FOR THE TREATMENT OF CANCERS THAT ARE SUSCEPTIBLE TO PROTEOSTASIS INHIBITION. AS OUR PRELIMINARY RESULTS STRONGLY SUGGEST THAT MM THERAPY COULD BENEFIT OF EMPLOYING IHSFS, WE WILL ASSESS THEIR EFFECTS IN CELLS OBTAINED FROM MM PATIENTS AS WELL AS IN AN IMMUNOCOMPETENT MOUSE MM MODEL. SOLID CANCER TYPES MIGHT BE SENSITIVE AS WELL TO THESE COMPOUNDS. WE HAVE FOUND THAT CERTAIN TRIPLE-NEGATIVE BREAST CANCER AND PROSTATIC ADENOCARCINOMA CELLS WERE SENSITIVELY KILLED BY IHSFS AND REDUCTION OF TUMOR GROWTH AFTER IHSF ADMINISTRATION WAS DETECTED IN A PC-3 PROSTATE CANCER XENOGRAFT MODEL. WHILE IHSFS MAY BE CONSIDERED FOR MONOTHERAPY OF SOME SOLID TUMORS, COMBINATION WITH FOCUSED MILD HYPERTHERMIA THERAPY MIGHT INCREASE THEIR EFFICACY. USING MINIMALLY INVASIVE HEATING TECHNOLOGY BASED ON PHOTOTHERMAL HYDROGELS, WE WILL TEST IN A PC-3 MOUSE XENOGRAFT MODEL WHETHER COMBINED ADMINISTRATION OF IHSF AND HYPERTHERMIA LEADS TO SYNERGIC EFFECTS. FINALLY, USING GENETIC ELIMINATION OF HSF1, HSF2 OR HSF1/2 WE WILL EXPLORE WHETHER INHIBITION OF HSF1 FUNCTION AFFECTS THE EFFICACY OF FDA-APPROVED ANTICANCER DRUGS. FURTHERMORE, ATTEMPTS WILL BE MADE TO RECAPITULATE OBSERVED INTERACTIONS IN CELLS TREATED WITH THE DRUGS CONCERNED AND IHSFS. SF1\NIR\HIPERTERMIA\PROTEOSTASIS\TUMOR\INHIBIDOR
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Línea de financiación: concedida
El organismo AGENCIA ESTATAL DE INVESTIGACIÓN notifico la concesión del proyecto el día 2021-01-01
Presupuesto
El presupuesto total del proyecto asciende a
218K€
Líder del proyecto
FUNDACIÓN PARA LA INVESTIGACIÓN BIOMÉDICA. HO...
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
4M
Perfil tecnológico
TRL
4-5
4M