Innovating Works

PID2019-110758RB-I00

Financiado
MEJORAS EN LA INMUNOTERAPIA DEL CANCER DE VEJIGA MEDIANTE INHIBIDORES EPIGENETIC...
BLADDER CANCER (BC) IS A HETEROGENEOUS DISEASE, TWO THIRDS OF PATIENTS DISPLAY A NONMUSCLE INVASIVE FORM (NMIBC), A RELATIVELY INDOLENT FORM TREATED BY TRANSURETHRAL RESECTION FOLLOWED IN SOME CASES BY INTRAVESICAL THERAPY, NMIBC... BLADDER CANCER (BC) IS A HETEROGENEOUS DISEASE, TWO THIRDS OF PATIENTS DISPLAY A NONMUSCLE INVASIVE FORM (NMIBC), A RELATIVELY INDOLENT FORM TREATED BY TRANSURETHRAL RESECTION FOLLOWED IN SOME CASES BY INTRAVESICAL THERAPY, NMIBC SHOWS AN EXTRAORDINARY HIGH RECURRENCE RATES, AND THESE SECONDARY TUMORS OFTEN DISPLAY AGGRESSIVE CHARACTERISTICS, THE REMAINING THIRD OF PATIENTS DISPLAY A MUSCLE INVASIVE BC (MIBC), A HIGHLY AGGRESSIVE AND USUALLY DEADLY DISEASE, CURRENT AGGRESSIVE TUMOR THERAPIES (SURGERY, RADIOTHERAPY, AND CHEMOTHERAPY) ARE IN MOST CASES INEFFECTIVE, AND NO IMPROVEMENT IN THE CLINICAL MANAGEMENT OF BC OCCURRED IN THE LAST 30 YEARS, THEREFORE, NEW POSSIBLE MOLECULARLY TARGETED THERAPIES ARE BEING EXPLORED, AS THE ALTERATIONS OF THE CHROMATIN REMODELING MACHINERY ARE PREPONDERANT IN BC, INHIBITORS OF THESE EPIGENETIC PATHWAYS HAVE BEEN SUGGESTED FOR BC MANAGEMENT, HOWEVER, NONE OF THESE IS IN THE CLINIC, THE USE OF IMMUNE CHECKPOINT INHIBITORS MAY REPRESENT A MAJOR IMPROVEMENT IN BC THERAPIES, ACCORDING TO MULTIPLE CLINICAL TRIALS, THESE INHIBITORS PROVIDE LONG SUSTAINABLE RESPONSES WITH MINOR SECONDARY EFFECTS, NONETHELESS, THE PERCENTAGE OF PATIENTS SHOWING POSITIVE RESPONSE IS STILL LIMITED (20-30%) AND, THERE IS NO RELIABLE AND VALIDATED BIOMARKERS PREDICTIVE OF THIS RESPONSE, ACCORDINGLY THE IMMUNOTHERAPY OF BC REQUIRES: 1) IDENTIFICATION AND VALIDATION OF THESE SUITABLE BIOMARKERS FOR CLINICAL ROUTINE, AND 2) IDENTIFICATION OF POSSIBLE THERAPEUTIC ALTERNATIVES TO INCREASE THE PROPORTION OF RESPONDING PATIENTS AND BETTER CLINICAL RESPONSES UPON IMMUNOTHERAPY, A MAJOR DIFFICULT TO ACHIEVE IMPROVEMENTS IN BC MANAGEMENT COMES FROM THE LACK OF RELIABLE PRECLINICAL MODELS OF THE DISEASE, IN PARTICULAR THOSE ALLOWING ACTIVE IMMUNE RESPONSES AGAINST TUMORS, IN THIS REGARD, WE HAVE RECENTLY REPRODUCED VARIOUS BC SUBTYPES (NMIBC OF HIGH RISK OF RECURRENCE AND PROGRESSION, AND METASTATIC MIBC DISEASE) THROUGH THE INTRAVESICAL DELIVERY OF CRE EXPRESSING ADENOVIRUS, TARGETED TO SPECIFIC CELL SUBTYPES, IN MICE BEARING SPECIFIC FLOXED ALLELE COMBINATIONS, UPON COMPARATIVE VALIDATION, BOTH TRANSGENIC MODELS ARE CURRENTLY BEING USED AS PRECLINICAL TOOLS, OUR PREVIOUS WORK REVEALED THAT A NOVEL DUAL G9A/DNMT INHIBITOR DISPLAY ANTITUMOR ACTIVITY IN THE METASTATIC BC TRANSGENIC MODEL, REMARKABLY, THIS ACTIVITY PROCEEDS THROUGH AN APPARENT REACTIVATION OF THE IMMUNE RESPONSES OF THE HOST CELLS AND POTENTIATES ANTI PD-L1 RESPONSES, OUR PRESENT PROPOSAL AIMS TO ANALYZE IN DETAIL THESE FINDINGS, FIRST, WE AIM TO STUDY CHROMATIN REMODELING MACHINERY IN BC, IN PARTICULAR FOCUSING ON EZH2-G9A INTERACTION AND THEIR ACTIVITY IN BC PATHOGENESIS, SECOND, WE WILL EXPAND OUR STUDIES ON COMBINATORIAL THERAPIES FOCUSING ON NOVEL MOUSE MODELS, INHIBITORS AND APPROACHES (CAR-NKS), THIRD, WE WILL DETERMINE PREDICTIVE BIOMARKERS OF IMMUNOTHERAPY RESPONSE IN VARIOUS SERIES OF BC PATIENTS EITHER UNDER CONVENTIONAL THERAPY OR ENROLLED IN VARIOUS CLINICAL TRIALS TO A BETTER IDENTIFICATION OF SUITABLE COHORTS OF POSITIVE RESPONSE TO IMMUNOTHERAPY AND TO PROVIDE POSSIBLE NEW THERAPEUTIC ALTERNATIVES, COLLECTIVELY, THESE OBJECTIVES BESIDES CONTRIBUTING TO OUR UNDERSTANDING OF BC PATHOGENESIS, MAY OPEN NEW AVENUES IN THE MANAGEMENT OF BC AND MAY ALLOW THE DEVELOPMENT OF NEW CLINICAL TRIALS, CANCER VEJIGA\TRANSGENESIS\GENOMICA\EPIGENETICA\IMMUNOTHERAPIA\RB\P53\PTEN\G9A\EZH2 ver más
01/01/2019
IFMIF- DONES
387K€
Perfil tecnológico estimado

Línea de financiación: concedida

El organismo AGENCIA ESTATAL DE INVESTIGACIÓN notifico la concesión del proyecto el día 2019-01-01
Presupuesto El presupuesto total del proyecto asciende a 387K€
Líder del proyecto
IFMIF- DONES No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico TRL 4-5 42M