NEW ANTICANCER THERAPIES BASED ON THE IMMUNOMODULATORY PROPERTIES OF PHARMACOLOGIC INHIBITORS OF THE MAPK ERK5

CANCER IS THE SECOND MAJOR CAUSE OF DEATH IN WESTERN COUNTRIES (THE FIRST FOR PEOPLE OLDER THAN 65 YO), REPRESENTING NOWADAYS AN ENORMOUS SOCIAL, HEALTH AND ECONOMIC BURDEN. OF RELEVANCE FOR THIS PROPOSAL, ENDOMETRIAL CANCER (EC) IS THE SIXTH MOST COMMON TUMOR IN WOMEN WORLDWIDE. HOWEVER, THE CLINICAL EFFECTIVENESS OF CURRENT TREATMENTS IS POOR IN ADVANCED, RECURRENT, OR METASTATIC EC TUMORS. HENCE, THERE IS AN URGENT NEED FOR NEW THERAPIES TO IMPROVE THE TREATMENT OF HIGH-RISK EC PATIENTS. IMMUNOTHERAPEUTIC AGENTS (IMMUNE CHECKPOINT INHIBITORS, ICI) HAVE BECOME INCREASINGLY IMPORTANT FOR TREATING PATIENTS WITH EC, SIGNIFICANTLY IMPROVING THE PROGNOSTIC OF EC. HOWEVER, FEW EC PATIENTS TYPICALLY RESPOND TO IMMUNOTHERAPY. IN THIS REGARD, THE USE OF PROTEIN KINASE INHIBITORS OF ONCOGENIC SIGNALING PATHWAYS IS EMERGING AS A TOOL TO IMPROVE IMMUNOTHERAPY, AS THEY TARGET BOTH CANCER AND IMMUNE CELLS. THE RATIONALE FOR TARGETING ERK5 TARGETING IN CANCER IS SUPPORTED BY NUMEROUS STUDIES THAT SHOW THAT GENETIC AND PHARMACOLOGIC MANIPULATION OF ERK5 GREATLY IMPACTS CANCER CELL AND TUMOR PROLIFERATION AND VIABILITY. HOWEVER, DATA OBTAINED WITH THE FEW ERK5 INHIBITORS DEVELOPED SO FAR HAS BEEN RECENTLY QUESTIONED, SINCE CLASSICAL ERK5 INHIBITORS ARE UNSPECIFIC AND TARGET OTHER PROTEINS INVOLVED IN CANCER PROGRESSION. WE HAVE DEVELOPED JWG-071, THE FIRST SPECIFIC ERK5 INHIBITOR WITH A FAVOURABLE PHARMACOKINETIC PROFILE IN MICE. WE FOUND THAT SYSTEMIC ADMINISTRATION OF JWG-071 RESULTED IN REDUCED ENDOMETRIAL TUMOR XENOGRAFTS GROWTH, AS A MONOTHERAPY OR POTENTIATING STANDARD CHEMOTHERAPY. THUS, WE ESTABLISHED THAT JWG-071 SHOWS ANTICANCER ACTIVITY. OUR PRELIMINARY DATA SUGGEST THAT JWG-71 COULD ALSO POTENTIATE THE CYTOTOXIC EFFECT OF LYMPHOCYTES T AND NK CELLS. IN AGREEMENT WITH THIS, OUR PRELIMINARY DATA ALSO SUGGESTS THAT JWG-071 TREATMENT COULD RESULT IN INCREASED RECRUITMENT OF IMMUNE CELLS TOWARDS THE TUMORS. JWG-071 TREATMENT SEEMS TO INDUCE IMMUNOGENIC CANCER CELL DEATH, A TYPE OF DEATH THAT ENHANCES THE CAPACITY OF DENDRITIC CELLS TO STIMULATE THE PRESENTATION OF TUMOR ANTIGENS TO T CELLS. THE ANTICANCER ACTIVITY OF A SPECIFIC ERK5 INHIBITOR HAS NEVER BEEN TESTED BEFORE IN IMMUNOCOMPETENT MICE MODELS. IN THIS PROPOSAL, WE AIM TO CHARACTERIZE THE IMMUNE MODULATORY PROPERTIES OF OUR ERK5I. WE HYPOTHESIZE THAT MODULATION OF ERK5 ACTIVITY WITH A SPECIFIC INHIBITOR ENHANCES THE ANTICANCER ACTIVITY OF IMMUNE CELLS, AND THAT TARGETING ERK5 KINASE ACTIVITY IS AN EFFECTIVE WAY TO TACKLE EC CANCER IN IMMUNOCOMPETENT ANIMAL MODELS. IF SO, THIS PROJECT WILL HELP TO UNDERSTAND THE ROLE OF ERK5 KINASE ACTIVITY IN THE IMMUNE SYSTEM, AND TO SUPPORT THE CLINICAL DEVELOPMENT OF JWG-071. WE WILL USE ENDOMETRIAL CANCER AS THE PARADIMG TO CHALLENGE OUR COMPOUND, AND WE PROPOSE THE FOLLOWING SPECIFIC OBJECTIVES: 1. IMMUNOMODULATORY EFFECT OF THE SPECIFIC ERK5 INHIBITOR JWG-071 IN ADVANCED ENDOMETRIAL CANCER. 2. IMMUNOMODULATORY EFFECT OF THE ERK5 INHIBITOR JWG-071 IN IMMUNE CELLS. 3. CHARACTERIZATION OF THE IMMUNE INFILTRATION IN HUMAN ENDOMETRIAL CANCER TUMORS. 4. IMMUNOMODULATORY EFFECT OF THE ERK5I IN VIVO, IN A TRANSGENIC MOUSE SYNGENEIC MODEL OF ENDOMETRIAL CANCER. WE HOPE THAT THIS STUDY WILL CONTRIBUTE TO SHED NEW LIGHT INTO THE MECHANISM BY WHICH TARGETED THERAPY CAN BE USE AS ADJUVANT TO IMMUNOTHERAPY, AS WELL AS TO GET INSIGHT INTO THE MOLECULAR MECHANISMS OF THE IMMUNE REGULATORY PROFILE OF THE MAPK ERK5.