NANO-IMMUNOTHERAPIES AIMED AT RELEVANT INTRACELLULAR TARGETS IN CANCER (Q3187566)
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Project Q3187566 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | NANO-IMMUNOTHERAPIES AIMED AT RELEVANT INTRACELLULAR TARGETS IN CANCER |
Project Q3187566 in Spain |
Statements
145,200.0 Euro
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181,500.0 Euro
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80.0 percent
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1 January 2018
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31 December 2020
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UNIVERSIDAD DE SANTIAGO DE COMPOSTELA
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15078
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ENTRE LAS TERAPIAS MAS AVANZADAS EN EL TRATAMIENTO DEL CANCER SE ENCUENTRAN LAS BASADAS EN ANTICUERPOS MONOCLONALES (MABS). LAS TERAPIAS COMERCIALIZADAS HASTA EL MOMENTO BASADAS EN MABS TIENEN COMO UNICO OBJETIVO EL ACCESO A DIANAS ACCESIBLES EN LA MEMBRANA O A NIVEL EXTRACELULAR. SIN EMBARGO, EXISTEN NUMEROSAS PROTEINAS DIANA, LOCALIZADAS EN EL INTERIOR DE LAS CELULAS TUMORALES Y DE OTRAS CELULAS RELEVANTES PRESENTES EN EL ESTROMA TUMORAL, COMO SON LOS FIBROBLASTOS ASOCIADOS AL CANCER (CAFS), QUE HASTA EL MOMENTO HAN RESULTADO INACCESIBLES PARA LOS MABS. ELLO SE DEBE A LA IMPOSIBILIDAD DE ESTAS GRANDES MOLECULAS PARA ATRAVESAR LA MEMBRANA CELULAR._x000D_ LA NANOTECNOLOGIA SE PRESENTA COMO UNA HERRAMIENTA PROMETEDORA PARA ABORDAR EL CITADO PROBLEMA GRACIAS A SU CAPACIDAD DE ORIENTACION SELECTIVA AL TEJIDO TUMORAL Y DE ATRAVESAR LA MEMBRANA CELULAR, LIBERANDO ASI EL FARMACO A NIVEL INTRACELULAR. ACTUALMENTE, SE CONSIDERA QUE SOLO UNA ESTRATEGIA DE ¿TARGETING ACTIVO¿ BASADA EN EL USO DE NANOSISTEMAS CAPACES DE CONDUCIR LOS FARMACOS A SUS DIANAS CELULARES, PODRA RESULTAR EN UNA MEJORA DRASTICA EN EL TRATAMIENTO DE CANCERES AGRESIVOS, COMO ES EL CASO DEL DE PULMON O PANCREAS. _x000D_ EL GRUPO SOLICITANTE HA DESARROLLADO UNA TECNOLOGIA DE PRODUCCION DE NANOCAPSULAS FUNCIONALIZADAS (MULTIFUNCTIONAL POLYMERIC NANOCAPSULAS, MPN) CUYO POTENCIAL HA SIDO VALIDADO DE FORMA INDIVIDUALIZADA PARA DOS TIPOS DE FARMACOS: (I) EL CITOTOXICO DOCETAXEL, PARA EL QUE SE HA LOGRADO UNA ACUMULACION MASIVA EN TUMOR Y EN METASTASIS LINFATICAS Y (II) UN MAB, CUYA DIANA SE ENCUENTRA EN EL CITOPLASMA DE CELULAS TUMORALES. EL OBJETIVO DEL PROYECTO SE CENTRA EN OPTIMIZAR LA CITADA TECNOLOGIA, APLICANDOLA A DOS TIPOS DE MABS, DIRIGIDOS A DOS DIANAS DISTINTAS: LA ONCOPROTEINA KRASG12D, CUYA PRESENCIA ES RELEVANTE EN LAS CELULAS TUMORALES DE CARCINOMA DE PULMON Y DE PANCREAS; Y LA PROTEINA COL11A1, CUYA PRESENCIA EN LOS FIBROBLASTOS CONTRIBUYE A SU RIGIDEZ ESTRUCTURAL Y, CONSECUENTEMENTE, A LA PROGRESION Y DIFUSION DE LAS CELULAS CANCERIGENAS. LA COMBINACION DE AMBAS ESTRATEGIAS TENDRA, PREVISIBLEMENTE, UN CLARO IMPACTO EN EL DESARROLLO TUMORAL. ASIMISMO, SE PRETENDE COMBINAR LAS POTENCIALES TERAPIAS BASADAS EN MABS CON LA ADMINISTRACION DE CITOTOXICOS TALES COMO EL DOCETAXEL Y LA GEMCITABINA, GRACIAS A SU CO-ENCAPSULACION EN EL MISMO SISTEMA MPN. PARA ELLO, SE CUENTA CON LA EXPERIENCIA PREVIA DE LA FORMULACION DE AMBOS FARMACOS. ELLO SE TRADUCE EN 5 POSIBLES COMBINACIONES DE TRATAMIENTOS (MAB ANTI-KRASG12D + MAB ANTI-COL11A1; MAB ANTI-KRASG12D + DOCETAXEL; MAB ANTI-KRASG12D + GEMCITABINA; MAB ANTI-COL11A1+ DOCETAXEL; MAB ANTI-COL11A1+ GEMCITABINA). LA CAPACIDAD DE LAS MPN DE SER INTERNALIZADAS POR LAS CELULAS DIANA SE ESTUDIARA A TRAVES DE LA REALIZACION DE ESTUDIOS IN VITRO, EN LINEAS CELULARES ADECUADAS Y DE ESTUDIOS DE BIODISTRIBUCION IN VIVO EN MODELOS MURINOS. LA EFICACIA DE LOS TRATAMIENTOS SE EVALUARA EN MODELOS MURINOS, CON INJERTOS DE CELULAS CULTIVADAS Y/O EXTRAIDAS DE PACIENTES. ESTE ULTIMO ASPECTO SE HARA EN COLABORACION CON LA COMPAÑIA ONCOMATRYX BIOPHARMA._x000D_ EL CITADO OBJETIVO COMBINA UN ALTO RIESGO, ASOCIADO AL DESARROLLO DE NUEVOS MABS DIRIGIDOS A DIANAS INTRACELULARES, CON UN RIESGO BAJO ASOCIADO A UNA TERAPIA QUE DIRIGE EL DOCETAXEL O LA GEMCITABINA DE UNA MANERA SELECTIVA A LAS CELULAS DIANA. _x000D_ EL PRODUCTO FINAL CONSISTIRA EN UNA NUEVA TERAPIA QUE, DE FORMA INDIVIDUAL O COMBINADA (CITOTOXICO Y/O MAB), PERMITA UN TRATAMIENTO EFECTIVO DEL CANCER DE PANCREAS Y/O DE (Spanish)
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MONOCLONAL ANTIBODIES (MABS)-BASED THERAPIES ARE AMONG THE MOST ADVANCED ONES FOR THE TREATMENT OF CANCER. THE OBJECTIVE OF THE SO FAR MARKETED MABS-BASED THERAPIES IS TO REACH THEIR TARGETS AT THE LEVEL OF THE CELL MEMBRANE OF THE STROMA. UNFORTUNATELY, THERE ARE MANY PROTEINS LOCALIZED INSIDE CANCER CELLS AND OTHER RELEVANT CELLS SUCH AS ¿CANCER ASSOCIATED FIBROBLASTS, (CAFS), WHICH ARE CRITICAL FOR THE PROGRESSION OF CANCER BUT ARE INACCESSIBLE FOR POTENTIAL MAB-BASED TREATMENTS. THIS IS DUE TO THE INABILITY OF MABS OF CROSSING THE CELL MEMBRANE._x000D_ NANOTECHNOLOGY OFFERS A GREAT OPPORTUNITY TO DEAL WITH THIS PROBLEM DUE TO THE CAPACITY OF NANOCARRIERS TO TARGET SELECTIVELY ANTICANCER DRUGS TO THE TUMOR ENVIRONMENT AND ALSO INSIDE THE CELLS. CURRENTLY, IT IS GENERALLY ASSUMED THAT ONLY AN ACTIVE TARGETING STRATEGY, BASED OF THE USE OF NANOCARRIERS ENDOWED WITH THE CAPACITY TO DELIVER DRUGS AT THE INTRACELLULAR LEVEL WILL RESULT IN A DRAMATIC IMPROVEMENT IN THE TREATMENT OF AGGRESSIVE CANCERS, I.E. LUNG AND PANCREATIC CANCER._x000D_ OUR RESEARCH GROUP HAS DEVELOPED A TECHNOLOGY FOR THE PRODUCTION OF ¿MULTIFUNCTIONAL POLYMERIC NANOCAPSULES¿ (MPN), WHOSE POTENTIAL HAS BEEN VALIDATED SEPARATELY FOR TWO CATEGORIES OF DRUGS: (I) THE CYTOTOXIC DRUG DOCETAXEL, WHICH WAS SHOWN TO MASSIVELY ACCUMULATE IN TUMOR AND METASTATIC CELLS, UPON ASSOCIATION TO THE MPNS, AND (II) THE MONOCLONAL ANTIBODY, ANTI-GASDERMINE, WHOSE TARGET IS LOCALIZED IN THE CYTOSOL OF TUMOR CELLS. BASED ON THIS, THE OBJECTIVE OF THIS PROJECT IS TO OPTIMIZE THE MPN TECHNOLOGY AND TO ADAPT IT TO TWO DIFFERENT MABS WITH TWO DISTINCT TARGETS: KRASG12D CONCOPROTEIN, HIGHLY RELEVANT IN LUNG AND PANCREATIC CANCER; AND COL11A1, WHOSE PRESENCE IN THE FIBROBLASTS IS RESPONSIBLE FOR UNDESIRABLE CAF FUNCTIONS AND CONTRIBUTES TO THE DISSEMINATION OF CANCER CELLS. THE COMBINATION OF THESE TWO STRATEGIES MAY POTENTIALLY IMPACT THE TUMOR GROWTH. AN ADDITIONAL GOAL OF THIS PROJECT IS TO COMBINE THESE MABS-BASED THERAPIES WITH CYTOTOXIC DRUGS SUCH AS DOCETAXEL AND GEMCITABINA, THROUGH THE CO-ENCAPSULATION IN THE SAME MPN. FOR THIS WE COUNT WITH THE PREVIOUS EXPERIENCE ON THE ENCAPSULATION OF THESE CYTOTOXIC DRUGS. IN TOTAL, THIS WILL RESULT IN 5 POTENTIAL COMBINATORY TREATMENTS (MAB ANTI-KRASG12D + MAB COL11A1; MAB ANTI-KRASG12D + DOCETAXEL; MAB ANTI-KRASG12D + GEMCITABINE; MAB COL11A1+ DOCETAXEL; MAB COL11A1+ GEMCITABINE). THE CAPACITY OF THE MPN TO BE INTERNALIZED BY THE CELLS WILL BE STUDIED BOTH IN VITRO AND IN VIVO, USING THE PERTINENT MODEL CELL LINES AND MURINE MODELS. FINALLY, THE EFFICACY OF THE TREATMENTS WILL BE EVALUATED IN MURINE MODELS XENOGRAFTED WITH CULTURED CELLS OR PATIENT CELLS. THIS LAST STUDY WILL BE DONE IN COLLABORATION WITH THE COMPANY ¿ONCOMATRYX BIOPHARMA¿._x000D_ THIS OBJECTIVE COMBINES A HIGH RISK ASSOCIATED TO THE DEVELOPMENT OF NEW MABS TARGETED TO INTRACELLULAR PROTEINS, WITH A LOW RISK ASSOCIATED TO THE ACTIVE TARGETED DELIVERY OF DOCETAXEL OR GEMCITABINE._x000D_ THE FINAL POTENTIAL PRODUCT WILL BE A NEW THERAPY THAT, EITHER IN AN INDIVIDUAL OR COMBINATION THERAPY (CITOTOXIC DRUG AND/OR MAB) WILL LEAD TO THE EFFECTIVE TREATMENT OF PANCREATIC AND/OR LUNG CANCER. (English)
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Santiago de Compostela
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Identifiers
SAF2017-86634-R
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