Optimisation of Gemcitabine-based chemoradiotherapy by a Poly-ADP ribose polymerase in pancreatic cancers
Description
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a cumulative 5- year overall survival of less than 9% for all stages. Current research that combine radiation with targeted therapy dramatically improve prognosis. We investigated preclinical outcomes of PARP inhibitor associated with radiotherapy and gemcitabine. In vitro, treatment with olaparib alone was not cytotoxic, but highly radiosensitized cell lines. The addition of olaparib to gemcitabine-based chemoradiotherapy enhanced significantly local control in vivo, especially with proton therapy. Whole-transcriptome analysis presented several dysregulated IncRNA and genes associated with extracellular vesicles. Finally, talazoparib enhanced radiation effect on PDAC cell lines by inhibiting PARylation and by enhancing PARP-1 trapping, compared to olaparib. (author)
Abstract (French)
L'incidence de l'adenocarcinome pancreatique (PDAC) est en nette augmentation en France durant ces dernieres annees. Son pronostic reste tres pejoratif avec une survie globale a 5 ans inferieure a 9%. Environ 30% des patients se presentent avec un cancer localement avance pouvant beneficier d'une chimioradiotherapie. Ce travail de these a evalue le potentiel de l'inhibition de la PARP par l'olaparib associe a la chimioradiotherapie a base de gemcitabine dans les PDAC. Apres avoir montre la radiosensibilisation in vitro sur 4 lignees cellulaires BRCA1/2 sauvage, nous avons valide cette radiosensibilisation in vivo et plus particulierement avec la protontherapie. L'analyse des donnees transcriptomiques apres traitement a montre une deregulation des genes impliquees dans la regulation des microvesicules, des ARN longs non codants et a identifie une signature associee au traitement par la gemcitabine. Enfin, en evaluant le talazoparib, nous avons montre que la radiosensibilisation est augmente comparativement a l'olaparib. (auteur)
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Additional details
Additional titles
- Original title (French)
- Optimisation de la chimioradiotherapie a base de gemcitabine par un inhibiteur de poly(ADP-ribose) polymerase dans les cancers du pancreas
Publishing Information
- Imprint Pagination
- 168 p.
- Report number
- FRNC-TH--14495
INIS
- Country of Publication
- France
- Country of Input or Organization
- France
- INIS RN
- 54066988
- Subject category
- S62: RADIOLOGY AND NUCLEAR MEDICINE;
- Resource subtype / Literary indicator
- Thesis
- Descriptors DEI
- ADENOMAS; ANTIMETABOLITES; APOPTOSIS; CELL CULTURES; CHEMOTHERAPY; COMBINED THERAPY; DNA REPAIR; ENZYME INHIBITORS; IN VITRO; IN VIVO; ION BEAM THERAPY; PANCREAS; PATIENTS; POLYMERASES; RADIOSENSITIVITY; RADIOSENSITIZERS; RNA; TUMOR CELLS
- Descriptors DEC
- ANIMAL CELLS; BIOLOGICAL RECOVERY; BIOLOGICAL REPAIR; BODY; CARCINOMAS; DIGESTIVE SYSTEM; DISEASES; DRUGS; ENDOCRINE GLANDS; ENZYMES; EXTERNAL BEAM RADIATION THERAPY; GLANDS; MEDICINE; NEOPLASMS; NUCLEAR MEDICINE; NUCLEIC ACIDS; NUCLEOTIDYLTRANSFERASES; ORGANIC COMPOUNDS; ORGANS; PHOSPHORUS-GROUP TRANSFERASES; PROTEINS; RADIOLOGY; RADIOTHERAPY; REPAIR; RESPONSE MODIFYING FACTORS; SENSITIVITY; THERAPY; TRANSFERASES
Optional Information
- Notes
- 158 refs.; Available from the INIS Liaison Officer for France, see the INIS website for current contact and E-mail addresses