Tipificació molecular de tumors neuroendocrins gastroenteropancreàtics. Desenvolupament de noves teràpies i búsqueda de nous biomarcadors

Abstract

The knowledge of the molecular biology of the neuroendocrine tumors carcinogenesis is still limited today. This fact has limited predictive and prognostic biomarker identification and the development of therapies aimed at this population of patients. The aim of this work was to identify genomic and epigenomic changes of neuroendocrine tumors of gastrointestinal tract and assess the possibility of creating mouse models derived from patients as a prelude to the design of clinical studies in patients based on the molecular alterations observed. The work has focused on primary colonic neuroendocrine carcinomas, a rare, treatment orphan and highly aggressive tumor._x000D_ Initially, through the national group of endocrine tumors (GETNE) paraffin-embedded tumor samples were identified of patients with neuroendocrine carcinoma of primary colonic. After centrally pathological confirmation genomic and epigenomic studies have been conducted to characterize the molecular alterations of this tumor type. Meanwhile, it has managed to create an animal model derived from patients with neuroendocrine carcinoma carrier of the gene mutation in BRAF to carry out experiments in vitro with targeted therapies against this mutation. In summary, the results have enabled us to identify the most prevalent mutations in neuroendocrine carcinomas of the colon, highlighting the high percentage of mutations V600E in the gene BRAF compared with the adenocarcinoma of the colon. Also, the DNA methylation profile of neuroendocrine carcinoma of the colon is significantly different from that observed in adenocarcinomas of the colon, which together with the genomic profile and chromosomal instability observed in neuroendocrine carcinomas confirm the differences in the origin of the two cancers, the molecular biology of both cancer types and the likelihood of response to targeted therapies confirmed in the PDX models._x000D_ The results of this doctoral thesis will continue with the study of the molecular characteristics of this patient population, the search for new biomarkers and the design of clinical trials aimed for an orphan patient population currently lacking of effective treatment.

Date of Award	27 Sept 2016
Original language	Undefined/Unknown
Awarding Institution	Vall d'Hebron University Hospital (HUVH)
Supervisor	Jorge Luis Giralt (Tutor) & Josep Maria Tabernero Caturla (Director)