Page 27 - MemoriaEHD-Eng

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Development and evaluation of methods for predicting response
Selection of to chemotherapy in liver, esophageal, stomach, pancreatic and

large projects
colorectal tumors.

PI: Marçal Pastor-Anglada and José J. García Marín.

The retrospective studies conducted by the CIBERehd using TLDAs have allowed
identifying groups of genes involved in different MoC, the expression of which is

characteristically high in hepatocarcinoma, hepatoblastoma, cholangiocarcinoma

and adenocarcinoma of the colon and pancreatic cancer. Some of these genes
encode proteins relating to drug uptake and expulsion by tumor cells, the main

pharmacological targets, the mechanisms of drug detoxification and DNA repair,

also including genes involved in cell proliferation and apoptosis. A very common
feature is the drop in expression of the SLC22A1 gene which encodes for an organic

cation transporter (OCT1), which is a determining factor in tumor cells absorbing
cationic drugs such as sorafenib. In addition, preliminary studies have detected

several inactivating mutations and aberrant splicing alternatives contributing to a

lower capacity to transport the drug across the plasma membrane. The group will
investigate if these changes also occur as a common characteristic in other gas-

trointestinal tumors. In turn, a retrospective multicentre study will be conducted

to elucidate if there is a relationship between disorders in the SLC22A1 gene and
the clinical response of patients to treatment with sorafenib. Furthermore, studies

aimed at investigating the mechanisms of control determining changes in the ge-

netic profile of tumors and determining the phenotype of the lack of response to
antitumor chemotherapy have indicated a nuclear receptor, FXR, and its interaction

with glucocorticoids as a possible control path relating to maintaining chemopro-
tection in healthy tissue and with the development of chemoresistance in tumor

tissue. Both aspects will be analyzed in depth in the immediate development of this

line of research.

Development and validation of biomarkers for the early diagno-
sis of colorectal cancer (EPICOLON III project)

PI: Antoni Castells and Luis Bujanda.

The progression of CRC is a complex multifactorial process involving interaction

between various genetic and epigenetic events. Better understanding of these phe-
nomena in the past decade has allowed developing molecular markers with clinical

utility potential (biomarker). Until now, the most significant advancements have

been made in the study of biomarkers in feces and in blood, based on genetic
disorders (somatic mutations in DNA) and epigenetic disorders of tumors (abe-
13
rrant DNA methylation, miRNA expression pattern disorder). However, essentially 20
all colorectal neoplasias are different and present molecular heterogeneity, which T
OR
complicates detection strategies. This is a critical consideration in developing CRC P
RE
biomarkers because no biomarker available today is capable of reliably detecting L
all CRCs. So the development of new non-invasive biomarkers (for determination A
NU
in biological fluids, such as blood or feces) with an approach that includes different N
A
types of molecules (DNA, methylation, miRNAs, proteins) in well-characterized po- D /
pulations, including patients with precursory lesions (particularly advanced adeno- H
E
ma) is fundamental.
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