Project proposal title: Novel targets to prevent Kidney failure in Dent’s patients
Principal Investigator: Anna Meseguer, PhD (VHIR)
Co-Principal Investigator: Vivek Malhotra, PhD (CRG)
Dent disease, a rare X-linked inherited disorder, is a proximal renal tubulopathy characterized by low-molecular-weight proteinuria, hypercalciuria and nephrocalcinosis that progresses to renal failure and fibrosis. We postulate that beyond the known functional effects of mutations in the ClC5 gene, there are mutation-associated pathways and mechanisms to be discovered regarding proximal tubule cell (PTC) function, that might better explain the (individual and familial) variability of the phenotype of Dent’s disease and the progression to fibrosis and end stage renal disease. Discovery of new genes and mechanisms relevant for proximal tubule function and, potentially, for the endosome-lysosome function, will lead to a better understanding of the fundamental processes affecting epithelial cell differentiation, regulation of transport mechanisms and role of tubular cells in renal disease progression; therefore providing with novel biomarkers and potential therapeutic targets for this disease.
Project proposal title: Role of dietary fatty acids in oral carcinoma metastasis
Principal Investigator: Coro Bescós Atin, MD PhD (VHIR)
Co-Principal Investigator: Salvador Aznar Benitah, PhD (IRB Barcelona)
Metastasis accounts for the vast majority of cancer-related deaths. For oral squamous cell carcinoma (OSCC), 50% of patients develop secondary lesions (mainly in lymph nodes and/or lungs) with a 40% overall survival rate. Therapeutic options for patients are limited, which translates into a clear unmet medical need. It is necessary to understand the mechanisms by which cells initiate and maintain metastatic growth to devise new OSCC treatments. We have recently identified which cells are uniquely responsible for the metastasis formation in OSCC, and they exhibit the following characteristics: i) they are exclusive in their ability to generate metastases; ii) they express the fatty acid translocase CD36, and express a unique lipid metabolic signature; iii) they directly link metastasis predisposition to dietary fat content; iv) they increase their metastatic initiation potency when treated with palmitic acid; v) they are highly sensitive to CD36 inhibition, which almost completely abolishes their metastatic potential in preclinical models (Pascual et al., Nature 2016). However, we still do not know the mechanism of action of CD36+ metastatic-initiating cells, and how extracellular free fatty acids and/or lipids contribute to metastatic progression in oral SCC. Here, we aim to uncover which fatty acids and/or lipids modulate metastatic stem cell functions and how they do it. To do so, we will combine human OSCC samples and metastatic orthotopic mouse models, with state-of-the-art quantitative transcriptomic, proteomic, metabolomic, and bioinformatic analyses to identify the effect of different dietary fatty acids in metastatic progression. We also aim at testing the effect of reducing the concentration of saturated fatty acids in the diet of patients with oral SCC, hence starting to translate our basic research results into the clinic.
Project proposal title: Prediction of therapeutic response of cancer patients by using STORM
Principal Investigator: Matilde Esther LLeonart Pajarín, PhD (VHIR)
Maria Pia Cosma, PhD (CRG)
This projects aims to predict the chemotherapeutic response from at least 50 patients with head and neck cancer (HNSCC) by using a super-resolution fluorescence microscopy (Stochastic Optical Reconstruction Microscopy: STORM). Preliminary results point out that the heterogeneity of HNSCC-Cancer Stem Cells (CSCs) determines the therapeutic response of such patients. Therefore the chromatin status of HNSCC-CSCs will be correlated with their clinical evolution.
Project proposal title: Integrative genomic analysis and drivers in extrahepatic cholangiocarcinoma
Principal Investigator: Josep M Llovet, MD PhD (IDIBAPS)
Co-Principal Investigator: Roger Gomis, PhD (IRB Barcelona)
Cholangiocarcinoma (CCA) is an emerging medical global problem with a rising incidence in Western countries. Treatment options for CCA, including intrahepatic (iCCA) and extrahepatic (eCCA), are limited, and no molecular targeted therapies have been approved so far. There is a limited understanding of the pathogenesis and its main drivers, as opposed to iCCA. The proposal is aimed at #1 Establish a molecular classification for eCCA, and #2 Determine and functionally validate the main driving candidate genes. For this purpose, we will assess the mutational and transcriptomic profile of 200 eCCA tumors already collected. In addition, once driver candidates have been defined, we will assess their oncogenic potential in cell lines, orthotopic and genetically engineered mouse models. Targeted therapies will be also assayed. The identification molecular subclasses and key drivers will enable a better understanding of the pathogenesis and appropriate targeted treatments for eCCA.
Project proposal title: Identification of neuromelanin-based pathophysiological pathways and candidate biomarkers in the prediagnostic phase of Parkinson’s disease
Principal Investigator: Miquel Vila, MD PhD (VHIR)
Co-Principal Investigator: Eulàlia Martí, PhD (CRG)
In Parkinson's disease (PD), there is a selective degeneration of neurons that contain a dark-brown pigment called neuromelanin (NM), especially dopaminergic (DA) neurons of the substantia nigra (SN) and noradrenergic (NA) neurons of the locus coeruleus (LC). In humans, NM appears in early childhood and accumulates progressively with age, and increasing age is the main risk factor for developing PD. However, the physiological significance of NM and its potential contribution to PD pathogenesis remain unknown because, in contrast to humans, commonly used laboratory animals, such as rodents, lack NM. To overcome this obstacle, we have recently generated genetically engineered humanized rodent models exhibiting age-dependent production and intracelular accumulation of human-like NM within PD-vulnerable neuronal groups. Using these animals we have found that progressive, agedependent intracellular accumulation of NM initiates PD-linked neuronal dysfunction/degeneration when reaching a certain threshold. To further understand how progressive intracellular NM accumulation interferes with normal cell function, in this project we will determine the transcriptomic changes associated to age-dependent intracellular NM accumulation, both in our newly generated NMproducing animals as well as in postmortem human brains. This study will lead to the identification of novel NM-related pathophysiological pathways linked to PD and to the discovery of novel candidate risk biomarkers for PD.
Project proposal title: Next generation sequencing for identification and characterization of clinically relevant drivers in advanced non-small cell lung cancer (NSCLC) and potential new mechanisms of resistance
Principal Investigator: Noemi Reguart, MD PhD (IDIBAPS)
Co-Principal Investigator: Núria López-Bigas, PhD (IRB Barcelona)
The discovery of targetable drivers in NSCLC has revolutionized the treatment of selected groups of patients. Patients with druggable gene fusions involving ALK and other kinases and splicing variants in MET show exceptional responses to kinase inhibitors but ultimately relapse. This project aims to use NGS techniques to characterize gene fusions and splicing variants and to identify new mechanisms of resistance.
Project proposal title: Precision medicine for children and adolescents with solid tumors
Principal Investigator: Soledad Gallego Melcon, MD PhD (VHIR)
Co-Principal Investigator: lvo Glynne Gut (CNAG-CRG)
In developed countries, survival of children and adolescents with cancer approximates 80%. Despite general good results, 20% of tumours rema in incurable. There is an unmet need to develop new anti-cancer drugs to improve survival of high risk, refractory or relapsed tumours, and reduce the burden of long-term toxicities for survivors.
The aim of the project is to establish a precision medicine program for all children and adolescents with high risk, refractory or relapsed salid tumours diagnosed or treated in the Hospital Vall d'Hebron (HVH). The molecular profile of the tumour will be analyzed using WES (Whole Exorne Sequencing) and RNA seq (RNA sequencing). Complementarily, the development of POOX (patient-derived orthotoplc xenograft) will be used to test tailored therapies according to the molecular profile. This strategy pretends to prioritize the most successfully therapies, preventing the patient from being exposed to ineffective treatments. The project will be developed at the Paediatric Oncology Unit of HVH led by Ora Soledad Gallego, and in collaboration with The Centre Nacional d' Analisi Genomica (CNAG), a non-profit organization funded by the Spanish Ministry of Economy and Competitiveness and the Catalan Government with extensive experience in sequencing, data analysis, data banking and data serving, led by lvo Glynne Gut.
Project proposal title: Multiple System Atrophy: Synuclein Regulation and Biomarkers Discovery
Principal Investigator: Gian Gaetano Tartaglia, PhD (CRG)
Co-Principal Investigator: Maria José Martí, MD PhD (IDIBAPS)
Multiple system atrophy (MSA) is a fatal neurodegenerative disorder associated with motor impairment and autonomic failure. Its defining neuropathological feature is the presence of glial cytoplasmic inclusions (GCIs) in oligodendroglia, formed by fibrillar alpha-synuclein protein. Yet the clinical and neuropathogical characterization of MSA is incomplete, disease-specific biomarkers are lacking, and pathophysiology remains largely unknown. The candidate will participate in an on-going collaboration between IDIBAPS (Dr. Martí) and CRG (Dr. Tartaglia) that aims to unravel regulatory factors of alpha-synuclein and MSA biomarkers. The work is designed to combine clinical assessment with experimental and in silico work.
Project proposal title: Splicing factor mutations in hematological malignancies
Principal Investigator: Dolors Colomer, PhD (IDIBAPS)
Co-Principal Investigator: Juan Valcárcel, PhD (CRG)
The groups of Dolors Colomer and Juan Valcárcel are already actively collaborating to study the impact of pre-mRNA splicing in the pathogenesis of -and potential therapies for- Chronic Lymphocytic Leukemia (CLL). The goal of the PhD project is to integrate clinical and molecular data to evaluate the antitumor activity of spliceosome modulators in in vitro and animal models of CLL, its dependence on the mutational status of splicing factors and the possibilities to combine these with other hemotherapies. The final aim is to identify key transcriptome changes and splicing regulatory mechanisms that can explain the pathogenic effects of splicing mutations and the therapeutic effects of drugs, as the basis for improved and personalized treatments.