Selección de proyectos

  • Personalized therapy for lung cancer with distinct mutational landscape through 3D organoid cultures

    Project title: Personalized therapy for lung cancer with distinct mutational landscape through 3D organoid cultures.
    Funding agency: BBVA (Becas Leonardo) .
    Duration: 18 months. from: 30/09/2018  to: 31/03/2020
    Amount: 40.000 €
    Principal Investigator: Silvestre Vicent.

    Summary:
    Lung adenocarcinoma (LUAD) constitutes the largest histo-molecular type of lung cancer. LUAD is characterized by a plethora of oncogenic drivers where KRAS are the most frequently detected. However, to date there are no effective therapies agains patients harbouring KRAS mutations, what is in contrast with targeted therapies against other oncogenic drivers such as EGFR, EML4-ALK, BRAF or MEK. In addition, concurrent mutations with KRAS in a diverse spectrum of tumor suppressor genes influence patient survival and therapy response, what increases the complexity of patient treatment even in cases where tumors are triggered by the same oncogenic driver.

    We propose to unveil personalized therapies for patients with KRAS mutations and coexisting mutations in various tumor suppressor genes taking advantage of the CRISPR/Cas9 technology, genetically-engineered mouse models and drug libraries. Our work will serve to discover new tailored treatments with medium-term implications for the treatment of LUAD patients.

  • Regulation of cell and non-cell autonomous mechanisms by novel synthetic-lethal interactions with KRAS

    Project title: Regulation of cell and non-cell autonomous mechanisms by novel synthetic-lethal interactions with KRAS: functional, molecular and clinical implications in lung cancer.
    Funding agency: MINECO (SAF2017-89944-R).
    Duration: 36 months. from: 01/01/2018 to: 31/12/2020
    Amount: 140.000 €
    Principal Investigator: Silvestre Vicent.

    Summary:
    KRAS represents the most frequently mutated oncogene in several solid tumors including lung adenocarcinoma (LUAD) where it associates with poor prognosis due to the lack of curative options. Previously we have described, through a multimodal strategy integrating cross-species transcriptome analyses and a bioinformatics approach of clinical data from multiple tumor types driven by mutant KRAS, a critically convergent and necessary gene signature for tumor homeostasis (Vallejo et al., Nature Communications, 2017). Subsequent functional and mechanistic dissection identified a member of this signature, FOSL1, as avulnerability in LUAD and other incurable solid tumors, demonstrating the robustness of our computational-clinical-functional strategy.

    This gene signature includes additional genes which are overexpresed in oncogenic KRAS tumors with potential clinical and functional relevance. In preliminary results we have determined the dependence on the expression of mutant KRAS of a new member of this signature and found that high expression levels of this gene associate with dismal prognosis in LUAD patients. We postulate that this gene constitutes a key element induced by oncogenic KRAS whose mechanism of action involves tumor cell and non-cell autonomous functions. In this project we will focus on understanding part of its mechanism of action in the context of KRAS oncogenesis in LUAD. 

    This project will contribute to define the role of a new KRAS effector and its regulated events in LUAD. Future studies will be aimed to assess potential inhibitory compounds against this protein or its mediators in preclinical models.   

  • Dissecting the role of KRAS-driven miRNAs in Lung Cancer

    Project title: Dissecting the role of KRAS-driven miRNAs in Lung Cancer.
    Funding body: Worldwide Cancer Research (16-0224).
    Duration: 36 months. from: 01/01/2016  to: 30/06/2019
    Amount: 159.000 €
    Principal Investigator: Silvestre Vicent.

    Summary:
    Lung cancer is the deadliest cancer in U.S. Lung cancer involves two major groups, Small-Cell Lung Cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC). NSCLC represents 80% of lung cancer cases, and includes the most prevalent lung cancer subtype, lung adenocarcinoma (LUAD). Around 30% of LUAD patients harbor mutations in KRAS oncogene. However, mutant KRAS remains refractile to pharmacological inhibition. Thus, a more detailed insight on the functional and molecular mechanisms involved in oncogenic KRAS signaling as well as their clinical impact in LUAD remains imperative for the identification of novel target genes.

    MicroRNAs (miRNAs) are small non-coding RNAs that act as post-transcriptional regulators of mRNA target genes, and have been involved in a plethora of biological functions. Preliminary results from our group unveiled a miRNA cluster as a potential downstream effector of oncogenic KRAS. Of note, genetic germ-line and conditional deletion of the cluster containing this cluster using genetically-engineered mouse models led to decreased tumor burden and increased overall survival, what strongly suggest a prominent role in LUAD. Thus, the current proposal will follow an integrative approach using mouse genetics, in vitro analysis and human specimens to delineate the functional and clinical role of this miRNA cluster in KRAS-driven LUAD.


"Estamos muy interesados en identificar nuevas dianas moleculares en tumores dependientes de KRAS y en descubrir estrategias terapéuticas innovadoras para el tratamiento de estos tumores", Dr. Silve Vicent.

Contactar

Contacto:
Marisol Ripa
Avda. Pío XII, 55
31008 Pamplona
España

(+34) 948 194 700 Ext. 1010
msripa@unav.es