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FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III

Country: Spain

FUNDACION CENTRO NACIONAL DE INVESTIGACIONES ONCOLOGICAS CARLOS III

94 Projects, page 1 of 19
  • Funder: European Commission Project Code: 617840
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  • Funder: European Commission Project Code: 101105041
    Funder Contribution: 181,153 EUR

    Ovarian Cancer (OC) is the most lethal gynecological tumor and has an especially high impact in Europe. 70% of patients develop an advanced stage due to the lack of early diagnosis tools and chemotherapy resistance. Therefore, a better understanding of altered molecular mechanisms driving OC progression is needed. Preliminary data from the host lab suggest that a complex formed by R2TP/TTT/WAC upon glucose and glutamine depletion, impairs mTOR activation. Moreover, the components of this complex are co-expressed in OC, a disease influenced by mTOR signaling and metabolic reprogramming. Thus, our hypothesis is that WAC regulates an mTOR activation pathway that influences OC progression and response to chemotherapy and that targeting this complex is a potential therapeutic prospect for the treatment of OC. In particular, we propose to (i) establish the mechanism and role of the R2TP/TTT/WAC/mTOR complex in OC and (ii) to identify new therapeutic strategies targeting this complex for the treatment of OC. We have envisioned this project as a diverse node of cancer signaling and protein experts, with a predicted outcome highly transferable to society. The translational character of this proposal, from molecular mechanism to therapeutics, relies on the integration of an interdisciplinary team formed by the host group proficiency in Structural Biology and my expertise in Molecular Biology and Drug Discovery, together with scientific experts on Experimental Therapeutics and Bioinformatics from the host institution and collaborators. Importantly, I will have the opportunity to develop new professional skills by both scientific exchanges and specific courses and to participate in dissemination activities to translate our findings to the scientific community and society. Thus, the MSCA fellowship will allow me to develop unique technical and transferable skills, to help me progress in my career developmental plan and establish myself as a leader in cancer research in Europe.

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  • Funder: European Commission Project Code: 893597
    Overall Budget: 160,932 EURFunder Contribution: 160,932 EUR

    Breast cancer is the most common cancer among women with significant death rates and economic impact. In daily routine clinics, breast cancer is usually classified on the basis of three immunohistochemical markers (ER, PR and HER2). Triple-negative breast cancer (TNBC) is a subtype defined by the negativity of all these markers, which shows an adverse clinical course. It is characterized by a considerable gene expression heterogeneity that leads to a lack of availability of targeted therapies. Positive clinical trials relying on various forms of immunotherapy have shifted the paradigm of diverse malignancies from cytotoxics to novel immunomodulator drugs. The results in TNBC, however, are not as positive. In a recent taxonomic effort of the hosting group, TNBC has been re-classified on the basis of the activation status of six protein kinases, which in turn constituted novel targets for this disease. One of them, the 70-kDa ribosomal protein S6 kinase (P70S6K), which was associated with an adverse clinical outcome, showed negative correlation with tumor-infiltrating lymphocytes (TILs) abundance. The fact that P70S6K has been associated with immunosuppressive mechanisms and that there is a positive correlation between the number of TILs and the clinical outcomes in TNBC, suggests that the role of P70S6K may be related to pleiotropic and/or opposing properties of tumor progression. By using a combination of multiparametric flow cytometry, bulk/single-cell gene expression analysis and in vivo experiments in mouse models, this proposal aims to unravel the impact of P70S6K modulation over the already known relevant immune-oncology targets/axes as well as the therapeutic consequences of P70S6K blockade in TNBC. These studies will provide a better understanding of the lymphocyte-related responses modulated by P70S6K, with the potential to find new therapies for patients suffering from TNBC and possibly a broader range of malignances.

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  • Funder: European Commission Project Code: 753442
    Overall Budget: 170,122 EURFunder Contribution: 170,122 EUR

    Melanoma is the cancer with the fastest rising incidence world-wide, and although recent therapies can achieve unprecedented response rates, a significant fraction of patients still succumb to metastatic lesions. Key pending questions in the field are the mechanisms underlying the inherent metastatic behaviour or melanoma, whereby seemingly thin primary lesions (≥2 mm in depth) bear high risk of dissemination to proximal lymph nodes and ultimately, to distal sites. A dynamic crosstalk has been proposed to be established between melanoma cells and the lymphatic vasculature at tumour-draining lymph nodes, favouring an immune-permissive “lymphovascular niche”. However, whether (and how) these lymphovascular interactions occur at distal sites is unclear. The Soengas group has generated unique “Lymphoreporter” melanoma mouse models for non-invasive and whole body imaging of tumour progression. These lymphoreporters demonstrated that primary melanomas induce neo-lymphangiogenesis at distal pre-metastatic sites, already from very early stages of the disease, before dissemination occurs. Proteomic analyses were then performed to identify factors in the melanoma secretome that could drive these long range-acting effects and subsequently filtered these proteins for novelty (i.e. no previous link to melanoma and lymphangiogenesis). Here I will focus on the top-ranking factors in this screening. In particular, I will define the impact of these newly-identified melanoma secreted factors on tumour progression and metastasis, focusing on key components of the lymphovascular niche (i.e. on the crosstalk of tumour- vasculature-immune system). Secondly, I will assess the impact of these genes as prognostic biomarkers and indicators of response to clinically-relevant treatments. These studies will be performed in collaboration with dermatologists, pathologists and oncologist to define the physiological relevance of our work.

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  • Funder: European Commission Project Code: 250297
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