Worlwide Cancer Research – Research Projects
Título/Title: Dissecting the roles of Fra proteins in lung adenocarcinoma progression and metastasis
Ref.: 13-0216
Investigador Principal/Principal Investigator: Wagner, Erwin
Fecha Inicio/Starting Date: 01/01/2013
Fecha Fin/Ending Date: 02/12/2016
Presupuesto/Budget: £151.364,00
Comentarios/Comments: Worlwide Cancer Research (formerly known as AICR)
Resumen/Summary
The two closely related transcription factors, Fra-1 and Fra-2, which are members of the AP-1 family, are expressed in a large variety of cancers in mice and human. Mitogen stimulation of Fra protein expression has been shown to be mediated by the Ras/Raf/MEK/ERK pathway and Fra proteins can regulate the expression of Cyclins, β1-integrin, MMPs and Zeb transcription factors. In some epithelial cancer cell lines, Fra proteins can induce epithelial to mesenchymal transition. In addition, over-expression of Fra proteins can induce lung epithelial cell invasion and anchorage-independent growth in vitro, but is insufficient for lung tumor formation in vivo. We have reported that Fra-2 over-expression is sufficient to cause pulmonary fibrosis in vivo. Our preliminary results show increased expression of Fra-2 Myc and p120 in lung adenocarcinoma patient samples and their expression correlates in mouse pulmonary epithelial cells in vivo. Therefore, we propose to generate genetically engineered mouse models (GEMMs) to over-express or eliminate Fra-2 at different time points during lung tumor progression in the background of K-Ras oncogene activation. Through multidisciplinary approaches including mouse genetics, molecular and cell biology, integrative genomic and translational research methods, we will characterize the GEMMs and define the roles of Fra-2, Myc and p120, in lung cancer. In addition, we propose to explore new molecular pathways regulated by Fra-2 during tumor progression and/or metastasis using deep sequencing technologies. Thus, discovering the molecular functions of Fra-2 during lung adenocarcinoma development will help to understand lung oncogenesis and develop new strategies for targeted therapies.
Worlwide Cancer Research – Research Projects
Título/Title: New therapeutic strategies by inhibiting Mastl in breast tumors
Ref.: 15-0278
Investigador Principal/Principal Investigator: Malumbres Martínez, Marcos
Fecha Inicio/Starting Date: 01/01/2015
Fecha Fin/Ending Date: 31/12/2017
Presupuesto/Budget: £198.500,00
Comentarios/Comments: Worlwide Cancer Research (formerly known as AICR)
Resumen/Summary
Mastl, also known as Greatwall in Xenopus and Drosophila, is a kinase recently reported to be involved in the control of PP2A phosphatases during mitosis. Greatwall was originally identified in Drosophila as a kinase required for proper chromosome condensation. Mastl/Greatwall inhibits phosphatase complexes formed of PP2A and B55 regulatory subunits (B55alpha-delta; also known as PPP2R2A-D). Inhibition of PP2A-B55 complexes by Mastl occurs in a kinase-dependent manner through the phosphorylation of small proteins of the endosulfine family. Inhibition of Mastl results in restoration of PP2A activity and defective chromosome segregation. Whereas the relevance of Mastl in human cancer is mostly unknown, preliminary data in our laboratory indicates that Mastl is overexpressed in a significant percentage of breast tumors, correlates with poor prognosis, and its inhibition results in defective proliferation of tumor cells. Depletion of this kinase results in restoration of the activity of PP2A-B55, a phosphatase with potent tumor suppressor activity in multiple cancers including breast tumors, in which PP2A-B55 is frequently deregulated. In specific tumor cells, Mastl ablation not only prevents mitotic progression but arrests cells in G1 in the absence of mitotic defects, suggesting a new mitosis-independent function with therapeutic value. We therefore propose here that inhibition of Mastl may have therapeutic benefits in specific tumors, not only by preventing chromosome segregation but also through the PP2A-dependent inhibition of major mitogenic routes in these tumor cells.
Worlwide Cancer Research – Research Projects
Título/Title: Oral microbiotic profiles and its association with risk of pancreatic ductal adenocarcinoma
Ref.: 15-0391
Investigador Principal/Principal Investigator: Malats Riera, Núria
Fecha Inicio/Starting Date: 01/04/2015
Fecha Fin/Ending Date: 31/03/2018
Presupuesto/Budget: £196.071,00
Comentarios/Comments: Worlwide Cancer Research (formerly known as AICR)
Resumen/Summary
Pancreatic ductal adenocarcinoma (PDAC) is a dreadful disease. Unfortunately, no advances have been made towards its control in the last decades. Chronic inflammation plays an important role in pancreatic carcinogenesis. Recent studies have highlighted the importance of the microbiota diversity and abundance on the development and progression of different diseases, including PDAC. However, current studies regarding PDAC are limited either by sample size and/or the targeted analysis of bacterial species. Additional evidence points to a complex association clouded by the interaction of the microbiota with different host factors. Therefore, this project seeks to identify specific microbiotic profiles in saliva and feces associated with PDAC, as well as to integrate the joint effect of the microbiota profiles and known risk factors of PDAC. We will work with PDAC cases and controls already recruited in the PanGen-EU study with availability of environmental and host-genetic data. We will first determine the oral microbiota for 50 cases and 50 controls using a metagenomic approach in saliva samples and determine the microbiotic profile (bacterial species differentially observed in both groups), this profile will be then evaluated in stool samples (50 cases and 50 controls) and in a larger set of saliva samples (700 cases and 700 controls). In addition, we will develop a risk model to evaluate the association between the microbiotic profile and PDAC risk while integrating other PDAC risk factors and exploring for their effect modification in order to make a more accurate assessment of PDAC risk. A better understanding of the association between human microbiota and PDAC has the potential of generating new clues of PDAC etiology and of creating and implementing primary and secondary (screening) public health prevention interventions to reduce the incidence and mortality of this disease.
Worlwide Cancer Research – Research Projects
Título/Title: Targeting regulatory mechanisms for allosteric cancer drug discovery
Ref.: 15-1177
Investigador Principal/Principal Investigator: Lietha, Daniel
Fecha Inicio/Starting Date: 01/06/2015
Fecha Fin/Ending Date: 30/10/2018
Presupuesto/Budget: £161.645,00
Comentarios/Comments: Worlwide Cancer Research (formerly known as AICR)
Resumen/Summary
Although enormous progress in basic cancer biology over the last decades has pinpointed key drivers of tumour formation and progression for the development of targeted cancer therapies, this has not been accompanied by a corresponding success in efficacious therapeutics. For Focal Adhesion Kinase (FAK), a key mediator of growth and adhesion signals, there is ample evidence that specific FAK inhibition can be a successful strategy to treat a number of solid tumours, in particular when combined with conventional cancer therapies. However, most current FAK inhibitors are ATP-site inhibitors that lack high specificity and therefore exhibit toxicity.
In this proposal we aim to discover allosteric FAK inhibitors that are likely much more specific, since allosteric regulatory mechanisms are not conserved across different kinases. Allosteric sites are often shallow pockets that are difficult to target. Therefore we propose a fragment-based ligand discovery strategy using smaller-than-druglike compounds for initial screening. We will apply two approaches: (1) Experimental screening using 19F-NMR to detect weak binders; and (2) a virtual screening approach using fragment-like virtual compound libraries. Validated binders will be structurally characterized to guide their elaboration into higher affinity compounds. The structural information together with our mechanistic insight will further allow tailoring the optimisation of hits into compounds that can block the activation sequence of FAK at specific steps. Our substantial preliminary data indicates that allosteric targeting of FAK is feasible within the timeframe of this project.
Targeting allosteric sites is challenging, and we believe requires a detailed structural and mechanistic understanding of native regulatory mechanisms. We recently uncovered a detailed multistep activation mechanism for FAK. Here we aim to utilize this information for the discovery of highly selective allosteric ligands that target FAK and provide lead compounds for the development of allosteric drugs to treat cancer.
Worlwide Cancer Research – Research Projects
Título/Title: Defining the role of macrophage-derived Wnts in squamous cell carcinoma
Ref.: 15-1219
Investigador Principal/Principal Investigator: Pérez Moreno, Mirna Alicia
Fecha Inicio/Starting Date: 01/06/2015
Fecha Fin/Ending Date: 31/12/2017
Presupuesto/Budget: £200.458,00
Comentarios/Comments: Worlwide Cancer Research (formerly known as AICR)
Resumen/Summary
Wnt signaling plays a central role in regulating the properties of numerous multipotent stem cells in adult tissues, such as skin and intestine. These signals function as short-range morphogens that are secreted from one cell or tissue type to activate surface receptors, signal transduction components and transcription factors in neighboring cells, regulating processes such as cell proliferation, survival or differentiation. The activity of Wnt signals is tightly regulated, whereas in cancer and other diseases they can escape this control.
In our laboratory we use skin as a model system, where it is well established that Wnt signals regulate the lifetime cyclic activation of stem cells in the hair follicle. Previous results from our laboratory have implicated macrophages in the cyclic initiation of hair growth by fueling stem cell activity. Of note, we have observed that a subset of macrophages surrounding the hair follicle stem cell compartment display an increase in the expression of Wnt ligands. Moreover, the short term pharmacological inhibition of macrophage-derived Wnts restricts hair follicle stem cell activation and hair growth.
Here, we propose to use mouse genetic approaches to analyze the effects of the loss of macrophage-derived Wnts in the control of cancer stem cells (CSC) in squamous cell carcinoma (SCC). Our main goal is to analyze if macrophage-derived Wnts causally contribute to CSC growth, thereby to tumor progression and maintenance in skin SCC. By defining the involvement of the enviromental cues in the regulation of skin stem cells, we are likely to uncover new targets for the development of cancer therapies.
Worlwide Cancer Research – Research Projects
Título/Title: Harnessing endo/exocytosis for a coordinated targeting of melanoma cells, their vasculature and the immune system
Ref.: 15-1374
Investigador Principal/Principal Investigator: Soengas González, María Soledad
Fecha Inicio/Starting Date: 01/06/2015
Fecha Fin/Ending Date: 31/05/2018
Presupuesto/Budget: £224.000,00
Comentarios/Comments: Worlwide Cancer Research (formerly known as AICR)
Resumen/Summary
Cutaneous melanoma is the deadliest form of skin cancer. Despite unprecedented clinical improvements in the last few years, long term survivors are still a minority in this disease. This proposal aims to validate novel anticancer agents that act by deregulating vesicular trafficking (involving endo and exocytosis) as strategy to target tumor cells and their microenvironment. This concept stems from the identification of a hyperactive endocytic activity in melanoma cells, which needs to be properly resolved to sustain tumor progression. Moreover, we found vesicular trafficking to define the fate (i.e. degradation vs secretion) of multiple factors with prometastatic activities. These include mediators of bidirectional interactions between melanoma cells, their vasculature and the immune system. Therefore, vesicular trafficking has the potential to exert therapeutic effects at a distance, beyond tumor cells. Screening for agents that could target endo/exocytic programmes in a selective manner, we found dsRNA nanoplexes as a new class of compounds able to (i) promote self-killing of melanoma cells, (ii) repress lymphangiogenesis, and (iii) recruit and activate key immune effectors. Here we have assembled an international team of experts in molecular biology, oncology, dermatology and pathology, to define the mechanisms underlying the three-pronged activity of dsRNA mimics (Aim 1). Aim 2 will validate these compounds as stimulatory agents to bypass the resistance to immune checkpoint blockers, a treatment modality actively pursued in the clinic. For physiological implementation of our results, human patient biopsies will be combined with an innovative set of “metastasis alert” mice engineered for non invasive imaging of melanoma development. Ultimately, we intend to use this information to support IND (Investigational New Drug) application to regulatory agencies. dsRNA sensors and immunomodulators are being evaluated in multiple tumor types. Therefore, our data may have a broad basic and translational impact in the oncology field.
Worlwide Cancer Research – Research Projects
Título/Title: Targeting telomeres in cancer
Ref.: 16-1177
Investigador Principal/Principal Investigator: Blasco Marhuenda, Maria A.
Fecha Inicio/Starting Date: 01/06/2016
Fecha Fin/Ending Date: 31/05/2019
Presupuesto/Budget: £249.999,00
Comentarios/Comments: Worlwide Cancer Research (formerly known as AICR)
Resumen/Summary
Telomeres are complexes of DNA and proteins (shelterins: TRF1, TRF2, TIN2, POT1, RAP1 and TPP1), located at the end of lineal chromosomes contributing to chromosome capping. Telomeres are considered anti-cancer targets, as telomere maintenance above a minimum length is necessary for cancer growth. This project aims the identification and development of small molecules affecting binding of shelterins to the telomeres, thus affecting telomere capping, and therefore compromising cancer cells survival. For this purpose, we have developed a cellbased system for high-throughput screening (HTS) in collaboration with the Experimental Therapeutic Program (ETP) at CNIO to screen for molecules that interfere with TRF1 binding to telomere. We carried out a small screening with 640 compounds and had identified several compounds. In order to determine the mechanism of action of these hits we will perform a biological validation, a deconvolution phase, as well as a chemical exploration around them to establish the structure activity relationships (SAR). A bigger screening of ETP-5000 compounds and a virtual screening are planned as strategy to enrich the possibilities to find out a good hit compound. Compounds validated in vitro in cell culture, with no pharmacological properties will enter into a medical chemistry program, in order to obtain analogues with properties allowing in vivo administration in mice to study efficacy and mechanism of action. The discovery of drugs that affect telomere function/capping opens the door to find and develop new drugs to fight against cancer. As a proof of concept, we have recently demonstrated (Garcia-Beccaria et al., 2015) that long-term whole-body deletion of TRF1, in adult mice did not impact on mouse survival and viability. But efficiently blocks lung cancer growth, increasing survival in a nonsmall cell lung cancer (NSCLC) mouse model, (Guerra et al., 2003). Thus, pointing out TRF1 as an attractive anti-cancer therapeutic target.
Worlwide Cancer Research – Research Projects
Título/Title: Evaluation of obesity as a novel risk factor in metastasis
Ref.: 16-1244
Investigador Principal/Principal Investigator: Peinado Selgas, Héctor
Fecha Inicio/Starting Date: 01/06/2016
Fecha Fin/Ending Date: 31/05/2019
Presupuesto/Budget: £188.810,00
Comentarios/Comments: Worlwide Cancer Research (formerly known as AICR)
Resumen/Summary
Obesity is probably one of the future problems in humankind; it has been associated to the increased risk to develop many pathologies including cancer in certain cancers such as melanoma, colon, breast and ovary. It is necessary to understand the biological processes linking obesity to tumor progression. Metastasis is associated with poor prognosis in most of the cancer types; approximately 90% of cancer-related deaths are due to metastasis. Our preliminary data suggest that exosomes secreted by tumor cells serve as novel communication mechanism between the tumor and the adipose tissue. In this proposal we plan, #1, to visualize and characterize the mechanism of crosstalk between tumor cells and adipocytes by secreted exosomes. This will be followed by detailed studies of the functional consequences regulating melanoma and breast cancer invasion and metastasis. We will expand these studies with a detailed lipidomic analysis of adipocyte secretome during melanoma and breast cancer metastasis. #2 we will build on preliminary results showing that adiponectin levels in circulating exosomes are reduced in melanoma patients and the role of this molecule as anti-inflammatory and potentially as anti-carcinogenic. After determining the contribution of tumor cells to downregulate the expression of adiponectin in the adipose tissue we will follow with experiments to determine what factor(s) regulate adiponectin expression and the mechanism(s) by which adiponectin affects invasion and metastasis. We ultimately aim to generate the signatures of circulating exosomes in breast cancer patients with obesity and compare with subject without cancer. We will correlate the number of circulating exosomes with BMI and metastatic risk determining lipidomic signatures to build rational therapies that can interfere with the metabolic pathways regulated during metastasis.
Worlwide Cancer Research – Research Projects
Título/Title: S100A9-dependent radiation resistance in brain metastasis
Ref.: 19-0177
Investigador Principal/Principal Investigator: Valiente Cortés, Manuel
Fecha Inicio/Starting Date: 01/01/2019
Fecha Fin/Ending Date: 31/12/2021
Presupuesto/Budget: £151.884,09
Comentarios/Comments: Worlwide Cancer Research (formerly known as AICR)
Resumen/Summary
With the advent of improved diagnosis and novel therapeutic approaches cancer patients live longer with systemic disease. However this increased survival is paradoxically associated with a growing incidence of brain relapses. Brain metastasis remains an unmet clinical need with limited therapeutic possibilities. Among them, brain irradiation has been applied for decades yet its efficacy to improve the course of the disease is controversial. Why radiation therapy does not yield better responses given its probed ability to penetrate the brain?. We want to perform in vivo experiments to test a biomarker of radiation resistance that we have discovered using a non-biased approach. This biomarker could be particularly important in situ. Consequnetly, our approach will use advanced models of brain metastasis from breast and lung cancer, including immunosuppressed models but also newly established immunecompetent ones and brain metastasis PDX. We present a research proposal by which, in collaboration with clinicians, we will be able to evaluate the translational potential of a biomarker to predict responses to radiation therapy, thus offering the possibility to personalized this therapeutic approach. In addition, to improve the efficacy of radiotherapy without inducing neurotoxicity, we will use a BBB-permeable drug that blocks the signaling pathway inducing therapeutic resistance downstream of the biomarker. Our proposal is based on strong preliminary data, leading expertise in brain metastasis research and experienced clinical collaborators that will allow us to make a significant contribution on the poorly defined biology of therapeutic resistance of brain metastasis.
US Department of Defense – Neurofibromatosis Research Program
Título/Title: Defining the role of exosome-secreted Endoglin in NF1 progression, a potential new target
Ref.: W81XWH-16-1-0131
Investigador Principal/Principal Investigator: Peinado Selgas, Héctor
Fecha Inicio/Starting Date: 01/07/2016
Fecha Fin/Ending Date: 30/06/2019
Presupuesto/Budget: $-
Comentarios/Comments: Department of Defense-Congressionally Directed Medical Research Programs (DoD-CDMRP)
Resumen/Summary
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that results from mutations in the tumor suppressor gene Neurofibromin [1]. This disease is the most common genetic disorder that affects approximately 1 in 3500 people with a predisposition to develop both benign and malignant tumors [2]. A second-hit mutation precedes the predominant NF1 neoplasms, including Schwann cell derived tumors: Neurofibromas, Plexiform Neurofibroma (PN) and Malignant Peripheral Nerve Sheath Tumors (MPNST). Cutaneous neurofibromas are present in almost all adult NF1 patients [3]. Plexiform neurofibromas (PN) occur in 30% of NF1 patients, and 10–15% of these benign tumors can have a transformation to MPNSTs (are highly aggressive soft tissue sarcomas with poor prognosis). Neurofibromas are highly vascularized [4], and development of MPNSTs depends in part on their ability to initiate neoangiogenesis [5]. Studies demonstrated that Nf1+/- mice have increased angiogenesis in vivo [6], but the mechanism by which neurofibromin regulates neoangiogenesis in Nf1+/- human endothelial cells (ECs) is not completely clarified yet. Beside vascular cells, neurofibromas are composed of Schwann cells, endothelial cells, fibroblasts, and degranulating inflammatory mast cells found within a dense extracellular matrix. Inflammation and alterations associated with the tumor microenvironment are increasingly recognized as critical components of tumor initiation and progression. In vitro experiments demonstrated that mast cells infiltration of pre-neoplasic peripheral nerves have a critical role for neurofibroma development in the NF1 context [7]. This inflammatory microenvironment hypothesis is supported by evidence that NF1 loss of heterozygosity (LOH) in the Schwann cell lineage is not sufficient for neurofibroma formation but the haploinsufficient state of the somatic tissue surrounding NF1 tumors has a functional contribution to tumor formation [8]. Although the neurofibroma microenvironment involves a tumor/stromal cross-talk, accelerating tumor formation and growth this interaction still remain incompletely understood. At the moment there are not reliable method to detect transformation of plexiform neurofibromas (PN) to MPNST. In this proposal we will analyze the role of tumor-secreted exosomes as the main process involved in NF progression and the use of circulating exosomes as a new surrogate marker to detect tumor transformation.
US Department of Defense – Breast Cancer Research Program
Título/Title: Radiolabeled Exosomes for the Early Detection of Metastases and to Predict Breast Cancer Premetastatic Niche
Ref.: W81XWH-13-1-0249
Investigador Principal/Principal Investigator: Peinado Selgas, Héctor
Fecha Inicio/Starting Date: 01/01/2015
Fecha Fin/Ending Date: 31/07/2016
Presupuesto/Budget: $-
Comentarios/Comments: Department of Defense-Congressionally Directed Medical Research Programs (DoD-CDMRP)
Resumen/Summary
Since current diagnostic tools fail to detect breast cancer (BC) metastatic spread at a very early stage, we proposed a new approach for the early detection of metastatic disease in BC patients using cancer cell derived particles known as exosomes as a guide. We hypothesized that exosomes tagged with appropriate radionuclides could be used as molecular imaging probes to study and non-invasively image metastatic spread, and to detect pre-metastatic niches using single-photon emission computed tomography (SPECT) or Positron emission tomography (PET). During this report period we have: 1) isolated and characterized exosomes from a series of BC cell lines of different metastatic capacity and tropism, 2) radiolabeled isolated BC exosomes with different radionuclides, such as 111In, 64Cu, 89Zr. We plan to 3) study the uptake and subsequent intracellular transport of radiolabeled exosomes by different cell types involved in pre-metastatic niche formation, 4) to study the in vivo stability, pharmacokinetics and biodistribution of radiolabeled exosomes following intravenous administration in naive and pathological mouse models. 5) Study the biodistribution and tumor uptake of radiolabeled exosomes (derived from peripheral blood of BC patients) in BC.
US Department of Defense – Breast Cancer Research Program
Título/Title: Organ-tropic metastatic secretomes and exosomes in breast cancer
Ref.: W81XWH-13-1-0427
Investigador Principal/Principal Investigator: Peinado Selgas, Héctor
Fecha Inicio/Starting Date: 01/01/2015
Fecha Fin/Ending Date: 27/09/2018
Presupuesto/Budget: $-
Comentarios/Comments: Department of Defense-Congressionally Directed Medical Research Programs (DoD-CDMRP)
Resumen/Summary
–US Department of Defense – Peer Reviewed Cancer Research Program
Título/Title: Exosomes in Development and Therapy of Malignant Mesothelioma
Ref.: W81XWH-14-1-0199
Investigador Principal/Principal Investigator: Peinado Selgas, Héctor
Fecha Inicio/Starting Date: 01/03/2016
Fecha Fin/Ending Date: 31/08/2016
Presupuesto/Budget: $-
Comentarios/Comments: Department of Defense-Congressionally Directed Medical Research Programs (DoD-CDMRP)
Resumen/Summary
Malignant mesothelioma (MM) is a deadly disease caused by asbestos. Military and veteran populations are at higher risk of developing MM due to service-related exposures to asbestos. In a large study, Navy or shipyard exposure accounted for about one-third of all MM cases (1). Cases of MM will continue to appear in the veteran and military population for decades to come due to their past exposures. The poor prognoses of MMs are mainly due to the lack of early diagnosis and ineffective therapies. To resolve this, we propose a very novel concept, the role of exosomes in development and therapy of MMs. Asbestos inhalation is the leading cause of MM; however, there is a big knowledge gap as to how asbestos causes MM which makes early diagnosis and treatment impossible for this cancer.
US Department of Defense – Prostate Cancer Research Program (PCRP)
Título/Title: Clinical qualification of DNA repair defects as prognostic and predictive biomarker in metastatic prostate cancer using genomics and tissue-based functional assays
Ref.: W81XWH-18-1-0770
Investigador Principal/Principal Investigator: Olmos Hidalgo, David
Fecha Inicio/Starting Date: 30/09/2018
Fecha Fin/Ending Date: 29/09/2021
Presupuesto/Budget: $-
Comentarios/Comments: Department of Defense-Congressionally Directed Medical Research Programs (DoD-CDMRP)
Resumen/Summary
Metastatic castration-resistant prostate cancer (mCRPC) is at present an incurable disease despite several agents being approved over the last decade. Understanding the inter-patient genomic heterogeneity in this disease renders the opportunity to advance towards personalized patient care, based on predictive biomarkers of benefit. We and others have identified enrichment for homologous recombination (HR) mediated DNA repair defects in mCRPC, accounting for 20-25% cases, with inheritable defects in almost
half of these cases. Germline BRCA2 mutations associate with worst prognosis from localized prostate cancer. There is an urgent need to assess how 1) HR defects impact prognosis among a late-stage CRPC population and 2) whether HR defects other than BRCA2 mutations have similar impact in outcome from standard therapies.
While limited data from retrospective series has been reported, it is critical to conduct prospective studies to address these questions. Here we will clarify the impact of genomic profiles, particularly HR defects, in the PROREPAIR study, in which clinical outcomes for 419 mCRPC have been prospectively annotated, with collection of tumor material and plasma.
In addition, preliminary clinical studies support further development of HR defects as a predictive biomarker for treatment with PARP inhibitors and platinum chemotherapy in prostate cancer.7–9 However, lack of standardization in next-generation sequencing techniques, affordability and limited knowledge about the functional impact of certain variants limit its implementation in clinical practice.10,11 We aim to evaluate tissue-based tests of HR proficiency to stratify patients to receive DNA repair targeting agents. In a two-step approach, we will optimize the test and study the correlation with genomic data in a cohort of mCRPC biopsies, to then implement the assay into a clinical trial to stratify patients for receiving treatment with carboplatin, a DNA damaging chemotherapy.
US National Institutes of Health – Research Project Grant Program
Título/Title: Exosome-mediated Transfer of c-MET to Bone Marrow Progenitors Promotes Metastasis
Ref.: R01CA169416
Investigador Principal/Principal Investigator: Peinado Selgas, Héctor
Fecha Inicio/Starting Date: 01/05/2013
Fecha Fin/Ending Date: 30/04/2018
Presupuesto/Budget: $-
Comentarios/Comments: National Institutes of Health (NIH)
Resumen/Summary
Metastasis is the most devastating phase of tumor progression in all cancers as commonly observed in melanoma. Historically, researchers have focused on tumor phenotype and genotype in seeking strategies that block tumor metastasis. However, evidence accumulated in the past decade supports a crucial role for cells, as well as secreted factors such as cytokines, chemokines and exosomes in the surrounding tumor microenvironment as critical components regulating primary tumor growth and metastatic behavior. The goal of the proposed project is to determine the mechanisms through which tumor-derived microvesicles, known as exosomes and bone marrow-derived cells (BMDCs) promote the highly metastatic phenotype associated with melanoma. We will define the molecular mechanisms, molecules and pathways involved in mediating crosstalk between melanoma-derived exosomes, BMDCs and the metastatic niche microenvironment using complementary in vitro and in vivo models. Since biomarkers predictive of melanoma metastatic progression are lacking, we propose to determine whether exosome cargo and BMDCs can be used as novel indicators of metastatic burden in melanoma. We plan to develop therapeutic strategies to block the activation of pathways, specifically c-MET oncogene signaling, that confer a highly metastatic behavior in melanoma, and that, when up-regulated in hematopoietic progenitors by tumor-derived exosomes, lead to the development of prometastatic BMDC subsets. We propose that these strategies will prevent metastasis or hinder its progression y simultaneously reducing the mobilization and recruitment of BMDCs to primary tumor and metastatic niches. The development of novel approaches to analyze the contribution of tumor-derived exosomes to metastasis as well as their capacity to “educate” other cell types is further described in the current proposal. Importantly, we identify novel mechanisms and propose to dissect specific pathways, such as c-MET signaling, involved in BMDC “education” by melanoma exosomes. Our studies in melanoma patients are the first to investigate whether the levels of circulating bone marrow progenitor cells and tumor-secreted exosomes could identify patients with metastatic disease. Ultimately, we propose to explore the possibility that inhibition of specific exosome cargo molecules or their targets in hematopoietic progenitors could block the recruitment of BMDCs and other stroma cell types in melanoma, providing a valuable combination therapy for the management of human disease. Furthermore, we hypothesize that targeting tumor-derived exosome function will contribute to the reduction of metastases and relapses responsible for patient lethality in melanoma, providing a rationale for development of targeted therapeutic approaches. In summary, we will focus on studying the mechanisms through which exosomes regulate BMDC mobilization and recruitment to pre-metastatic and metastatic niches in melanoma models and melanoma patients.
Our proposed studies in melanoma patients are the first to investigate whether the levels of circulating bone marrow-derived progenitor cells, and tumor-secreted microvesicles, also known as exosomes, could identify patients with or at risk for metastatic disease. We propose to explore the possibility that melanoma exosomes activate the c-MET oncogene in bone marrow-derived progenitor cells thus “programming” these cells to promote melanoma dissemination. Furthermore, we hypothesize that inhibiting c-MET mediated tumor-derived exosome function and bone marrow-derived progenitor cell “reprogramming” will contribute to the reduction of metastases and relapses responsible for patient lethality in melanoma, providing a rationale for development of targeted therapeutic approaches.
US National Institutes of Health – Research Project Grant Program
Título/Title: Targeting Mdm2-MdmX E3 ligase for treatment of drug-rresistant lymphoma
Ref.: R01CA208352
Investigador Principal/Principal Investigator: Muñoz Fernández, Inés Gab
Fecha Inicio/Starting Date: 01/04/2017
Fecha Fin/Ending Date: 31/03/2022
Presupuesto/Budget: $-
Comentarios/Comments: National Institutes of Health (NIH)
Resumen/Summary
This application is a translational study of novel antineoplastic agents MMRi (stands for Mdm2-MdmX RING-domain inhibitors) that targets the RING domain E3 ligase activity of Mdm2-MdmX E3 complex. Our newly developed MMRi36 potently induce apoptosis in drug-resistant lymphomas in vitro. This application will investigate MMRi’s in vivo therapeutic efficacy using rituximab resistant lymphoma mouse model and MdmX-driven mouse lymphoma model as well as to lucidate the mechanisms of action for MMRi
US National Institutes of Health – Collaborative Research in Integrative Cancer Biology and the Tumor Microenvironment (U01), PAR-11-146
Título/Title: Breast Cancer Exosomes in Malignacy
Ref.: U01CA169538
Investigador Principal/Principal Investigator: Peinado Selgas, Héctor
Fecha Inicio/Starting Date: 01/09/2015
Fecha Fin/Ending Date: 31/08/2017
Presupuesto/Budget: $-
Comentarios/Comments: National Institutes of Health (NIH)
Resumen/Summary
Our collaborative project expands on the concept of ‘metastatic niche’ as an important determinant of malignancy in the breast. Over the past decade, we have enhanced our conceptual understanding of the microenvironment as a potential driver of tumor growth and metastasis. Our next challenge is to dissect the precise cellular interactions that drive malignant behaviors of susceptible epithelial cells in the breast as well as their secondary homes (i.e., those that they disseminate to, and where they sit in a ‘dormant’ fashion waiting to strike again). Based on Dr. Lyden’s groundbreaking recognition and molecular dissection of the pre-metastatic niche and Dr. Bissell’s pioneering analysis of cell-extracellular matrix (ECM) interactions specifying normal versus malignant behavior and the crucial role of the microenvironmental regulation of breast tumors, we conceive of niches within primary and secondary tumor sites. These are governed by the crosstalk between breast tumor cells and their stroma that is mediated by secreted factors like chemokines/cytokines, ECM components, and exosomes, which contain both classes of molecules. Specifically, we hypothesize that exosome-mediated crosstalk in the primary tumor microenvironment and within the bone marrow microenvironment facilitates tumor progression.
Since biomarkers predictive of breast cancer (BC) progression and metastasis are lacking, we propose to isolate exosomes (poorly studied small vesicles surrounded by membranes and full of proteins and RNA that are released by tumor cells that could cause potential harm) from BC patients and healthy controls to determine whether exosome content are predictive of patient stage, metastatic burden and survival. We will define proteomic signatures of breast tumor-derived exosomes that can be used clinically for diagnosis and may provide therapeutic targets. We will also utilize 3-dimensional co-culture models to determine how malignant progression and concomitant disruption of tissue architecture influences the exosome release and incorporation of potentially malicious content. The function of these exosomes will be tested by measuring their ability to activate neighboring ‘normal’ breast stromal cells and to elicit reciprocal tumor-promoting functions from these cells. Finally, we will utilize animal models and 3D co-cultures to measure BC exosome interaction with bone marrow cells and whether exosomes elicit formation of pre-metastatic niches within the bone marrow or disrupt dormant niches within the tissue.
All the proposed studies will keep a therapeutic focus by targeting protein content within exosomes to determine whether doing so eliminates tumor-promoting effects. The long-term objectives of our work are to identify targetable molecules contained within exosomes to hinder tumor progression and halt metastatic relapse.
US National Institutes of Health – Genomic resource Grants for Community Resource Projects (U41) PAR-11-095
Título/Title: GENCODE: comprehensive gene annotation for human and mouse
Ref.: U41 HG007234
Investigador Principal/Principal Investigator: Tress, Michael
Fecha Inicio/Starting Date: 01/04/2013
Fecha Fin/Ending Date: 31/05/2021
Presupuesto/Budget: $-
Comentarios/Comments: National Institutes of Health (NIH)
Resumen/Summary
The CNIO have developed a pipeline for annotating transcripts with protein information such as structure and function and with information from cross-species alignments. APPRIS has two main roles, the evaluation of likely effects of alternative splicing on protein features and the selection of one (or more) variants as the constitutive variant based on the annotations APPRIS consists of eight methods that are used to flag variants that generate proteins that are likely to have altered structure, function or localisation, and variants that have exons that are evolving in a non-neutral fashion. APPRIS flags transcripts and genes that have unusual protein and conservation-based features. The pipeline has had an important role as a means of quality control on the human annotations in the GENCODE gene annotation pipeline.
Protein-coding transcript verification pipeline: a pipeline to evaluate the protein coding potential of GENCODE annotations that uses MS data generated in Peptide Atlas, GPM and in targeted proteomics experiments. Analysis of the spectra from Mass Spectrometry experiments has already allowed us to detect the translation to protein of protein coding genes, alternative isoforms and nonsense-mediated targets. The reliable verification of the translation of protein-coding isoforms will continue with each new GENCODE release. Detected peptides integrated into the evidence tracks by the annotation team can be used to confirm isoforms annotated as putative or novel, and can help reclassify nonsense-mediated decay targets.
Proteogenomics: the reliable evaluation of the protein-coding potential of gene models, pseudogenes and other non-coding regions that are not generally regarded as protein coding. This is an emerging collaboration with a groundbreaking protocol that employs a powerful proteogenomics tool. Our work with collaborators in ETH, Zurich, will allow us access to the cutting edge TripleTOF 5600 System and a novel measurement technique (SWATH acquisition) that will make possible the detection of hard-to-find peptides from complex samples. SWATH acquisition will also allow us to quantify the peptides detected in individual experiments.
Melanoma Research Alliance – Team Science Award
Título/Title: Imaging and therapeutic targeting of lymphangiogenesis in melanoma
Ref.: 269626
Investigador Principal/Principal Investigator: Soengas González, María Soledad
Fecha Inicio/Starting Date: 01/05/2013
Fecha Fin/Ending Date: 31/07/2016
Presupuesto/Budget: $900.000,00
Comentarios/Comments: Melanoma Research Alliance (MRA)
Resumen/Summary
A main limitation for rational drug design in cancer, particularly in melanoma, is the lack of physiologically-relevant models and tracers to monitor metastatic cells in vivo. To overcome these complications we have assembled a team of experts in melanoma progression and drug response, tumor spectroscopy, biological chemistry, dermatology, pathology and oncology. Our main focus is neo-lymphangiogenesis. This is a process whereby cancer cells induce the formation of vessels (lymphatic capillaries) that favor tumor dissemination. We have customized new lymphatic probes, and have generated the first melanoma Lymphoreporter mouse model. A unique feature of this strategy is the possibility of imaging early events occurring before cells actually colonize distal organs. The metastatic behavior of melanoma cells can also be analyzed prior, during and after treatment. With this approach we have also found new potent blockers of lymphangiogenesis. The most effective of these compounds were nanoparticles based on dsRNA (referred to as BO-110 for simplicity). The ability of studying cells in their natural environment allowed for the identification of unexpected points of crosstalk with innate immunity programs, opening alternative avenues for therapeutic intervention. This proposal builds on this infrastructure to translate these results into the clinic. In particular, we will center on key melanoma oncogenes (including BRAF, NRAS, cMET or MITF), whose roles in lymphangiogenesis remain unknown. Further functional testing of BO-110 will be performed as single agent or in combination with therapeutic agents that are being actively pursued by the pharmaceutical industry. Results will be validated in biopsies obtained from patients at different stages of melanoma progression. The long-term goal of this proposal is to provide the melanoma community with new diagnostic and prognostic indicators, tools for pharmacological screening, and ultimately, more efficient anticancer treatments.
Melanoma Research Alliance – Established Investigator Award
Título/Title: Prognostic and therapeutic impact of lymphovascular niches in melanoma
Ref.: 348673
Investigador Principal/Principal Investigator: Soengas González, María Soledad
Fecha Inicio/Starting Date: 01/05/2015
Fecha Fin/Ending Date: 30/04/2018
Presupuesto/Budget: $337.500,00
Comentarios/Comments: Melanoma Research Alliance (MRA)
Resumen/Summary
The long-term goal of this proposal is to identify long-range signals induced by melanomas at early stages of development as a strategy to discover new progression biomarkers and therapeutic targets. The rationale stems from the need to address one of the key defining features of this disease, namely, the fact that seemingly thin lesions bear high risk for dissemination to neighboring (sentinel) lymph nodes, and ultimately, to distal sites. We will center on the ability of aggressive melanoma cells to remodel the lymphatic nodal vasculature and promote the so-called lymphovascular niche. This is a protective microenvironment that avoids recognition and attack by the immune system. Intriguingly, while lymph node removal is considered a standard of care for thick melanomas, this procedure cannot consistently improve patient survival. Therefore, alternative mechanisms of melanoma metastasis have been suggested, but their identity remains elusive. A translationally-oriented experimental plan has then been designed to address the following fundamental questions: (i) how are distal metastases established in melanoma, (ii) are lymphovascular niches engaged at these sites, and if so, (iii) how to deactivate them without secondary toxicities? Our experimental plan combines unique mouse models for whole-body imaging of melanoma progression, with a large set of serum specimens and tissue biopsies obtained in the context of active clinical trials for FDA-approved and experimental compounds. First, we will validate the prognostic value of specific proteins we found with unexpected roles in distal lymphangiogenesis. Secondly, we will define the mode of action of novel pharmacological agents that deactivate lymphovascular niches and synergize with therapeutically-relevant immune-checkpoint blockers. We expect to contribute to the melanoma field with new indicators of metastatic risk, and by setting the proof of concept for the clinical testing of new investigational compounds.
Melanoma Research Alliance – Team Science Award for Women in Scientific Research – L’Oreal Paris USA
Título/Title: Imaging and targeting dormant and pro-metastatic melanoma lesions in vivo
Ref.: 401181
Investigador Principal/Principal Investigator: Soengas González, María Soledad
Fecha Inicio/Starting Date: 15/05/2016
Fecha Fin/Ending Date: 14/05/2019
Presupuesto/Budget: $900.000,00
Comentarios/Comments: Melanoma Research Alliance (MRA)
Resumen/Summary
Melanoma is an aggressive form of skin cancer that is well known for its propensity to spread to multiple organs (metastasis). However, a critical and outstanding question in the field is why some melanoma patients succumb to metastasis within months of surgical excision of the primary tumors, while in others, tumor cells can remain dormant for years. This proposal aims to identify and target signaling cascades that define tumor cell fate (metastasis or dormancy), by regulating the mechanisms (secreted factors) that melanoma cells use to condition the sites they will subsequently colonize. We have identified new pro-invasive factors secreted in a differential manner by melanoma cells and by surrounding fibroblasts, and will now define how these signals are wired depending on whether metastasis is productive or held in a dormant state (Aim 1). The Team has also discovered unanticipated age-associated changes in the melanoma secretome, and will dissect their prognostic impact in metastatic relapse (Aim 2). Anticancer agents in clinical use and proprietary pharmacological compounds that target and disorganize secretory programs will be exploited with the objective of promoting long-term therapeutic responses (Aim 3). These studies will take advantage of state-of-the-art animal models (mice, zebrafish) specifically engineered for live imaging and controlled on-off switch of melanoma progression in vivo. Clinically-annotated tissue specimens with long term follow up will be used for mechanistic validation and assessment of prognostic relevance. Acknowledging that there is still a pervasive bias against female researchers, our team of four senior and one junior women-lead laboratories will join efforts to foster career development for women in science. Our work will aid in the imaging and treatment of otherwise intractable melanomas, and together we will strive to empower female investigators to achieve the much needed gender balance in science.
Melanoma Research Alliance – MRA Young Investigator Award
Título/Title: Blocking melanoma brain metastasis by targeting the microenvironment
Ref.: 498103
Investigador Principal/Principal Investigator: Valiente Cortés, Manuel
Fecha Inicio/Starting Date: 15/05/2017
Fecha Fin/Ending Date: 14/05/2020
Presupuesto/Budget: $225.000,01
Comentarios/Comments: Melanoma Research Alliance (MRA)
Resumen/Summary
Melanoma is a paradigm of cancers where targeted therapy and immunotherapy represent major breakthroughs in the treatment of metastatic disease. Unfortunately, response rates are still incomplete. This proposal focuses on a main unmet need in the field, namely, patients where melanomas have disseminated to the brain. Traditionally, most studies in melanoma brain metastasis have focused on alterations affecting the malignant cells themselves. However, we have found a subtype of cells in the brain (i.e. reactive astrocytes) that plays a key role in the control of brain metastasis. Specifically, we have identified signaling cascades, whose inhibition in astrocytes inhibits the growth of metastatic cells in the brain. Here we would like to move these results further: (1) defining the mechanisms underlying the crosstalk between melanoma cells and astrocytes, and (2) targeting these signals from a therapeutic perspective. Innovative features of our aims are the combination of cell lines with specific tropism to the brain with mouse models engineered with specific genetic defects in astrocyte populations. In addition, we will use sophisticated techniques for gene transfer in vivo (in utero and in established melanomas). In collaboration with medical oncologists, neuro-oncologist and dermatopathologists, we will test the combination of astrocyte-targeted compounds with local and systemic treatments (radiation and immunotherapy, respectively) that are being actively pursued in the clinic. We therefore expect to provide new insight on actionable targets that may ultimately serve for a more efficient design of anticancer treatments for patients with metastatic melanoma to the brain.
HHMI International Early Career Scientist Program
Título/Title: Exploring the role of replicative stress in cancer and ageing
Ref.: –
Investigador Principal/Principal Investigator: Fernández-Capetillo, Óscar
Fecha Inicio/Starting Date: 01/02/2012
Fecha Fin/Ending Date: 31/01/2018
Presupuesto/Budget: $715.000,00
Comentarios/Comments: Howard Hughes Medical Institute (HHMI)
Resumen/Summary
DNA damage is the source of procancerous mutations. In addition, recent evidence has also suggested that the reverse connection might also exist; namely that oncogenes can promote the generation of DNA damage. However, the nature of the damage that arises either by oncogenes or endogenously is still poorly understood. My laboratory has centred its research in trying to understand how cells respond to “replicative stress” (RS), a type of DNA damage which arises unavoidably every time that a cell replicates its DNA, and which is mainly prevented by ATR and Chk1 kinases. Unfortunately, the essential nature of these kinases has limited their study, particularly at the organism level. In order to overcome these limitations, a significant part of our work in these years has focused in the development of cellular and animal models for the study of ATR/Chk1 function. Altogether, our main aim is to understand how genome maintenance is safeguarded – particularly during replication – and to exploit this knowledge as a way to fight against cancer or delaying age-related pathologies.
Bristol-Myers Squibb-MRA Young Investigator Award
Título/Title: Blocking melanoma brain metastasis by targeting the environment
Ref.: 498103
Investigador Principal/Principal Investigator: Valiente Cortes, Manuel
Fecha Inicio/Starting Date: 15/05/2017
Fecha Fin/Ending Date: 14/05/2020
Presupuesto/Budget: $225.000,00
Comentarios/Comments: Melanoma Research Alliance (MRA)
Resumen/Summary
Survival of stage IV melanoma patients is highly reduced if systemic disease affects the brain. Clinical trials including these patients have shown beneficial responses with immune checkpoint inhibitors, but long-term responders are still limited. This proposal focuses on cellular populations in the brain we have found as potential contributors to immunosuppressive microenvironments. Specifically, we have demonstrated that tumor cells with metastatic tropism to the brain remodel the microenviroment, with a particular impact on reactive astrocytes. Combining functional studies in brain slices, with histological and expression studies in mouse models, we have identified a selective induction of the transcription factor Stat3 in a subpopulation of reactive astrocytes. We have confirmed these findings in experimental mouse models of brain metastatic melanoma as well as human biopsies. Moreover, we have demonstrated that blocking Stat3 function in astrocytes compromises the growth of metastatic cells from melanoma and a variety of tumor types with brain tropism, further consolidating the significance of our studies. We have identified a series of downstream effectors of Stat3 with putative immunomodulatory functions. Here we will dissect the impact of astrocytes in the establishment of immune-permissive environmental niches in the brain (Aim 1), and will define the underlying mechanisms (Aim 2). In addition, will evaluate the potential therapeutic of targeting this subpopulation of astrocytes (Aim 3) using a specific blood-brain barrier permeable inhibitor as single agent or in combination with clinically relevant local and systemic treatments (radiation and immune checkpoint blockers). To this end, we will take advantage of a series of cell lines with brain tropism, combined with genetically-engineered mouse models for the development of melanoma in the context of conditional depletion of Stat3 in astrocytes.
ECTS/Amgen Bone Biology Fellowship
Título/Title: Cross talk between skin and bone: Role of IL-17A signaling in inflammatory bone disease
Ref.: –
Investigador Principal/Principal Investigator: Uluçkan, Özge
Fecha Inicio/Starting Date: 01/08/2013
Fecha Fin/Ending Date: 31/07/2016
Presupuesto/Budget: 100.000,00 €
Comentarios/Comments: The European Calcified Tissue Society (ECTS)
Resumen/Summary
The aim of this study is to investigate the molecular mechanisms by which inflammation of the skin disrupts bone homeostasis. Many studies focus on the genetic regulation of bone cells, and their interaction with stromal cells in bone. However, the emerging field of osteoimmunology, the regulation and interaction of bone cells with immune cells, requires further investigation. We have a model where specific deletion of JunB in the epidermis induces an inflammatory response leading to osteopenia via decreased bone formation. Thus, this mouse model is an excellent tool to further understand key molecular pathways/cell types in the field of osteoimmunology and identify novel targets of IL-17A that regulate osteoimmunology.
Aim 1: Investigate the mechanism by which IL-17A leads to OB inhibition.
Aim 2: Investigate the role of Lipocalin-2 downstream of IL-17A.
Aim 3: Investigate the role of Lipocalin-2 in inflammatory bone loss.
EFSD/Lilly European Diabetes Research Programme
Título/Title: Growth factors and nutrlents in type 2 diabetes: role of URI in beta cell plasticity and glucose homeostasis
Ref.: –
Investigador Principal/Principal Investigator: Djouder, Nabil
Fecha Inicio/Starting Date: 01/06/2015
Fecha Fin/Ending Date: 31/12/2016
Presupuesto/Budget: 100.000,00 €
Comentarios/Comments: European Foundation for the Study of Diabetes (EFSD)
Resumen/Summary
Nutrients overload can dysregulate beta cell growth, proliferation and survival, thereby affecting the glucose homeostasis and leading to the onset of Type 2 diabetes (T2D). Using genetically engineered mouse models (GEMMs) for URI gain- and loss- of function, a downstream target of mTOR/S6K1 pathway, we aim at better understanding the in vivo contribution of growth factors and nutrients in development of T2D. Using biochemical and cell biological techniques combined with mouse genetic studies, we would like to give a particular consideration to mechanisms implicated in URI-mediated beta-cell plasticity and glucose homeostasis regulation.
EFSD/Lilly European Diabetes Research Programme
Título/Title: Elucidating mechanisms of epigenetic changes in type 1 diabetes and treatment with DNA demethylating drugs
Ref.: –
Investigador Principal/Principal Investigator: Djouder, Nabil
Fecha Inicio/Starting Date: 01/01/2019
Fecha Fin/Ending Date: 31/12/2019
Presupuesto/Budget: 100.000,00 €
Comentarios/Comments: European Foundation for the Study of Diabetes (EFSD)
Resumen/Summary
The objective of the project is to study the contribution of DNA hypermethylation through URI loss-mediated DNMT1 upregulation during enterovirus infection-induced T1D.
GOAL 1. MECHANISMS OF ALTERATION OF BETA CELL FUNCTIONS AND IDENTITY BY CVB.Various CVB strains will be used for the infection of in vitro beta cell lines and in vivo tolerant mouse models. This will comprise the following points:
- Generation of an immunocompetent mouse model suitable for enterovirus infections
- Validation of URI as a marker of enterovirus infections and core element of host response to viruses’ infection.
- Study of the signalling pathways in regards of methylation status, b cell functions identity, and capabilities of transdifferenciation.
GOAL 2: MECHANISMS OF PDX-1 AND DNMT1 REGULATION BY URI LOSS.
GOAL 3: SCREENING OF DNMT1 INHIBITORS FOR Β CELL IDENTITY BOOSTERS AND T1D PROTECTION AND TREATMENT.
Paradifference Foundation
Título/Title: Genomic dissection of SDHB related PPGLs to identify druggable targets and novel therapeutic strategies
Ref.: –
Investigador Principal/Principal Investigator: Robledo Batanero, Mercedes
Fecha Inicio/Starting Date: 01/07/2015
Fecha Fin/Ending Date: 30/06/2018
Presupuesto/Budget: 420.000,00 €
Comentarios/Comments: Paradifference Foundation
Resumen/Summary
Pheochromocytomas and paragangliomas (PPGLs) are highly heterogenous neuroendocrine tumors featuring one of the richest hereditary backgrounds among all neoplasms. Commonly these tumors have a low risk of aggressive metastatic involvement and in such cases are usually cured by surgical intervention. However, in PPGLs due to mutations of the succinate dehydrogenase subunit B (SDHB) gene up to 80% of affected patients develop metastatic disease. For these and other patients with metastatic PPGLs there is currently no effective cure. Available therapies are palliative and rarely result in complete remission. There is now, however, considerable promise for identifying effective therapies for metastatic PPGLs based on advances in mapping the signaling pathways responsible for the tumors. This mapping, well in advance of that for most other neoplasms, has been achieved largely through high-throughput omics based technologies linking the rich hereditary landscape of mutated genes in PPGLs to downstream impacts on signaling pathways and molecular processes. The present proposal outlines a Roadmap for utilizing and expanding upon this knowledge base in order to realize the identification and development of new therapies and eventually a cure for patients with metastatic PPGLs due to mutations of SDHB. The outlined pipeline of inter-related projects matches high-throughput screening of drug candidates with comprehensive omics-based signaling pathway profiling to identify the most suitable therapeutic targets for drug candidates. Evaluation of these targets and drug candidates will take advantage of existing experimental model systems as well as new model systems developed to more closely mimic the pathways impacted by the human disease. Continuing omics-based evaluations of drug effects on signaling pathways and molecular processes in relation to therapeutic responses will faciltate identification of the most promising drug candidates for translation into the clinical trial infrastructure of the consortium.
Paradifference Foundation
Título/Title: Integration of multi-omics profiling and immune contexture in metastatic PPGL patients
Ref.: –
Investigador Principal/Principal Investigator: Robledo Batanero, Mercedes
Fecha Inicio/Starting Date: 01/01/2020
Fecha Fin/Ending Date: 31/12/2022
Presupuesto/Budget: 109.647,00 €
Comentarios/Comments: Paradifference Foundation
Resumen/Summary
Therapeutic options for metastatic pheochromocytoma and paraganglioma (mPPGL) show variable response rates among patients, likely reflecting the intrinsic molecular heterogeneity of the disease. To date, omics-based strategies have clearly demonstrated their utility to identify diagnostic and prognostic markers in PPGL, as well as novel candidate therapeutic targets. Recent immunogenomic analyses suggest that PPGL patients may be stratified based on immune profiles with a potential impact on immune response patterns. The proposed project aims to study the immune profile using the Paradifference PPGL-OMIC repository in order to determine if mPPGL patients are candidates to receive immunotherapy. This repository will be also interrogated to 1- identify additional prognostic markers in PPGL patients, as well as 2- key altered pathways in cell and animal models (established by our partners). This latter will identify molecular mechanisms contributing to radioresistance of PPGLs, and dissect the effect of targeted modulation of oxidative stress, or after kynurenine treatment.
Stewart Rahr-PCF Young Investigator Award
Título/Title: Integration of Clinical, Molecular and Biological Characteristics to Define an Aggressive Subtype of Prostate Cancer Based on Deficient Homologous Recombination
Ref.: –
Investigador Principal/Principal Investigator: Olmos Hidalgo, David
Fecha Inicio/Starting Date: 20/01/2014
Fecha Fin/Ending Date: 20/01/2017
Presupuesto/Budget: $225.000,00
Comentarios/Comments: Prostate Cancer Foundation (PCF)
Resumen/Summary
BRCA is a gene that mediates DNA repair. Mutations in BRCA cause genomic instability and greatly enhance risks for developing breast, ovarian, and other cancers.
Dr. David Olmos has found that men carrying inherited mutations in BRCA genes develop more aggressive prostate cancers and earlier resistance to androgen receptor (AR)-targeted therapies.
In this project, the mechanisms by which BRCA mutations and genomic instability contribute to aggressive prostate cancer and resistance to AR-targeted therapies will be studied in patients and experimental models. Biomarkers that identify disabled BRCA functions in tumors will also be discovered.
If successful, molecular mechanisms by which inherited BRCA mutations contribute to aggressive prostate cancer will be characterized.
PCF Young Investigator Award
Título/Title: Prospective study of lethal prostate cancer clinical and genomic evolution in DNA repair deficient tumours
Ref.: –
Investigador Principal/Principal Investigator: Castro Marcos, Elena
Fecha Inicio/Starting Date: 10/07/2017
Fecha Fin/Ending Date: 09/07/2020
Presupuesto/Budget: $225.000,00
Comentarios/Comments: Prostate Cancer Foundation (PCF)
Resumen/Summary
Up to 23% of tumours from metastatic castration resistant prostate cancer (mCRPC) patients may harbour DNA repair defects with a significant proportion of these alterations already present in the germline. Although most patients will respond to platinum-based chemotherapy and poly (ADP)-ribose polymerase (PARP) inhibitors, resistance will eventually occur and little is known about the benefit these patients may get from currently approved therapies for mCRPC such as docetaxel, cabazitaxel, abiraterone, enzalutamide or radium-223.
HYPOTHESES
- Germline and/or somatic DNA repair defects are enriched in lethal prostate cancer and may confer different prognosis 2. Specific DNA repair defects favour chromosomal instability or hypermutated phenotypes which could lead to distinct genomic changes along prostate cancer evolution
GENERAL AIMS
- To address clinical associations between germline mutations and response to currently available treatments for mCRPC.
- To assess and compare the genomic evolution of DNA repair mutant prostate cancer with non-mutant prostate cancer using tumour biopsies and sequential plasma samples from patients included in the study
HFSP Research Grants
Título/Title: Photochemical trap and high-resolution imaging of transient chromatin complexes from living cells
Ref.: RGP0031/2017
Investigador Principal/Principal Investigator: Llorca Blanco, Óscar
Fecha Inicio/Starting Date: 01/12/2017
Fecha Fin/Ending Date: 30/11/2020
Presupuesto/Budget: $420.000,00
Comentarios/Comments: Human Frontier Science Program (HFSP)
Resumen/Summary
Multi-subunit protein complexes regulate most of cellular processes. To understand how these machineries work we need to know the chemical details of how they recognise their substrate and how they modify it. Since most of these complexes are formed in a very transient and dynamic fashion, it is frequently very difficult to isolate them from their native sources in quantity and quality suited for high-resolution analysis. Reconstituting macromolecular complexes in vitro from purified recombinant components overcomes some of these limitations, but it is often impossible to recapitulate in vitro the physiological complexity of biological systems. Chromatin is a good example of a system whose complexity cannot be fully reconstituted in vitro. Indeed chromatin is regulated by hundreds of chromatin remodeling enzymes and hundreds of possible combinations of histone post-translational modifications (PTMs) and variants. We propose a novel combination of synthetic biology, mass spectrometry (MS) and high-resolution cryo-electron microscopy (cryo-EM) to investigate the chemical details of chromatin regulation in all its physiological richness. We will use genetic code expansion technology to introduce non-natural amino acids carrying a photo-activatable cross-linker into the histone proteins in vivo. The histones containing the cross-linker will create in vivo photochemical traps that will “freeze” proteins bound to chromatin while they act. These traps will allow us to study protein-protein interactions, especially the very transient ones that could be disrupted or missed by conventional purification or bulk chemical cross-linking. By applying state-of-the-art cryo-EM and image processing methods on the trapped protein-chromatin complexes, we will sort out the conformational complexity of these in vivo interactions at high resolution, whilst MS will map the interactions between remodelers and histones, as well as quantitatively describe all chromatin PTMs associated to specific remodelers. A constant dialogue between the information from MS, the cryo-EM structures and the synthetic biology will improve and tune the trapping reaction in vivo. This way, we will be able to analyse the spatio-temporal activity of chromatin-bound complexes at high-resolution.
Beug Foundation for Metastasis Research Award
Título/Title: Altered brain vessels as a novel target in brain metastasis
Ref.: –
Investigador Principal/Principal Investigator: Valiente Cortés, Manuel
Fecha Inicio/Starting Date: 08/09/2017
Fecha Fin/Ending Date: 07/09/2018
Presupuesto/Budget: 12.500,00 €
Comentarios/Comments: Beug Foundation for Metastasis Research
Resumen/Summary
Brain metastasis is an unmet need in high demand of novel and effective therapies. We propose to develop an innovative approach aiming to evaluate the possibility of targeting pro-metastatic components of the microenvironment induced by cancer cells. Specifically we propose to focus our efforts on brain metastasis associated vessels. We previously defined the critical contribution of the interaction between cancer cells and vessels for the progression of metastasis in the brain. We now want to discover molecular alterations induced by the presence of brain metastatic cells on endothelial cells. We will consider the process of vascular co-option (occurring early during brain colonization) as well as angiogenesis (occurring at more advanced stages of brain metastasis) as the targets of our research. Describing these altered states of brain vessels compared to normal vessels will be critical to initiate an ambitious project aimed to define molecular alterations in endothelial cells correlating with altered permeability to drugs, novel therapeutic targets to impair the progression of brain metastasis as well as innovative biomarkers. In this proposal we describe a research plan to perform a comprehensive molecular characterization of brain metastasis associated vessels, which will be the central pillar for subsequent mechanistic and functional studies.
Cancer Research Insitute/Clinic and Laboratory Integration Program (CLIP)
Título/Title: Brain-specific strategies to improve responses to immunotherapy
Ref.: 54545
Investigador Principal/Principal Investigator: Valiente Cortés, Manuel
Fecha Inicio/Starting Date: 01/07/2018
Fecha Fin/Ending Date: 30/06/2020
Presupuesto/Budget: $198.700,00
Comentarios/Comments: Cancer Research Insitute (CRI)
Resumen/Summary
Therapies based on activating the immune system to target cancer have been recently applied to patients with brain metastasis. Although responses have been reported, they are limited to a minority of them. I hypothesize that the brain microenvironment is responsible for preventing anti-tumor responses of immunotherapies. Using genetic and pharmacologic experiments we have discovered that, induced by metastatic lesions, astrocytes modify their function and generate a pro-metastatic niche. This pro-metastatic glial cell population, which we have characterized by the expression of specific molecular markers, was found in experimental and human brain metastasis from breast cancer, lung cancer and melanoma. Our experiments have probed the ability of pro-metastatic astrocytes to impair the function of activated lymphocytes thus suggesting a potential role as local suppressors of anti-tumor immunity. I propose to evaluate pro-metastatic astrocytes as key determinants of local responses to immunotherapies. We will test this possibility by: 1) Dissecting the influence of reactive astrocytes on CD8 T-cells. 2) Testing the synergistic effects of combining therapies blocking prometastatic reactive astrocytes with immune-checkpoint inhibitors and the contribution of reactive astrocytes to novel biomarkers. Our research proposal will interrogate the basic principles of brain metastasis immunosuppression to define novel approaches that have the potential to increase the efficacy of immunotherapies in this organ. Since metastatic progression of cancer to the brain involves increased morbidity and mortality our proposal is expected to benefit the treatment of systemic cancer.
Lustgarten Foundation -Stand Up to Cancer
Título/Title: Identification of genomic and immune factors in high-risk populations for pancreatic cancer
Ref.: –
Investigador Principal/Principal Investigator: Malats Riera, Núria
Fecha Inicio/Starting Date: 15/05/2019
Fecha Fin/Ending Date: 14/05/2021
Presupuesto/Budget: $ 1.000.000,00
Comentarios/Comments: Lustgarten Foundation -Stand Up to Cancer Collective
Resumen/Summary
We have assembled an interdisciplinary, multi‐institutional, and international team that combines expertise in cancer genomics (Rabadan), genetic and molecular epidemiology (Malats and Molina‐Montes), and the microbiome (Korem) with physicians and translational researchers specializing in pancreatic cancer (Manji and Olive). Here we will leverage the power of large datasets including the UK Biobank, European Study on Digestive Illnesses and Genetics (PanGenEU), TCGA, and ICGC to comprehensively assess the compounded risk of well‐established clinical factors together with novel genomic and microenvironmental markers in pancreatic cancer. Our specific aims are (1) the identification of common and rare germline variants associated with pancreatic tumors, (2) the characterization of the tumor microenvironment including microbiome and HLA allele‐specific expression, and (3) their validation using two cohorts from Europe and the US. If successful, we will provide an integrated quantitative approach to studying genomic and immune components for the identification of populations at high risk of pancreatic cancer.