NUOVO-SOLDATI FOUNDATION FOR CANCER RESEARCH
Research grants in cancer research

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Laureates 2014 - 2015

Madame Sarah WATSON
Monsieur Thomas CLUZEAU
Monsieur Wulfran CACHEUX
Monsieur Pierre-Andrien BOLZE
Monsieur Nicolas GOOSSENS
Monsieur Mikael ROUSSEL
Monsieur Benjamin ALLANSON
Monsieur Charles-André PHILIP

Renewal

Monsieur Pierre MORDANT

Madame Sarah WATSON

Title of the project: Development of zebrafish models to identify and characterize new recurrent translocations in Ewing-like sarcoma

Place of the training course: University of Texas, Southwestern Medical Center Department of Pediatrics (Dr J. Amatruda)
5323 Harry Hines Boulevard
Dallas, Texas, 75390-8534


Résumé du projet de recherche: Ewing family tumors (EFTs) are characterized by the presence of a chromosomal translocation leading to the expression of a fusion oncogene, mostly EWS-FLI1. BCOR-CCNB3, CIC-DUX4 and EWS-NFATc2 fusions are expressed in a subset of tumors that are related to EFTs based on clinical and pathological criteria. Transcriptomic analyses carried out in our lab show that those tumors differ from classical EWS-FLI1 sarcoma in terms of gene expression, and that they biologically constitute distinct tumor entities. These data have been obtained on human tumor samples, and then confirmed in heterologous cell line models.
In order to better understand the pathways involved in the oncogenesis of these tumors, our project is to establish transgenic models in the zebrafish, a new and powerful tool to study the molecular bases of cancer initiation and progression. This will enable us to study the role of the different fusion oncogenes in an in vivo model and to raise potential therapeutic options for those tumors of very bad prognosis.

Monsieur Thomas CLUZEAU

Title of the project:

Place of the training course: H. Lee Moffitt Cancer Center and Research Institute,
12902 Magnolia Drive,
Tampa, FL 33612.

Summary of the project: Scientific background:
Myelodysplastic syndromes (MDS) are characterized by dysplastic morphologic features and ineffective hematopoiesis. In early MDS, cytopenias arise or are exacerbated by humoral and cellular immune-mediators that suppress hematopoietic progenitor survival and alter the bone marrow environment. 30-50% of MDS patients experience hematologic improvement with immunosuppressive therapies. Recently, Alan List's team identifies that myeloid-derived suppressor cells (MDSC) can induce MDS. MDSC expansion is driven by the interaction of the proinflommatory molecule S100A9 with CD33. S100A9 is also known to interact with TLR4 that have been implicated in the ineffective hematopoiesis and apoptosis maturing bone marrow precursors.
Description of project:
The aim of project will be to characterize TLR4 and CD33 pathways in order to identify targets in order to inhibit MDSC expansion. We proposed to evaluate drugs targeting MDSC, cytokines releasing by MDSC, or the S100A9/TLR4 and S100A9/CD33 pathways to treat MDS and restore normal hematopoiesis.
Results:
Expected results are identifying of one or several targets that could be inhibited. We will use cell lines, transgenic mouse model overexpressing S100A9 and bone marrow samples from MDS patients to confirm these targets. From these results, we will propose a French-American clinical trial in MDS patients to start a new collaboration between Moffitt Center and French Group of Myelodysplasia.

Monsieur Wulfran CACHEUX

Title of the project: IDENTIFICATION OF A MOLECULAR SIGNATURE PREDICTING PREFERENTIAL METASTATIC SPREAD TO THE LIVER: A COMPARATIVE TRANSCRIPTOMIC ANALYSIS OF METASTATIC UVEAL MELANOMA AND COLORECTAL CANCER.

Place of the training course: Hôpitaux Universitaire Genève,
Service de Pathologie Clinique, Unité de Pathologie Moléculaire,
CMU, rue Michel Servet 1,
1211 Genève 4, Suisse.

Summary of the project: Colorectal cancer (CRC) is the third most frequent form of cancer in western countries. Liver metastases in CRC are frequent and have a major impact on the prognosis despite recent medical and surgical advances. Recent studies have defined the genomic landscape across a range of primary tumours by systematic next-generation sequencing approaches, but the mutational evolution that contributes to metastatic disease progression is poorly characterized. Uveal melanoma (UVM) is known to have a strong predilection for hematogenous diffusion and a nearly exclusive metastatic dissemination to the liver. Little data are currently available on the molecular and biological process leading to and explaining this hepatic tropism. We propose therefore an original and detailed comparative analysis of transcriptomic profile of UVM and CRC in order to define a specific predictive signature of metastatic hepatic spread.

Monsieur Pierre-Adrien BOLZE

Title of the project: Role of NLRP7 mutations in the prediction of post-molar malignant transformation.

Place of the training course:

Summary of the project: LGestational trophoblastic diseases have are characterized by an abnormal proliferation of placental tissue. They include pre-malignant stages (hydatidiform moles) and malignant lesions named gestational trophoblastic tumors (GTT). GTT may follow a normal pregnancy or a miscarriage but they are most commonly seen after hydatidiform moles (3-15 % of moles become GTT). The key to the management of patients with trophoblastic disease stage is the precocity of the diagnosis of post-molar malignant transformation. This diagnosis is based on abnormal evolution of hCG serum levels which is usually monitored weekly after hydatidiform mole. To date, no study has identified an earlier marker. In some countries, hCG follow-up can be compromised especially for economic reasons. The earlier identification of patients at high risk of malignant transformation would optimize their diagnostic and therapeutic management. NLRP7 is a gene involved in the recurrence of hydatidiform mole. Mutations of NLRP7, which favor the recurrence of hydatidiform moles, appear also associated with a higher rate of post-molar malignant transformation. We will clarify the cellular mechanisms of this predisposition to malignant transformation and evaluate their interest in diagnosis

Monsieur Nicolas GOOSSENS

Title of the project: Systems Biology Approach to Assess Diagnostic and Prognostic Markers for Hepatocellular Carcinoma and other Liver-Related Outcomes in Patients with Non-Alcoholic Fatty Liver Disease

Place of the training course: Division of Liver Diseases, Department of Medicine,
Icahn School of Medicine at Mount Sinai,
New York, New York, USA

Summary of the project: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disorders ranging from bland steatosis to steatohepatitis with fibrosis or cirrhosis. NAFLD is rapidly becoming one of the predominant causes of liver disease in Western countries. Patients who develop progressive liver disease are at risk of liver-related complications such as hepatocellular carcinoma (HCC) and death. Multiple epidemiological studies have found clinical factors associated with worse outcomes and HCC in NAFLD patients but these are rarely useful for individual patients. We aim to integrate multiple –omic approaches to identify molecular signatures in NAFLD patients associated with major patient-oriented clinical outcomes and important histological outcomes.
To achieve these aims we plan to perform genomic studies (genome wide association studies and, where possible, whole exome sequencing) and gene expression profiling. In a second phase of the study, these approaches will be integrated with urinary metabolomics and proteomics on liver tissue. Finally, all these approaches will be integrated using a systems biology approach to identify pathophysiological networks involved in the progression of liver disease and the development of HCC in patients with NAFLD.

Monsieur Mikael ROUSSEL

Title of the project: Phenotypic and functional characterization of MDSC in DLBCL by mass cytometry (CyTOF)

Place of the training course: Irish Lab, Vanderbilt University,
Nashville (TN, USA)

Summary of the project: Diffuse Large B-cell Lymphoma (DLBCL) is the most frequent high-grade lymphoma in adults. Our ongoing study highlighted a Myeloid-Derived Suppressive Cell (MDSC) gene expression signature in the blood of DLBCL patients. Human MDSC are heterogeneous cells expanded during cancer and able to suppress both adaptive and innate immune responses. Different phenotypes have been described without specific markers.
We identified, by conventional flow cytometry, accumulation of MDSC subsets in the blood of DLBCL patients and pinpointed their immunoregulatory capabilities. Our project is to decipher the phenotype and functional properties of MDSC in DLBCL using mass cytometry (CyTOF). This tool has revolutionized phenotypic profiling for single cells. We expect a refining of MDSC phenotype and mechanisms of activation/expansion supporting their functionality. Recruitment of MDSC and crosstalk with malignant B cells will also be explored using CyTOF, phospho-flow cytometry, and functional approaches. Our project may bring a deeper understanding of immune responses related to MDSC and potential therapeutic benefits in DLBCL.

Monsieur Benjamin ALLANSON

Title of the project: Correlation of morphological features of Oesophageal and Gastro-oesophageal Junctional cancers with HER2 amplification status, stage of disease and survival

Place of the training course: Hôpitaux Universitaires de Geneve
Pathologie clinique
C.M.U.
Rue Michel-Servet 1
1206 Genève

Summary of the project: Adenocarcinoma of the oesophagus and gastro-oesophageal junction (GOJ) are increasing in incidence globally. At least two pathways of carcinogenesis have recently been suggested with resulting carcinomas of different morphology & immunophenotype. Prognostic significance of these types has as yet not been well established. Currently the stage at presentation is the most important prognostic factor. A sub-set of these cancers show HER2 amplification which may prove to be an important prognostic factor as monoclonal antibody targeted therapy for this growth factor receptor is now available. In gastric and GOJ cancers HER2 status is believed to be prognostically relevant. Through a collaboration of centres in Australia and Switzerland, this project will subtype the cancers on morphology, immunophenotype and HER2 related gene expression correlating with the stage at presentation and survival data. A further aim is to identify specific subtypes that show different behaviour and different response to therapy including targeted therapy.

Monsieur Charles-André PHILIP

Title of the project: Ovarian cancer with BRCA mutation: creation of xenografts models to study the mechanisms of resistance to PARP inhibitors

Place of the training course: Lady Davis Institute (Mc Gill University)
Jewish General Hospital,
3755 Chemin de la Côte-Sainte-Catherine, Montreal, QC H3T 1E2, Canada

Summary of the project: Despite the increase in survival associated with surgery and chemotherapy, ovarian cancer remains a fatal disease in more than 50 per cent of cases. The PolyADP-ribose polymerases (PARP) inhibitors, new targeted therapies, are a new hope in this pathology.
PARP is involved in DNA single strand break repair. It acts upstream of the "Breast Cancer" (BRCA) protein, which repair double strand breaks. The combined inhibition of these 2 proteins is responsible of an accumulation of DNA double strand break and leads to apoptosis. BRCA mutations are involved in many ovarian cancers.
A recent study showed an objective response rate of 41% in patients with BRCA mutation, but other studies show significant resistance to PARP inhibitors in many patients (spontaneous or induced by treatment). It is also known that platinum-resistant tumors are often resistant to PARP inhibitors, but in vitro study is impossible so far as there is no cell lines of platinum-resistant ovarian cancer with BRCA mutation.
We propose to create a murine model with NOD/SCID mice to evaluate the genetic and phenotypic stability of platinum-resistant BRCA mutated ovarian tumors grown as serially transplanted xenografts. Then, we will assess it response to PARP inhibitors and try to identify mechanisms of resistance to treatment.

Pierre MORDANT

Title of the project: Etude de la régénération épithéliale au cours du reconditionnement ex vivo des greffons pulmonaires

Place of the training course:Latner Thoracic Surgery Research Laboratories,
Toronto General Hospital,
Toronto, Canada

Summary of the project: L'adénocarcinome mucineux à extension lépidique est un cancer bronchique primitif caractérisé par une extension septale et alvéolaire menant à l'insuffisance respiratoire sans maladie métastatique. Par le passé, certains de ces patients ont pu bénéficier de transplantations pulmonaires, mais des récidives étaient observées sur le greffon, discréditant temporairement cette technique. Depuis, la faible efficacité des traitements médicaux, les bons résultats tardifs de la greffe, et l'augmentation du nombre de greffons pulmonaires dans le cadre des programmes de reconditionnement de greffons plaident pour une réévaluation de la transplantation en traitement de l'adénocarcinome mucineux à extension lépidique. En préalable, ce projet a pour but l'étude de la régénération épithéliale au cours du reconditionnement ex vivo des greffons pulmonaires.