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

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Laureates 2013 - 2014

Mr. Etienne DAGUINDAU
Mrs. Ulrike SCHICK
Mrs. Florence RABIAN
Mr. Johan GAGNIERE
Mrs. Emanuela ROMANO
Mr. julien PERON
Mr. Pierre MORDANT
Mr. Daniel NGUYEN

Etienne DAGUINDAU

Title of the project: Identification de nouveaux biomarqueurs éligibles à une thérapie ciblée dans la maladie du greffon contre l'hôte après allogreffe de cellules hématopoïétique pour hémopathie maligne

Place of the training course: Indiana University, Melvin and Bren Simon Cancer Center
Wells Center for Pediatric Research
1044 W. Walnut Street
Indianapolis, IN, 46202

Summary of the project: Despite beneficial effect of graft-versus-tumor effect, the efficacy of allogeneic stem cell transplantation procedure has been impeded by frequent and severe graft-versus-host disease (GvH). The ability to identify patients at high risk for GvH with biomarkers early in their transplant course has important therapeutic consequences including more stringent monitoring and preemptive interventions.

It has been shown in a control cohort that protein sST2 was expressed early after transplant course and was more elevated in patients who developed GvH. The research project aims to validate the early predictive potential of sST2 on the GvH occurrence and also the 6 month non-relapse mortality. To validate this objective, we will benefit of plasma samples from patients transplanted in two U.S. centers. Beyond the sST2 protein, we will use proteomic techniques to identify other candidate biomarkers with differential levels in pooled plasma samples before therapy initiation for therapy-responsive and unresponsive patients.

The second objective is to inhibit the interaction between sST2 and its only known ligand, as proof-of principle of a drug targetable GvH biomarker. In practice, we use several mice models of GVH to prove that prophylactic infusion of anti-sST2 decreases the severity of GVH (regardless of the murine strain) without altering the antitumor effect of the graft.

Ulrike SCHICK

Title of the project: Investigating the in vitro and in vivo radiosensitising effect of MEK inhibition

Place of the training course: Institute of Cancer Research,
Department: Targeted Therapy Team, Chelsea, London, UK.

Summary of the project: Radiation therapy is now increasingly used in melanoma as adjuvant or palliative therapy. Historically melanoma has been thought to be radioresistant, but recent advances in preclinical and clinical studies have demonstrated that this is no longer the case. However, local control remains suboptimal.
The intracellular Ras-regulated MAP kinase cascase is a key pathway controlling multiple cellular functions (including DNA synthesis, cell cycle, proliferation, differentiation and apoptosis). This pathway is often deregulated and activated in melanoma through somatic mutations of genes encoding Ras and Raf proteins. Within this pathway, mitogen-activated protein kinase kinase (MEK) has been identified as an attractive therapeutic target. Pharmacological manipulation using the recently developed inhibitor Trametinib (a potent and selective inhibitor of MEK1/2), has shown promising results in phase II/III clinical trials.
The objective of this study is to evaluate the preclinical radiosensitsation effects of Trametinib using a panel of clinically relevant melanoma tumour cell lines (WT, Ras/Raf mutated), and optimise strategies to enhance radiation-induced tumour cell kill.

Florence RABIAN

Title of the project: Déterminer la nécessité des voies dépendantes de MLL pour l'initiation et la maintenance des leucémies aiguës lymphoblastiques T

Place of the training course:Ernst Laboratory
Department of Genetics
Geisel School of Medecine at Dartmouth
http://geiselmed.dartmouth.edu/ernst/


Summary of the project: Leukemia often starts with chromosomal breakage, resulting in mutations that cause blood cells to grow in an uncontrollable manner. The MLL1 (Mixed Lineage Leukemia) gene is frequently mutated by chromosomal breakage in childhood leukemia. Conventional chemotherapy is not effective at curing this type of leukemia, with most patients relapsing with incurable disease. Using animal models, members of the Ernst lab have shown that the normal (wild-type) mouse MLL1 protein is also essential for maintaining the growth of all blood cells. They have discovered that the role that MLL1 plays in maintaining blood cell growth involves a particular network of genes, and that this network differs very slightly from the network of genes that are altered in leukemia cells. Therefore, we will investigate how broadly NOTCH1 and other leukemia oncogenes use the MLL1 network to propagate themselves at the expense of the normal blood cells.
The aim of this study is to determine the requirement of MLL1 dependent pathways in initiating and maintaining a pathologic self-renewal program in leukemia initiating cells.
The information gained in the course of completing these experiments will be of fundamental importance for understanding how leukaemia and possibly other non-hematologic cancers propagate themselves and epigenetically adjust to evade chemotherapy. This analysis will especially identify genetic pathways that can be targeted to treat leukemia, without damaging other developing tissues, which is particularly relevant for young patients.

Johan GAGNIERE

Title of the project:Role of Escherichia coli strains in colonic carcinogenesis: Involvement of oxidative stress

Place of the training course:

Summary of the project: Studies reported that some bacteria, as pathogen Escherichia coli, could be involved in colonic carcinogenesis by induction of oxidative stress. Oxidative stress is defined as an imbalance between production of reactive oxygen species (ROS) and efficiency of antioxidant systems. This imbalance often leads to cell damages involved in carcinogenesis. In a preliminary study, we reported the abnormal colonization of the gut mucosa of colorectal cancers (CRC) patients by pathogenic strains of Escherichia coli (E. coli-CRC). These strains might be involved in colonic carcinogenesis by both production of ROS and by alteration of some antioxidant systems such as DNA repair pathways. These changes could lead to an accumulation of mutations involved in the adenoma-cancer sequence. The effect of bacteria on antioxidant systems has not been well reported. Therefore, aim of this work is to study: 1) the induction and monitoring of ROS in intestinal cells infected with different strains of E. coli-CRC, 2) the modulation of antioxidant systems focusing on DNA repair pathways in cells infected with these pathogenic strains. Experiments will be performed on in vitro models, on a CRC mice models (APCmin/+ mice) and specimens of colonic mucosa and tumor from CRC patients.
This study will allow better understanding of host-bacteria interactions during colonic carcinogenesis, and might finally help to develop new therapeutic strategies targeting bacterial colonization and/or antioxidant systems.

Emanuela ROMANO

Title of the project: Comprehensive evaluation of the endogenous immunity and the microenvironment in peripheral blood and tissues derived from human malignancies.

Place of the training course:Service d'Oncologie
Département d'Oncologie
Centre Hospitalière Universitaire Vaudois
Lausanne, Suisse

Summary of the project: The immune system has evolved to allow robust responses against pathogens, while avoiding autoimmunity. This is notably enabled by stimulatory and inhibitory signals, which contribute to the regulation of immune responses. The over-expression of inhibitory receptors has been associated to T-cell exhaustion in cancer patients. Several evidences both in vitro and in vivo suggest that this anergic state can be reverted by blocking the interactions between co-inhibitory molecules and their ligands. The main goal of this proposal is to comprehensively profile immune cells as well as cells from the tumor microenvironment of patients with malignant diseases, in particular melanoma and gastro-intestinal tumors for the expression of molecules that inhibit or activate an endogenous anti-tumor immunity as well as to characterize the tumor microenvironment at a cellular level. The proposed axis of investigation has significant clinical potential in that targeting immune suppression mechanisms represents a promising approach for reversing tumor immune escape and enabling protective immunity. .

julien PERON

Title of the project: Using generalized pairwise comparisons to assess the benefit / risk ratio of a new treatment in medical oncology

Place of the training course:Laboratoire Biostatistique Sante, UCBL Equipe de l'UMR CNRS 5558
Centre Hospitalier Lyon Sud - Bâtiment 4 D
165 Chemin du Grand Revoyet 69495 PIERRE BENITE CEDEX


Summary of the project: The purpose of the present project is to use generalized pairwise comparisons to analyse data from randomized clinical trials in medical oncology in order to decide which variables are the more pertinent primary endpoints depending on their surrogacy potential for clinical endpoints. Then, the method proposed here makes it possible to compare two samples in terms of several outcome measures, such as benefit and risk endpoints, simultaneously. Hence the benefit / risk ratio of interventions would be assessable.
We will use analytic methods, simulations and real datasets to evaluate the performance of this method in several clinical research situations. Thanks to collaboration with the National Cancer Institute of Canada and with several European collaborative clinical research groups, we will access to data of randomized clinical trials in medical oncology.

Pierre MORDANT

Title of the project:Epithelial regeneration during ex vivo lung perfusion

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

Summary of the project: Bronchioloalveolar carcinoma is a particular subgroup of non-small cell lung cancer characterized by superficial alveolar and septal extension, leading to respiratory failure without metastatic spread. In the past, some patients with bronchioloalveolar carcinoma have benefited from lung transplantation, but recurrences have been observed on the graft, and the technique has been tentatively discouraged. Since then, the disappointing results of medical treatments, the acceptable long-term outcome of transplantation, and a recent increase in graft availability argue for the reappraisal of lung transplantation as a treatment of advanced bronchioloalveolar carcinoma. As a first step, we sought to study epithelial regeneration during ex vivo lung perfusion.

Daniel NGUYEN

Title of the project: Development of a novel monoclonal Antibody-Drug-Conjugate targeting Prostate-Specific Membrane Antigen for the treatment of prostate cancer

Place of the training course:Laboratory of Urological Oncology and Prostate Cancer Research Center
Cornell University/Weill Medical College
New York, Etats-Unis

Summary of the project: Therapeutic modalities for castration-resistant prostate cancer remain unsatisfactory. In this context, targeted therapy of prostate cancer has gained increasing interest and novel antibody-based therapies are under investigation. Among them are prostate-specific membrane antigen (PSMA)-targeted therapies. PSMA is a very well defined, highly restricted prostate cancer cell-surface antigen. It is a membrane protein that is not secreted, expressed by virtually all prostate cancer cells and upregulated in advanced disease, becoming greatest in castration-resistant and metastatic prostate cancers. Antibody-drug conjugates (ADC) take advantage of monoclonal antibody specificity to selectively deliver their attached drug only to cells expressing the target antigen. The monoclonal antibody huJ591was developed in the laboratory of urological oncology at Cornell University. It binds PSMA with nanomolar affinity. In a clinical trial investigating an ADC that combined huJ591 with the drug maytansine, partial clinical (RECIST criteria) and PSA-responses were observed. Our goal is to develop an even more effective (cytotoxic) and less toxic ADC for the treatment of prostate cancer. We will use ADCs based on huJ591 and a drug of the anthracycline family, 100-1000-fold more potent than doxorubicin. A series of in-vitro experiments and tests on xenograft models will be performed. A final generation of ADCs will be prepared based on all the available data.