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

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Laureates 2018 - 2019

Samuel ABBOU
Sylvain GARCIAZ
Camilla JANDUS
Amaury LERUSTE
Judith MICHELS
Pierre PHILOUZE
Alexandre ROUX
Camille TLEMSANI

Samuel ABBOU

Title of the project: Adapting liquid biopsy assays for prognostication, identification of actionable mutations and treatment response monitoring in pediatric sarcomas

Place of the training course: between nov 2017 to oct 2019 : Pediatric oncology, Dana Farber Cancer institute, Boston, Massachusetts, USA.
Until nov 2019 : Children and adolescent cancer department, Gustave Roussy, Villejuif, France



Summary of the project: Rhabdomyosarcoma is an aggressive pediatric cancer which can start in any muscle and typically occurs during childhood. Despite major progress in treating localized disease, the majority of patients with metastatic disease or relapse will ultimately die. With the scientific advances in biotechnology, we are now able to analyze the DNA of a tumor to identify changes in the DNA that cause cells to become cancerous. These DNA changes, or “mutations”, are necessary for the cancer cells to grow. However, treatments that specifically target these mutations uniquely attack the cancer cells, leaving normal cells in the body unharmed. Such “targeted therapy” can induce dramatic responses in the patient with relatively few side effects. To identify the appropriate targeted therapies for each patient, genetic testing of a patient tumor must be performed. Until recently, this has always required a surgical procedure to obtain a piece of the patient’s tumor. Our research project utilizes a new technological advancement that allows us to detect tumor DNA from a simple blood sample in a patient with cancer. With this technology, we may be able to identify targeted therapies for patients with a non-invasive blood draw and study how a patient’s tumor responds to therapy over time. In this project, we propose to adapt these new blood biopsy approaches for patients with rhabdomyosarcoma first, then other pediatric sarcomas. Our goal is to bring this technology into routine clinical care for patients with aggressive pediatric sarcomas and improve outcomes by enhancing our ability to monitor treatment responses in each patient.

Sylvain GARCIAZ

Title of the project: Click-Chemistry of 5-azacitidine in Acute Myeloid Leukemia

Place of the training course:Peter MacCallum Cancer Centre, Melbourne, Australia

Summary of the project: DNA methyl transferase inhibitor 5-azacitidine (5-aza) is the most advanced epigenetic therapy used in the myeloid malignancies. Nevertheless, little is known about its mechanism of action. Moreover, patients mainly experiment transient responses to 5-aza and it remains difficult to ascribe a particular altered methylation pattern to clinical response. In this project, I want to explore the direct interaction of 5-aza on its targeted genes. To do so, the Mark Dawson’s laboratory has developed an innovative technology (Tyler et al. Science 2017). I will treat AML cell lines with a functionalized derivative 5-aza, tagged by “click chemistry”, and explore genomic consequences at a genome-wide level. We will sequence the DNA bound with the functionalized 5-aza to explore direct genomic targets of the drug. We will also assess consequences of the treatment on DNA-methylation by genome wide bi-sulfite sequencing. These experiments will be combined with RNA sequencing to precisely define the impact on mRNA expression. Given that 5-aza is also efficiently incorporated into RNA, I want to identify those RNAs, using a modified-RNA immunoprecipitation protocol coupled to next generation sequencing. These results could pave the way to explore mechanisms of 5-aza resistance that have not yet been elucidated, and to define new biomarkers clinically available.

Camilla JANDUS

Title of the project: A novel human innate lymphoid cell subset : its clinical relevance in acute myeloid leukemia ?

Place of the training course:Department of Oncology, University of Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland

Summary of the project: Immunotherapy of cancer has gained wide recognition in recent years with the first significant and impressive clinical successes. Yet, there are still major areas of immune responses to tumors that remain to be studied. Recently, a distinct family of immune cells, so called Innate Lymphoid Cells (ILCs), has been identified and shown to phenocopy the functional specialization of helper CD4 T cells. ILCs have emerged as a heterogeneous group of innate effector cells, involved in a number of physiologic and pathologic processes. However, their role in cancer remains poorly defined.
In preliminary experiments, we were able to identify a previously unrecognized subset of human ILCs, that possesses cytotoxic functions. Therefore, in this project, we will focus on the evaluation of the mechanisms of action of this population, and their quantification and phenotyping in human tumors in correlation to disease status and survival. This novel cell population might be targeted in the development of optimized immunotherapy for cancer.

Amaury LERUSTE

Title of the project: Influence of microenvironment on Chimeric Antigen Receptor T cells efficacy in the context of rhabdoid tumors.

Place of the training course:Crystal Mackall laboratory, Department of Pediatrics, Stanford University, Stanford, California, USA

Summary of the project: Rhabdoid tumors are particularly aggressive cancers of very young children, whose prognosis remains severe despite maximalist treatments and with long-term side effects. Immunotherapy for cancer is one of the most recent major therapeutic advances and aims to induce or restore an anti-tumor immune response. In malignant tumors, induction of an immune response through autologous T-cell therapy with chimeric antigen receptor (CAR T cells) may be altered by tumor microenvironment, requiring preclinical evaluation in immunocompetent mouse models. The aim of the project will be to demonstrate the relevance of such an approach on human and murine rhabdoid tumor cells, and to study in vivo the impact of the microenvironment of these tumors on the efficacy of injected CAR T cells, with a view to a combined therapeutic approach.

Judith MICHELS

Title of the project: Study of the immune response induced by p53 reactivation in ovarian cancer and the rational to combine with immunotherapy.

Place of the training course:Laboratory of Immunology of Pr Jedd D. Wolchok, Memorial Sloan-Kettering Cancer Center (MSKCC), New York.

Summary of the project: P53 is a master regulator in cell homeostasis, it is the most studied tumor suppressor gene and its function is altered in almost all cancers. Mutant TP53 is a driver mutation in the pathogenesis of high grade serous ovarian cancer. New drugs have been developed to restore p53 function in tumors. There is growing evidence that the immune system plays an important role into the clearance of P53 reactivated cells. The present project is aimed to better delineate the role of p53 reactivation in inducing an immune response against tumor and confirm whether there is rational for combination with immunotherapeutic strategies to boost their mutual effect.

Pierre PHILOUZE

Title of the project: Prognostic and predictive role of circulating tumor cells in patients with head and neck squamous cell carcinoma : a prospective study.

Place of the training course:Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC,Canada

Summary of the project: Apart from HPV status, there is no biomarker prognosis for survival of patients with squamous cell carcinoma of the upper aero-digestive tract. In the treatment of breast and prostate cancers, for example, circulating tumor cells have been shown to provide real-time information on tumor behavior. In the literature, authors have shown the existence of these cells in squamous cell carcinoma of the head and neck but for the moment have shown only the possibility of detection and there is currently no published work making these CTCs a true biomarker prognosis and especially predictive of relapse. Our hypothesis is that CTCs must play an important role added to clinical and radiological examinations when monitoring patients. The objective of this work is to detect the circulating tumor cells with ISET technique in patients bearing an advanced tumor and to perform a kinetics of these cells by repeated blood sampling during the treatment of patients and follow-up. The secondary objective is to perform immunohistochemical staining on CTCs such as PDL1 in order to easily select patients eligible for new targeted therapies during a relapse.

Alexandre ROUX

Title of the project: Development of a probabilistic cerebral atlas of adult glioblastomas to anticipate the extent of resection and epileptic risk.

Place of the training course:Institute of Psychiatry and Neuroscience of Paris - IMA-Brain – INSERM U894
Neurosurgical Oncology Team
Paris - France



Summary of the project: The aim of this project is to develop a probabilistic three-dimensional brain atlas of adult glioblastomas using a pre- and post-operative MRI standardization methodology correlated with medical findings.
We will use a multimodal database of 593 adult patients with supra-tentorial glioblastomas operated at the Neurosurgery Department of the Sainte-Anne Hospital - Paris Descartes University in Paris, between 2005 and 2016. It will contain demographic, clinical, histo-molecular (WHO 2016), imaging, oncology and follow-up data.
The implementation of this atlas will be carried out in 5 main stages: 1 / organize the IRM database according to the Brain Imaging Data Structure format ; 2 / semi-automatic segmentation of glioblastomas on pre-operative MRI ; 3 / semi-automatic segmentation of tumor residue from early postoperative MRI (<72h) according to the same modalities ; 4 / normalization of pre- and post-operative MRIs as well as segmented volumes in a reference template (Montreal Neurological Institute) ; 5 / incorporation of multimodal data.
The final aim is to obtain probabilistic maps, which will allow a better understanding of : 1) the preferential topography of glioblastomas according to multimodal data; 2) the pathogenesis of glioblastoma-related epilepsy as well as epileptic risk management ; and 3) the place of the extent of resection and the estimation of tumor resectability.

Camille TLEMSANI

Title of the project: Characterization of molecular and functional consequences of somatic NF1 mutations in non-small cell lung cancers

Place of the training course:Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology (Directeur Dr. Pommier), National Cancer Institute, Bethesda, Etats-Unis.

Summary of the project: La voie RAS-MAPK est bien caractérisée dans les cancers bronchiques non à petites cellules (CBNPC). Cependant, l’implication de NF1, gène suppresseur de tumeur inhibiteur de la voie RAS-MAPK, a été peu étudiée. J’ai confirmé l’implication de NF1 dans les CBNPC par une approche ciblée de NGS (Next Generation Sequencing) sur une cohorte de 138 échantillons tumoraux : 36 altérations somatiques (26%) ont été retrouvées et une corrélation génotype-phénotype a pu être établie. Afin de déterminer les conséquences fonctionnelles des altérations de NF1, j’ai établi des modèles cellulaires mutés NF1 grâce au système d’édition génomique CRISPR/CAS9. J’ai évalué les conséquences de l'inactivation mono- ou bi-allélique de NF1 en montrant notamment que la perte de fonction de NF1 entraine une activation de la voie RAS-MAPK. Les conséquences fonctionnelles sont en cours d’évaluation : analyse des transcriptomes différentiels et étude pharmacologique au sein de modèles murins xénogreffés. Dans la continuité de ces travaux, des cribles génétiques et pharmacologiques (létalité synthétique et outil bioinformatique CellMiner) dans le cadre d’une collaboration internationale au National Cancer Institute (Bethesda) permettront d’identifier d’éventuels acteurs coopérant avec NF1 dans la carcinogénèse des CBNPC et l’identification de nouvelles cibles thérapeutiques.