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

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Laureates 2017 - 2018

Samuel ABBOU
Dulce ALFAIATE
Annika BLANK
Laurent DERCLE
Aurélien DUPRE
Vassilis GENOUD
Thimothée JACQUESSON
Charles RICORDEL
Clémentine SARKOZY
Camille TLEMSANI

Samuel ABBOU

Title of the project: Replication stress in pediatric recurrent cancers and its exploitation to find new therapeutic strategies

Place of the training course:Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children’s Hospital, Boston, Massachusetts, USA

Summary of the project: The genes driving cell proliferation induce DNA replication stress. It can also be induced by several factors including oncogenes and DNA damaging agents. Although TP53 alteration is rare in pediatric tumors at diagnosis, it is the most frequent alteration found in the relapse pediatric molecular profiling trial MOSCATO-01 (19%). Our hypothesis is that genomic abnormalities acquired during treatment induce high rate of replication stress which give to TP53-deficient tumor cells a selective advantage for survival.
The aim of this project is to explore replication stress, TP53 and DNA damage repair pathway alterations in pediatric recurrent cancers to elaborate strategies of treatment in suitable preclinical models.
Whole exome sequencing and RNAseq of pediatric tumor samples from MOSCATO-01 and MAPPYACTS precision medicine clinical trial will be analyzed to identify alterations in TP53 and DNA damage repair (DDR) pathways. Replication stress phenotype will be analyzed to validate a relation between genomic abnormality and replication stress with immunochemistry and western blot. Functional analyses of DDR mechanisms and checkpoint activation will be performed in order to elaborate treatment strategy with targeted therapy and conventional chemotherapy. This work will be done in partnership with Gustave Roussy, CNRS laboratory in Villejuif and Dana Farber Cancer Institute and Boston Children’s Hospital.

Dulce ALFAIATE

Title of the project: Evaluation of the impact of chronic Hepatitis D Virus infection on the progression of liver disease and the development of hepatocellular carcinoma

Place of the training course:Geneva University Hospitals – Division of Gastroenterology

Summary of the project: Co-infection by hepatitis B (HBV) and hepatitis D (HDV) viruses leads to the most severe form of viral hepatitis. Co-infected patients (15-20 million worldwide) have faster progression of liver fibrosis, cirrhosis and a significantly increased risk of hepatocelullar carcinoma (HCC). The physiopathology of HBV/HDV co-infection remains largely. We hypothesize that direct viral modulation of hepatocyte gene expression may contribute to disease phenotype, specifically to the development of HCC. We propose to characterize the direct oncogenic potential of HDV infection in precancer stages, by a combined strategy relying on (i) a high throughput characterization of gene expression in liver biopsy samples of chronic hepatitis D patients – compared to chronic hepatitis B patients - and on (ii) hypothesis-driven validations both in liver tissue and in in vitro models. Our aim is to clarify the complex mechanisms involved in HBV/HDV co-infection and thus contribute to the development of novel clinical progression markers.

Annika BLANK

Title of the project: Characterization of tumor buds on the DNA and protein level in liver metastases and the corresponding primary tumor in stage IV colon cancer

Place of the training course:University of California, San Francisco, Department of Pathology & Laboratory Medicine

Summary of the project: Tumor budding is defined as single cells or cluster up to 4 cells at the invasive front of colorectal cancer and an independent prognostic factor in colorectal cancer. Nevertheless, tumor budding in liver metastases is still poorly understood. The aim is therefore to compare tumor buds in liver metastases to the corresponding primary tumor based on DNA and protein level. Tumor buds of liver metastases and their corresponding primary tumors will be micro-dissected by laser capture and a NGS analysis will be performed. Additionally, an ngTMA will be used for an immunohistochemical investigation using downstream molecules of the ras and wnt signaling and EMT markers. The results from the NGS analysis will be compared with the immunohistochemical results and will probably reveal new aspects of the tumor budding pathogenesis in different tumor microenvironment such as the liver in comparison to the colonic wall.

Laurent DERCLE

Title of the project: Early evaluation of the efficacy of immunotherapies by studying the prognostic and predictive value of quantitative imaging biomarkers

Place of the training course:Department of radiology. Columbia University Medical Center, NY, NY, USA

Summary of the project: The objective of this research is to optimize the management of cancer patients treated with immunotherapy. Therefore, this project aims at the early identification of responders and the improvement of the understanding of response profiles. This is a crucial issue as immunotherapies targeting immune control checkpoints will be widely prescribed. However, new response patterns (delayed efficacy, pseudoprogression, abscopal effect, hyperprogression) have emerged and complicated the evaluation of therapeutic efficacy.
The explored solution is the evaluation and validation of quantitative imaging biomarkers in comparison with patient survival and data extracted from biopsies performed before and during treatment. The interest of imaging biomarkers is that they are widely available, not expensive, non-invasive, evaluate the whole body and can be repeated along the treatment sequence. These biomarkers characterize patient anthropomorphic characteristics (CT-scan), tumor burden, site of metastasis, the texture of each tumor and its metabolism (PET).

Aurélien DUPRE

Title of the project: Prehabilitation in liver surgery. Impact on post-operative complications and survival after cancer treatment

Place of the training course:Hepatobiliary unit, Aintree University Hospital, Liverpool, United Kingdom

Summary of the project: Liver surgery is the gold standard treatment for several liver tumours. Surgery is a physiological and a psychological stress, which is associated with post-operative complications. A prehabilitation program could increase the physiologic reserve in the anticipation of surgery. Prehabilitation is based on 3 components: (1) physical management, (2) nutritional care and (3) psychological care, over a period of 4-8 weeks. Prehabilitation could improve nutritional and physical status in order to decrease post-operative complications. Prehabilitation has been associated with a decrease in morbidity rate after cardio-thoracic surgery, but its benefit in digestive surgery has to be proven. The aim of our study is to evaluate the effect of prehabilitation on post-operative complication and on survival after surgery for colorectal liver metastases.

Vassilis GENOUD

Title of the project: Molecular and histological study of the mechanisms determining responses to immune checkpoint blockade in a novel non-immunogenic glioblastoma model.

Place of the training course:Hôpitaux universitaires de Genève
Département d’oncologie
Laboratoire d’immunologie des tumeurs cérébrales
Rue Gabrielle-Perret-Gentil 4
1211 Genève 14
Suisse

Summary of the project: Immunotherapy, and particularly immune checkpoint blockade is radically changing the way we treat patients with cancer. Clinical studies are underway for almost all kinds of cancer, but tumors are not equally susceptible to these new therapies. Glioblastoma is a brain tumor that is considered to be relatively non-immunogenic and which is unlikely to fully benefit from immune checkpoint blockade. With our model that faithfully recapitulates key immunological characteristics of glioblastoma, we will study mechanisms that drive resistance to immunotherapies. By combining different treatment modalities, we have identified promising candidates for sensitizing to immune checkpoint blockade. We have now accumulated a comprehensive bank of tumor and tissue samples from different treatment groups responding distinctively to checkpoint blockade. From these, we will perform molecular analyses to identify tumor signatures linked to immunogenicity. We will also study in depth the features of the immune infiltrate at the tumor site, longitudinally pre- and post- treatment, as well as between the groups, to establish what criteria are decisive for an effective immune infiltrate to achieve tumor control. To complete the project our findings will be compared with human samples from patients treated with immunotherapy to validate observations made in our model.

Thimothée JACQUESSON

Title of the project: MRI tractography of cranial nerves: feasibility, development and interest in skull base tumor surgery»

Place of the training course:Neurosurgical anatomy laboratory, cranial base center of UPMC - Pittsburgh, PA, USA

Summary of the project: Human brain connectivity was historically investigated through post mortem dissections. Progress in imaging recently allowed an in vivo non-invasive description of the white mater anatomical that raised the curiosity from the whole scientific community. The diffusion tensor imaging (DTI) tractography has thus proved its interest in large white fiber tracking depicting association between brain areas and sensorimotor signal projection. Nonetheless, this new MRI tool is not yet applied to small fibers such as cranial nerves. Skull base tumor surgery remains an ongoing challenge due to their deep location within a complex neurovascular environment, and therefore predicting cranial nerve trajectory could be a significant asset for surgery. Tracking nerves stretched or encased around or within tumors would thus improve surgery safety and the functional outcome. In 2016, one study reported tracking all cranial nerves thanks to dedicated MRI sequences and a specific computational process. Dr. Fernandez-Miranda headed this work achieved in the Neurosurgical Anatomy and Fiber Tractography Laboratory affiliated with the cranial base center of Pittsburgh. This way I am planning a fellowship within this team to research further in cranial nerves tractography, skull base surgery and tridimensional anatomy.

Charles RICORDEL

Title of the project: Régulation de l’expression du gène suppresseur de tumeur ING2 dans les cancers bronchiques non à petites cellules et létalité synthétique génomique

Place of the training course:Annie Charbonneau Cancer Institute – Robson DNA science network center – University of Calgary (Canada).

Summary of the project: ING2 protein belongs to the ING gene family (INhibitor of Growth). ING2 has recently been characterized has a tumor suppressor gene and is involved in chromatin remodeling (histone acetylation) and DNA repair in response to genotoxic stress. Expression of ING2 is lost in human tumors and especially in non-small cell lung cancer. However, the precise mechanism of ING2 loss has not been clearly elucidated to date. Preliminary results suggest that a post-transcriptional regulation through a mi-RNA (especially miR-18a) could occur. Noteworthy, ING2 loss of expression in tumor cell lines induces a vulnerability to genotoxic chemotherapy, notably in tumors bearing others DNA repair genes alterations. The aim of this work is to confirm in vitro that ING2 expression is regulated by the miR-18a and validate ING2 as a candidate gene for genomic synthetic lethality in lung cancer. Moreover, we want to retrospectively confirm these results in a primary tumor cohort of non-small cell lung cancer (international collaboration) using an immunohistochemistry approach.

Clémentine SARKOZY

Title of the project: Molecular characterization of mediastinal grey zone lymphoma

Place of the training course:British Columbia cancer Agency in Vancouver

Summary of the project: In 2008, mediastinal grey zone lymphomas (MGZL), defined as B cell lymphoma with intermediate features between primary mediastinal B cell lymphoma (PMBCL) and classical Hodgkin lymphoma (CHL), entered the 2008 WHO classification of B cell neoplasm as a provisional entity. Given the lack of data to define clear pathological criteria for diagnosis of MGZL, reproducibility of final diagnostic assignments is poor with implications for clinical decision making. These patients have a poor prognosis. Deeper insight into the pathogenesis of the disease and development of associated biomarker could help the clinician to improve the poor prognosis of these patients. We conducted a retrospective series thanks to the LYSA (the Lymphoma Study Association) network and centrally reviewed 160 cases of MGZL. Thanks to gene expression and mutational analysis of MGZL, I aim at individualizing molecular markers and specific pathway involved in lymphomagenesis to improve the diagnostic accuracy and finally define new therapeutic targets.

Camille TLEMSANI

Title of the project: Molecular and functional characterisation of somatic NF1 mutations in non-small cell lung cancer

Place of the training course:EA7331 (Directeur Pr Vidaud), Faculté de Pharmacie, Paris Descartes

Summary of the project: The NF1 gene encodes an inhibitor of the RAS-MAPK pathway, a major carcinogenesis pathway. According to TCGA (The Cancer Genome Atlas) data, NF1 somatic mutations are found in 12% to 15% of non-small cell lung cancer (NSCLC). Mutation detection in NF1 is challenging owing to the large size of the gene, the presence of numerous pseudogenes, and the absence of mutation hotspots. Little is known about NF1 somatic mutations in NSCLC and their functional consequences. During my first year of PhD, I confirmed the involvement of NF1 in NSCLC using a targeted next generation sequencing approach: NF1 mutations were identified in 26% (36/138) of NSCLCs. Building on this previous work, my first objective is now to better characterize patients with NF1-mutated NSCLCs. The second objective is to determine the functional consequences of NF1 alterations: cellular models of NF1-mutated NSCLC are actually in progress using the CRISPR-Cas9 system. I will then evaluate the sensitivy to anti-MEK and anti-mTOR therapies according to mono- or bi-allelic inactivation of NF1.