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

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Laureates 2021 - 2022

Waisse A. WAISSI
Elsa CURTIT
Loïc DJAILEB
Edouard AUCLAIN
Aurore PIRE
Ania WISNIAK
Amir EL RAHAL
Marion PANHALEUX

Waisse A. WAISSI

Title of the project: Radiosensitizing pancreatic cancer with DNA damage response inhibitors in patient derived pancreatic cancer organoids and genetically engineered mouse models.

Place of the training course: Cancer Research UK RadNet Glasgow Centre, Glasgow, United Kingdom

Summary of the project: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a cumulative 5-year overall survival of less than 9% for all stages. Over the past few years, studies have focused on the development of targeted radiosensitizers such as DNA damage response inhibitors (DDRi). We hypothesize that DNA damage response inhbition will radiosensitize pancreatic cancer by enhancing pancreatic cancer cells killing and by modifying pancreatic microenvironement. Our objective is to evaluate the radiosensitising properties of three different DDR inhibitors (ATMi, ATRi, PARPi) in an existing panel of patient derived pancreatic cancer organoid models. Then, we will correlate radiosensitivity and response to DDR inhibition with molecular and genetic features. Finally, we will undertake spatial transcriptomic and multiplex immunohistochemical analysis of murine KPC pancreatic tumours that have been irradiated +/- DDR inhibitors in order to investigate the impact of tumour heterogeneity and the microenvironment on response and resistance.

Elsa CURTIT

Title of the project: BRCA2 C.5645C>A (P.SER1882X)  germline mutation analysis : founder effect ; clinico-pathological characteristics associated with mutation ; comprehensive analysis in Swiss CoLaus database and in public genetic databases

Place of the training course: CHUV de Lausanne, Suisse

Summary of the project: Germline BRCA1/2 mutations are the main genetic causes of breast cancer and ovarian cancer predisposition. Some mutations are founder mutations. Among patients diagnosed in Lausanne University Hospital (CHUV, Lausanne, Swiss) with germline BRCA1/2 mutation, the most frequent  mutation is BRCA2 C.5645C>A (P.SER1882X). The aims of this project are : 1/ to identify a founder mutation through a shared haplotype ; 2/ to analyse clinico-pathological characteristics associated with this mutation ; 3/ to assess the prevalence and characteristics of this mutation in Swiss CoLaus database and in public genetic databases.

Loïc DJAILEB

Title of the project: Optimization of 177-Lu-PSMA Radioligand therapy in metastatic and castration-resistant prostate carcinoma.

Place of the training course: Ahmanson Translational Imaging Division du Department of Molecular and Medical Pharmacology, UCLA, Los Angeles

Summary of the project: In metastatic prostate cancer, progression from a hormone-sensitive state to castration-resistance marks a transition to the lethal phenotype of the disease. Despite recent innovations for the treatment of metastatic castration-resistant prostate cancer (mCRPC), more than 250.000 men are still dying from prostate cancer each year. PSMA is a cell surface glycoprotein overexpressed on prostate cancer cells. PSMA ligands enable whole-body tumor-specific imaging (68Ga-PSMA11 positron emission tomography/computer tomography; PSMA PET/CT) and systemic targeted therapy (177Lu-PSMA617 radionuclide therapy; LuPSMA). LuPSMA showed high PSA response rates, low toxicity, and symptomatic improvements in men with mCRPC who progressed after standard treatments. However, up to 50% of patients do not respond to LuPSMA despite documented tumor PSMA expression. The mechanisms underlying response vs. resistance to LuPSMA are poorly understood. This gap in knowledge represents a key barrier to the development of more effective therapeutic approaches in advanced prostate cancer. Based on these findings, we hypothesize that clinical parameters, laboratory test values, and PSMAPET/CT derived tumor burden parameters can be used to stratify patients into likely LuPSMA responders vs. non-responders. Our goal is to improve therapeutic responses to LuPSMA in, and by doing that, improve quality of life and survival in men with mCRPC.

Edouard AUCLIN

Title of the project: Impact of higher fiber intake on gut microbiota composition, tumoral immune infiltration, and outcomes under immune checkpoint inhibitors in patients treated for a non small cell lung cancer.

Place of the training course: Centre de Recherche du CHU de Montréal, Laboratoire du Dr Bertrand Routy

Summary of the project: Immunotherapy with immune checkpoint blockade (ICB) has achieved unparalleled clinical success in non-small cell lung cancer (NSCLC); however, long-lasting control appears only in a minority of patients. Recently, gut microbiome (GM) profiling by metagenomics sequencing has revealed that high bacterial diversity and specific commensal bacteria were associated with cytotoxic CD8+ T and CD4+ T cell activity, which correlated with improved clinical response to ICB. Recent evidence suggests that diet can modulate the GM composition, potentially promoting carcinogenesis and influencing response to cancer therapeutics. Our hypothesis is that specific microbiome signatures predict response to ICB in NSCLC and that a high-fiber diet correlates with a beneficial microbiome signature and immunogenic tumor microenvironment. Altogether, the GM as a biomarker would help identify ICB non-responders who could benefit from personalized nutrition as a new therapeutic strategy to increase ICB efficacy.

Aurore PIRE

Title of the project: Impact of immunomodulation on chemosensitivity and tumor progression of high-risk hepatoblastoma.

Place of the training course: Centre de Recherche des Cordeliers, Paris, in collaboration with XenTech, Evry, France; and in co-surpervision with the Université Catholique de Louvain, Belgium.

Summary of the project: In pediatric population, liver malignancies represents 1% of pediatric tumors. Hepatoblastoma is the most common pediatric liver malignancies. The current management of hepatoblastoma is the combination of cisplatin-based chemotherapy and surgical resection with liver transplantation if necessary. At diagnosis, one-third to two thirds of patients have high-risk tumors, metastatic or unresectable requiring a liver transplantation, with a higher risk of recurrence and worse outcome. Moreover, patients relapsing after a liver transplantation have a higher risk of treatment failure. Accordingly, immunosuppressive therapy after liver transplantation could play a role in term of “immunotolerance” towards the tumor and could decrease the efficacy of treatments. My research project will explore the impact of the immune system and the surrounding microenvironment on hepatoblastoma development, to identify alterations that can lead to tumor immunotolerance and impair or limit anticancer drug efficacy.

Ania WISNIAK

Title of the project: Fertility of Cameroonian women after cervical intraepithelial neoplasia treatment by thermal ablation

Place of the training course: Gynecology and obstetrics department, Dschang District Hospital, Dschang, Cameroon.

Summary of the project: Cervical cancer is the second most frequent cancer in Sub-Saharan Africa and the deadliest, despite being preventable through screening. However, coverage of screening programs remains insufficient in low-resource settings, in part due to women’s fear of adverse effects on fertility. Thermal ablation is an efficient and easily implemented treatment option for cervical intraepithelial neoplasia of grade 2 or higher (CIN2+), but its effect on fertility has not yet been studied. The objective of this project is to assess the impact of thermal ablation on fertility and first trimester complications of pregnancy. This study is embedded in a cervical cancer screening program taking place in Cameroon. Women with a suspicion of CIN2+ receive immediate treatment by thermal ablation or loop electrosurgical excision procedure (LEEP), as appropriate. Women having undergone thermal ablation will be compared with a control group of untreated women for the outcomes on fertility. We hope to demonstrate the security of thermal ablation as a treatment option of CIN for future fertility, thus contributing to improving uptake of screening programs in regions highly impacted by cervical cancer.

Amir EL RAHAL

Title of the project: Cellular Glioblastoma phenotype detection by morphometrics feature extraction: Towards safer resection margins

Place of the training course: Département Neuro-oncologique - l’hôpital Universitaire de Freiburg-Im-Breisgau en Allemagne

Summary of the project: Glioblastoma has shown that it has the capability to respond to its microenvironment, by clonal selection of specific phenotypes. Using the same mechanisms, malignant GBM develop intrinsic mechanisms to resist chemotherapeutic treatments. Single cell RNA (scRNA) sequencing results show that the GBM cells different into neuron like (NPC-like), astrocyte like (AC-like), oligodendrocyte like (OPC-like) and mesenchymal like (MES-like) cells. Clusters of cells within each GBM population can be detected solely based on morphological features. We aim to classify cells within samples that are H&E stained to be able to detect the same phenotypic variety within the GBM cells. Images will be used to carry out segmentation and cellular detection, using the recently published U-net algorithm. The segmented cells will then be used for morphological feature extraction, used for further machine learning (ML) based clustering to accurately detect cell types based on morphological data. Transcriptomic validation of the detected cell phenotype will be carried out using Spatial Transcriptomic technology. We hope to establish a quick and reliable system that is able to detect and provide information about the extent to which GBM infiltration occurs in the margin of tumors. So, the surgical team would be able to make a decision intra operatively on the resection borders and margins using an instantaneous machine learning tool to achieve a local control of the tumor.

Marion PANHALEUX

Title of the project: Identifying potential tissue and cell biomarkers predictive of efficacy and toxicity of checkpoint inhibitor treatment in cancer patients.

Place of the training course: Laboratory of Molecular Immunology, Jules Bordet Institute, Pr Karen Willard Gallo, Bruxelles, Belgique

Summary of the project: Immune checkpoint inhibitors (ICI), alone or combined with other drugs, are currently used both as standard of care or in experimental settings for various cancers. ICI treatment currently induces objective clinical responses in only 20-40% of patients. ICI drugs purposely release immune regulatory controls and consequently increase immune activities; however, this also provokes a significant risk of immune-related adverse effects (irAE). These irAE’s can lead to autoimmune-like events affecting multiple organs with clinical manifestations ranging from mild to fatal. The identification of biomarkers for use in patient selection and irAE management is therefore a top priority. This project seeks to identify blood and tissue biomarkers that reflect ICI response(s) and/or predict irAE onset and development in treated patients by identifying and quantifying potential circulating and tissue biomarkers associated with: 1) treatment responses; and 2) irAE’s.