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

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Laureates 2020 - 2021

Emily ALOUANI
Vahan KEPENEKIAN
Elise NASSIF
Cristiano PERON
Florence RENAUD
Marion TONNEAU
Camille VERRY
Marc ZANELLO

Emily ALOUANI

Title of the project:Pancreatic tumor micro-environment monitoring: Correlative study of a pilot clinical trial combining BL-8040 (CXCR4 inhibitor), Cemiplimab (anti-Pd1), Gemcitabine and nab-paclitaxel in metastatic pancreatic adenocarcinoma.

Place of the training course: Herbert Irving Comprehensive Cancer Center, Columbia University – New-York, USA

Background: Immunotherapy has changed the face of multiple solid malignancies. However, single-agent immune checkpoint blockade have failed so far in Pancreatic ductal adenocarcinoma (PDAC). A main reason is that PDAC exhibits an immunosuppressive tumor microenvironment (TME), which likely needs to be reprogrammed for immunotherapies to be efficient. Preclinical data from Dr Manji’s team shows that in KPC mouse model of PDAC, combination therapy with a CXCR4 inhibitor, anti-PD1 agent, and gemcitabine resulted in a decrease in tumor growth and prolonged mice survival. Interestingly, TME was reprogramed, with a significant increase in the proportion of CD8+ T cells to FoxP3+ T cells (TILs/Tregs) within tumors from mice treated with all three agents. Therefore, we hypothesize that BL-8040 (a CXCR4 inihibitor) will result in increased availability of T-cells into the TME, allowing for Cemiplimab (anti-PD1) to activate them and chemotherapy to more effectively target tumor cells.

Method: This is a pilot study testing combination BL-8040, Cemiplimab, Gemcitabine, and Nab-paclitaxel in first line setting in metastatic pancreatic adenocarcinoma. Core biopsies will be taken from accessible metastases prior, during treatment, and eventually at progression to monitor immune cell population and determine gene signatures, which are expected to be modified by the treatment using quantitative multiplex immunofluorescence, mass cytometry and RNAseq, respectively.

Vahan KEPENEKIAN

Title of the project: Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) with the combination of N-acetyl-cysteine and Bromelain to treat mucinous peritoneal metastasis: pre-clinical study in a rabbit model, and implementation of a phase I/II study in pseudomyxoma peritoneï patients.

Place of the training course: Saint-George hospital
Peritonectomy Unit
Level 3 Pitney Building
Short Street
Kogarah NSW 2217

Summary of the project: Pseudomyxoma peritoneï (PMP) is an orphan disease characterized by mucus accumulation in peritoneal cavity, from the rupture of a primary tumor. Surgical cytoreduction followed by hyperthermic intraperitoneal chemotherapy allows good long-term outcomes but at the cost of high severe postoperative complications rates and deteriorated quality of life. Despite good overall survival, recurrences are frequent with iterative surgery as only efficient therapeutical opportunity.

PMP pathogenesis is centered on mucus which is comprised of large glycoproteins, mucines, known also to be involved in lots of oncogenic process. So mucus and mucines are attractive targets.

Professor Morris team developed a new mucolytic agent that combines Bromelain (Br) and N-acetyl-cystein (NAC). In vitro, in vivo and clinical experiments confirmed the mucolytic efficiency with a good tolerance profile and, also, a chemosentization effect.

The project is to evaluate the intraperitoneal administration of Br-NAC via PIPAC (Pressurized IntraPeritoneal Aerosol Chemotherapy) in vitro, in vivo with a peritoneal carcinomatosis rabbit model, and clinically through an international phase I study.

Elise NASSIF

Title of the project: Biomarkers of response to immunotherapy in sarcomas: evaluation of immune infiltration and microbiota

Place of the training course: Sarcoma Department, MD Anderson Cancer Center, Houston, Texas, USA

Summary of the project: Soft tissue sarcomas (STS) are rare malignancies, accounting for 1% of human cancers. With the advent of new checkpoint inhibitors (CPI), two histological subtypes of STS have shown interesting response rates of 20 to 40%: dedifferentiated liposarcomas and undifferentiated pleomorphic sarcomas. A phase 2 trial enrolled both histological subtypes in a pre-operative setting. Biological specimens were therefore collected at diagnosis and at surgery. Our aim is to characterize and compare the immune infiltrate of STS before and after immunotherapy is administered. As an increasing amount of data suggests a role of intestinal microbiota, we will also look at its composition and diversity before and after CPIs. Both the immune infiltrate and the microbiota will be correlated to the pathological response. Our aims are a better selection of patients who will respond to CPIs, as well as a better understanding of the mechanisms of action of these molecules in STS.

Cristiano PERON

Title of the project: Characterisation of SPRTN protease in DNA replication and repair

Place of the training course: Department of Oncology, University of Oxford.
Old Road Campus Research Building
Roosevelt Dr, Headington
Oxford OX3 7DQ

Summary of the project: DNA-protein crosslinks (DPCs) are a specific type of DNA lesion where proteins are covalently attached to DNA. The inability of cells to remove and repair DPCs leads to genomic instability associated with cancer and accelerated ageing. However, despite DPCs being very common DNA lesions, how they are repaired is still largely under-investigated.

In recent years, the DNA-dependent metalloprotease SPRTN have emerged as the core enzyme for DPC proteolysis repair. My work will help elucidating the role of SPRTN in repairing DNA damage induced by topoisomerase inhibitors like Irinotecan and other chemotherapeutic agents, especially the one currently used for the treatment of colorectal cancer.

Florence RENAUD

Title of the project: Prognostic impact of the immune contexture in gastric adenocarcinoma with microsatellite instability

Place of the training course: Team microsatellite instability and cancer, Prof Alex Duval, Saint Antoine research center, Inserm UMRS 938, Paris, France

Summary of the project: Gastric adenocarcinoma (GA) is the third cause of oncological death worldwide and more than one million new cases were estimated in 2018. Approximately 10-15% of GA are characterized by microsatellite instability (MSI). This phenotype has been associated with a better prognosis, promising response rates to immunotherapies, and post-hoc analyses from clinical trials have suggested a relative chemoresistance. In this context, our project aims at describing the immune infiltrate and immune genes expression in MSI AG and to assess their prognostic impact. Morphological characterization and molecular profiling of a large series of well-annotated GA will be performed, using especially RNA-sequencing. The results should enable to unferstand the impact of immune genes on the prognosis in MSI AG, which is the first step to further propose more precise treatment for the patients.

Marion TONNEAU

Title of the project: Building an artificial intelligence-based biomarker to predict clinical response to immunotherapy in non-small cell carcinoma by combining clinical, radiomics, genomics and immune features

Place of the training course: Centre de Recherche du Centre Hospitaliser Universitaire de Montréal (CRCHUM), Montréal, Qc, Canada, laboratoire du Docteur Routy

Summary of the project: Lung cancer is the most lethal malignancy in the World, accounting for more deaths than colon, prostate and breast cancer. Unfortunately, the vast majority of patients are initially diagnosed with advanced disease, which makes them not amenable to a curative surgical approach, and only eligible for systemic treatments. In the past few years, treatments targeting the immune system have drastically modified the therapeutic landscape of advanced non-small lung cancer (NSCLC), notably with the use of immune checkpoint inhibitors (ICIs). These drugs facilitate the recognition of tumor cells by the immune system, enabling immune cells to eliminate them more effectively. However, only 20 to 30 % of patients will benefit from this type of treatment: it is therefore critical to accurately identify those who will be susceptible to respond to these expensive treatments. This project aims to develop and validate a clinical tool relying on artificial intelligence (AI) technology to generate a model integrating clinical, radiological and molecular data of a patient and his tumor in order to predict the likelihood of treatment response. We will first fully characterize the tumor and the clinical profile of patients treated with ICI after a diagnosis of advanced NSCLC. Parameters from radiologic features, tumor immune microenvironment as well as molecular profile in relation to response to treatment will be analyzed in order to generate a predictive biomarker algorithm based on artificial intelligence. In the era of precision medicine, this research will allow us not only to improve patient’s management but also to optimize the costs related to these expensive treatments.

Camille VERRY

Title of the project: Use of gadolinium nanoparticles to increase the efficacy of radiotherapy in humans

Place of the training course: Dana Farber Cancer Institut, Harvard Medical School, Boston

Summary of the project: The project concerns the study of gadolinum nanoparticles, a new drug designed to improve the effectiveness of radiotherapy. These nanoparticles represent a new therapeutic class of MRI contrast agent and radiosensitizing agent used in intravenous injection. Initial clinical results in patients with brain metastases from the NanoRAD Phase 1 study are encouraging in terms of safety and efficacy. This research project consists of further investigating these nanoparticles and optimizing their performance using a new machine named "MR-Linac" coupling an MRI and a radiotherapy accelerator. This research will be conducted as part of a phase 1-2 clinical trial at the Dana-Farber Cancer Center in Boston on locally advanced pancreatic cancers and non-operable lung cancers. The contribution of MR-Linac will enable a precise study of the distribution of nanoparticles in the target volumes at the time of irradiation. The objective is to achieve very precise irradiations with an improvement in the therapeutic effect of radiotherapy and the hope of a remission in certain tumors previously considered incurable.

Marc ZANELLO

Title of the project: : Brain biopsy : a possible automation ?

Place of the training course: Prof. Fabrice Bartolomei ; Service de Neurophysiologie Clinique, Timone Hospital at the Assistance Publique - Hôpitaux de Marseille, 264 Rue Saint-Pierre 13385 MARSEILLE

Summary of the project: In neurosurgery, stereotaxis is used to reach an intracerebral target with millimeter precision. Stereotaxy has become essential in neuro-oncology following the update of the WHO classification in 2016 with the need for multiple brain biopsies. If the stereotaxic robots have developed, the planning of the stereotaxic trajectory is still carried out manually by the neurosurgeon. The aim of this work is to develop a stereotaxic planning assistance software, ideally capable of automating the rectilinear trajectory’s calculation. This work consists in developing this software to help stereotaxic planning and to test it during various procedures. This work will be multicentric with reference teams in stereotaxic neurosurgery: it must lead to a gain in safety for the patient and efficiency for the surgeon. This work can then be extended to other areas of oncology requiring biopsies.