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Reference : UMR7284-SONMAR-001
Workplace : NICE
Date of publication : Monday, November 04, 2019
Scientific Responsible name : Sonia MARTIAL
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 6 January 2020
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
New strategies of targeted therapies for pediatric medulloblastoma: Combined benefits of proton therapy, proangiogenic cytokines, VEGFC and immune check points.
Medulloblastoma, tumor of the cerebellum, is the most widespread and aggressive brain tumor in children. In 80% of the cases, it concerns children less than 15 years old; it is a rare pathology in adults. Current treatments combine surgery, radio and chemotherapy. They are very negative for the patient's development and quality of life, resulting in numerous sequelae (motor skills, posture, balance, speech, concentration, etc.) and a neurocognitive deficit. Although the cure rate reaches 70%, relapse remains fatal because of the resistance to treatment and the heterogeneity of the disease (4 subgroups of increasing aggressiveness). To improve the overall treatment or to treat relapses, new targeted therapies, more effective and of lower toxicity, are needed for these patients. The objectives of our research project are:
1. We will try to understand which are the molecular agents involved in the development of medulloblastomas. From our preliminary studies, it appears that these drivers and / or their mode of activation differ according to the medulloblastoma subgroup. Determining the nature and function of these drivers would provide biomarkers for each subgroup and pave the way for targeted therapy strategies.
2. Several families of molecules, already effective in other cancers, will be tested for their ability to reduce or prevent tumor growth, block tumor metastasis through vessels (blood, lymphatic), or even prevent the development of said vessels.
3. The treatment of medulloblastomas includes a high-energy X-ray radiotherapy phase, which is very pejorative for the development of young children and may induce numerous sequelae and secondary cancers. The appearance of proton radiation therapy, which is much more targeted to the tumor and spares healthy tissue, represents a therapeutic hope. We will investigate whether this irradiation technique provides a real biological improvement over X-rays.
4. One of the hallmarks of cancer cells is to mask the immune system from surface proteins that would cause them to be recognized as foreign bodies by the immune system. This is the phenomenon of anergy, which allows the cancer cells not be destroyed by the patient's antibodies. We will develop therapeutic strategies allowing the reactivation of the antitumor immune system (immunotherapy), during a preclinical study on animal models.
5. We will analyze clinical data obtained by our collaborators from the hospitals of Marseille and Newcastle University to find our molecular targets of interest. We will also be able to analyze medulloblastoma samples from Nice University Hospital.
In vitro tests
Tumor aggressiveness will be evaluated in MB models already available in the laboratory: cells inactivated for VEGFC (CRISPR-Cas9 technology) or overexpressing the gene (cellular transduction). Other models will be constructed: cells resistant to CXCR1 / 2 inhibitors, cells resistant to proton irradiation.
The following parameters will be measured:
• Cellular proliferation and dependence on VEGFC; signaling pathways involved
• Cellular sensitivity to irradiation, chemotherapy (etoposide, vincristine), combined treatment (chemo-radiotherapy). A model of radiation-resistant cells (two different cell lines) is also available in the laboratory.
• Cellular migration / invasion; epithelio-mesenchymal transition; stem cells
Expression of immune control points and relationship with VEGF expression and resistance to irradiation and chemotherapy
In vivo tests
Tumor aggressiveness will be assessed in MB models already available in the laboratory:
MB growth and metastatic spread will be assessed in immunodeficient or immunocompetent mice (allogeneic or orthotopic xenografts).
• Generation, growth, and metastatic spread of MB (from VEGFCKO, VEGFC ++ cells, radiation-resistant cells, or CXCR1 / 2-resistant cells)
• Development of blood vessels and lymphatic vessels / lymph nodes / immune cells
• Tumor sensitivity to chemotherapy (subcutaneous / intracranial xenografts of cells of different models). Influence of the microenvironment.
• Isolation of cells derived from the tumor by a procedure developed in the laboratory. The effect of several immunomodulators on MB cells resistant to different treatments will form the basis of the coupled inhibition in vivo (use of anti-PD1 / PDL1, anti-CTLA4 / B7-1 / B7-2).
• Tumorigenesis with radio-resistant cells / chemotherapy (syngeneic grafts) and anti-immune check point treatments.
Clinical Correlation: Patient Studies
The correlation between the level of VEGFC or cytokines and the aggressiveness / relapse of the tumor will be evaluated on patient samples, in online databases and in databases generated by our collaborators.
• Collaboration with Marseille hospitals (Dr Nicolas André, La Timone, MB collection included in paraffin)
• Collaboration with Newcastle University (Prof. Steven Clifford, Wolfson Childhood Cancer Research Center, 250 samples containing transcriptomic and clinical data, including overall survival and progression-free survival).
• Access to paraffin-embedded MB samples from Nice University Hospital
• MB commercial tissue samples (http://www.biomax.us/tissue-arrays)
Thus, during the project, we will develop new therapeutic tools against this incurable cancer. In addition, our project will provide elements for the initiation of clinical projects validating one or more biological markers that would allow selective management of patients stratified so far on insufficiently accurate clinical and genetic markers. Strict stratification would improve the quality of life of patients and streamline health expenditures.
The Ph.D. student will benefit from the environment, the equipment and the know-how of the laboratory "Normal and pathological angiogenesis", directed by Dr. Gilles PAGES. This team is working on the characterization of "mechanisms of tumor resistance to treatments" with several models of tumors (kidney, breast, brain, etc.). The so-called "bench-top to the bed of the patient and from the bed of the patient to the bench" approach is favored, generating translational studies, in collaboration with the Antoine Lacassagne Center (to obtain samples and irradiate the cells) and the Nice University Hospital (for pathology studies).
The laboratory is located within IRCAN, an institute specialized in oncogenesis and aging, which possesses many technical platforms (cytometry, imaging, animal facilities, etc.). The project thus benefits from a very favorable working environment and a very dense skill set. The regular organization of conferences in which the students are both speakers and / or listeners promotes their openness to various research themes and the enrichment of their range of skills.
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