Master 2 position available
"Microenvironment’s role on drug resistance mechanisms in tumor organoids".
- Drug screening
- Flow cytometry
The objectives of the laboratory are to identify and characterize the metabolic pathways and protein complexes altered during oncogenesis in breast cancers, visceral cancers, prostate cancer, lung cancer and myeloid leukemia. Results are then discussed between researchers and clinicians, as means to improve classification, prognosis, therapeutic efficicency and/or therapeutic options.
This challenge is addressed through 3 axes, divided in 6 interconnected research groups:
- Genomic of Solid Tumors
- Genomic of Lung Cancer
- Genomic of Myeloid Leukemia
BIOMARKERS & MODELS
- Circulating tumor cells & Metastases
- Circulating free DNA
- Nanoparticles & Therapeutic Targeting
- Antibody Drug Conjugate (ADC)
Genomic of aggressive tumors
Breast cancer (BC), as most cancers, is a heterogeneous disease that can be classified according to histoclinical features and to molecular biology. Our goal is to progress in the molecular and cellular definition of aggressive cancers, especially breast tumors, and help improve their treatment. For this, in collaboration with clinicians, we initiated a personalized medicine program enrolling metastatic patients. The program comprises: metastasis biopsy, banking, extraction of nucleic acids, NGS, grafting to obtain Patient-derived xenograft (PDX), establishment of the molecular identity of a metastasis and its drug response. Therapies are selected upon two types of results: genomics studies and model-based. We established a bank of well characterized primary and metastatic tumors (mostly from breast metastases so far). These xenografts conserve the genome and gene expression of their cognate tumors and are therefore excellent models for functional studies and drug testing. We are now also involved in the next generation ex vivo modelling of tumors, using patient-derived tumoroids.
Genomic of Lung cancer
Lung cancer is the leading disease in the field of predictive oncology with 10 predictive biomarkers assessed routinely in advanced stages. However, some of the most frequent mutations (ie KRAS) are still undruggable, and our team wants to understand the heterogeneity of this protein and its related pathways in order to develop new therapeutic options. In addition, our works focus on known oncogenic addictions (ie EGFR, ALK, etc) and the prediction of mechanisms of resistance to current targeted agents and also occurrence of specific metastic sites (ie, brain).
Malignant myeloid diseases
The "Hematology" group studies the molecular alterations of malignant myeloid hemopathies: acute leukemias, myelodysplastic and myeloproliferative neoplasms, and chronic myelomonocytic leukemias.
We want to determine, through next-generation sequencing, which molecular markers are responsible for disease aggravation, but also to characterize and correlate the impact of these markers on life expectancy and clinical behavior of the patients. To understand the mechanisms involved, we test the impact of a "cytoreductive" treatment, hydroxyurea, on a transgenic murine model of JAK2V617F myeloproliferative neoplasia, modified to evolve into acute myeloid leukemia. The aim is to determine if this treatment, commonly used to stabilize myeloproliferative neoplasia, affects or not leukemogenesis.
Circulating tumor cells & Metastases
Our project is to develop tools able to predict drug efficiency in real timefor each patient.
This will be achieved by addressing 2 challenges:
Establishing the role of Circulating Tumor cells (CTCs) as a - not very invasive - biomarker for therapeutic efficiency and more specifically to detect early signs of drug resistance mechanisms development,
Developing “complex tumor units”, the next generation of patient-derived tumor organoids or tumoroids. They are 3D tumor units composed of malignant cells interacting with their microenvironment (particularly with fibroblasts, which represent the major cell population within the tumor microenvironment or stroma, endothelial and/or immune cells).
These two approaches, combined with microfluidic technology, will lay the basis of a “metastasis-on-a-chip” device. This fully humanized and personalized "tumor on a chip" model, will help us understanding the different steps involved during metastases occurrence and how they can be targeted at an early stage.
Nanoparticles & Therapeutic Targeting
We identified Hsp27 as a highly overexpressed gene in castration resistant prostate cancer (CRPC). Hsp27 knockdown using antisense oligonucleotides (ASO) and siRNA increases apoptosis and enhances hormone- and chemo-therapy in PC.
We developed a 2nd generation ASO targeting Hsp27 that has been licensed (OGX-427) and a clinical trial phase II is ongoing. We identified 226 Hsp27 interacting partners using two-hybrid screens and found new potential Hsp27 functions such as telomere maintenance, RNA splicing and DNA repair by NHEJ. We hope to understand the mechanisms leading to Hsp27 over-expression and identify the molecular switches underlying PC.
We showed the role of Hsp27 partner TCTP during PC evolution: ASO-induced TCTP silencing restores hormone and docetaxel sensitivity by enhancing apoptosis and delaying tumor progression. We developed and patented a first generation TCTP phosphorothioate backbone ASO that downregulates mRNA and protein expression level. We recently developed and patented a second generation lipid-modified antisense oligonucleotides (LASO) with the ability to downregulate TCTP levels without any transfecting agent (TCTP-LASO) in prostate cancer cells, leading to restoration of the normal function of p53, a tumor suppressor protein. We also demonstrated that TCTP-LASO forms nanomicelles that we can use to include drugs for combined therapy. We will now develop functional versatile and biocompatible nanocarriers for PSMA-targeted delivery of radiopharmaceutics and anticancer drugs as innovative theranostics in prostate cancer therapy.
This program is now labeled by Aix-Marseille Université Initiative d’excellence (Amidex Emergence et Innovation 2018 “Nucleolipid-based nanocarriers for theranostics in prostate cancer”).
ADCs are a rapidly evolving therapeutic class and many efforts are done to improve efficacy and safety. Design of an effective ADC for cancer therapy requires the identification of an appropriate target, a monoclonal antibody against the target, potent cytotoxic agents, and the conjugation of the monoclonal antibody to one of these agents.
We identified nectin-4 as a potential therapeutic target in breast cancer. Nectin-4 (encoded by the PVRL4 gene) is a cell adhesion molecule involved in the formation and maintenance of adherens junctions. Nectin-4 is expressed during foetal development, but is re-expressed as a tumor-associated antigen with pro-oncogenic properties in various carcinomas. In breast cancer, we have shown the correlation of nectin-4 expression with basal biomarkers, Triple-negative (TN) status and HER2 expression. Recently, we showed that nectin-4 is both a new prognostic biomarker and a therapeutic target for ADC in patients with TN breast cancer. We thus developed an ADC (N41mab-vcMMAE) comprising a human anti-nectin-4 monoclonal antibody conjugated to the toxin monomethyl auristatin-E (MMAE). In vitro, this ADC bound to nectin-4 with high affinity and specificity and induced its internalization as well as dose-dependent cytotoxicity on nectin-4-expressing breast cancer cell lines. In vivo, it induced rapid, complete and long-lasting responses of xenografted nectin-4-positive TN BC samples including primary tumors, local relapses, and metastatic lesions; efficiency was dependent on both the dose and the nectin-4 expression level. Clinical development is currently under process.
We plan to evaluate the targeting of nectin-4 in treatment-resistant HER2-positive breast cancer and in other carcinomas like lung cancer.