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Mitochondria, potential new therapeutic targets in pancreatic cancer -

The objectives of the laboratory are to identify and characterize the pathways altered during oncogenesis in breast cancers, visceral cancers and prostate cancer.
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 :

  • TRANSLATIONAL ONCOLOGY PROGRAMS FOR BREAST & COLON CANCERS
    • BIOMARKERS & MODELS OF METASTASIS & THERAPEUTIC RESISTANCE
      Circulating Tumor Cells & Metastases
    • COMPUTATIONAL BIOLOGY & in silico ANALYSES
  • PERSONNALIZED MEDICINE
    Genomics of Solid Tumors
  • NEW THERAPEUTIC STRATEGIES
    Nanoparticles & Therapeutic Targeting
    Antibody-Drug Conjugate (ADC)
BIOMARKERS & MODELS OF METASTASIS & THERAPEUTIC RESISTANCE

Our project is to develop tools able to predict drug efficiency in real time, for each patient.

This is achieved by addressing 2 challenges:

  • Establishing the role of Circulating Tumor cells (CTCs) as a - not very invasive - biomarker for therapy 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 for a “metastasis-on-a-chip” device. This fully humanized and personalized "tumor on a chip" model, will help us in the understanding and the targeting of the steps involved during metastases occurrence.

PERSONNALIZED MEDICINE

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 involved in the next generation ex vivo modeling of tumors, using patient-derived tumoroids.

NEW THERAPEUTIC STRATEGIES
Nanoparticles & Therapeutic Targeting Palma Rocchi group
Antibody-Drug Conjugate (ADC)

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.