Team MARIE-CARDINE

Onco-Dermatology and Therapies

Axis 1: Cutaneous T-cell lymphomas: cellular characterization and development of new therapies

Cutaneous T-cell lymphomas (CTCLs) represent a heterogeneous group of non-Hodgkin lymphomas originating in the skin. Our research focuses primarily on two types of CTCL: mycosis fungoides (MF), in which tumor cells accumulate in the skin, and Sézary syndrome (SS), a highly aggressive form characterized by the presence of malignant cells in both the skin and the blood. The pathophysiology of these diseases remains controversial, particularly regarding the origin of tumor cells and the triggering factors of tumorigenesis. Although malignant cells have been identified as a clonal expansion of memory-phenotype CD4+ T lymphocytes, their phenotypic detection relies on the loss of pan-T antigens such as CD26 and/or CD7. Our previous work identified the first positive marker of malignant cutaneous and circulating T lymphocytes in MF and SS: the NK cell receptor KIR3DL2. A pre-clinical study performed in the laboratory demonstrated that it was possible to promote tumor cell depletion in vitro, ex vivo, and in vivo in the presence of an anti-KIR3DL2 antibody. Following this proof of concept, a Phase I/II clinical trial was initiated, which showed convincing results in terms of safety and therapeutic efficacy in patients with Sézary syndrome.

Given that 10% of Sézary syndrome patients present malignant T lymphocytes that do not express KIR3DL2, we are continuing our research to identify novel tumor antigens specific to CTCLs. We have already identified new tumor targets (e.g., CD39, CCR8) for which the promotion of tumor depletion in the presence of recognizing antibodies is currently being evaluated.

Axis 2: CD160, a novel tumor antigen in melanoma and breast cancer

Axis 1: Protein-protein interactions in apoptosis control: therapeutic developments

Cancer represents a major public health problem and, in this context, a considerable challenge for drug discovery, both in terms of identifying relevant therapeutic targets and developing innovative treatments. Among the molecular targets involved in the pathogenesis of various cancer types, protein-protein interactions (PPIs) play a determining role. Within this framework, our research program aims to design and develop low-molecular-weight PPI antagonists acting on key regulators of apoptosis.

One of the major factors contributing to the persistence of malignant cells lies in the imbalance between pro-survival and pro-apoptotic molecules. Furthermore, evasion of apoptosis, considered one of the hallmarks of cancer, confers significant resistance to currently available therapeutic approaches on tumor cells. In this perspective, deciphering the molecular mechanisms governing apoptosis in cancer should allow: i) a deeper understanding of the studied pathologies and ii) a rational basis for the development of compounds specifically designed to modulate pathological apoptosis.

Building on this observation, our project aims to identify novel therapeutic targets through the study of protein interactions in the field of apoptosis. The objective is to produce active therapeutic probes through the control of protein-protein interactions. The chosen approach consists of starting from proteins whose function in apoptosis is known, identifying their partners through exhaustive yeast two-hybrid screens, characterizing their biological functions, and interrogating the relevance of these partners as pharmacological targets. Once targets are selected, the structural determinants of the protein-protein interaction are dissected in order to construct a peptide-type inhibitor — initially — bearing the key motifs involved in the interaction. The molecules thus produced are then evaluated in terms of efficacy, toxicity, tolerability, and pharmacodynamic properties in various murine xenograft models using cell lines or patient-derived xenografts. This approach has enabled us to design and patent a series of cell-penetrating peptides capable of targeting scaffold proteins ubiquitously expressed in cancer cells and required for their survival, but not that of healthy cells. These peptides are thus capable of inhibiting tumor growth in various murine cancer models.

Axis 1: Signaling and targeted therapies in melanoma

The projects we are developing on melanoma focus on studying signal transduction downstream of the main oncogenes mutated in melanoma, with the goal of discovering new therapeutic targets for these tumors. We work in close collaboration with the onco-dermatology department in order to rapidly translate our results into the clinic through translational studies and clinical trials.

Phosphodiesterase type 4 (PDE4) is a major regulator of the cyclic AMP signaling pathway and is emerging as an important player in several cancers where its expression is often associated with poor prognosis. We have demonstrated that inhibition of the cAMP signaling pathway by PDE4 proteins is required for melanocyte transformation by BRAF and RAS oncogenes, and that PDE4D protein is overexpressed in metastatic melanomas and regulates invasion through its interaction with FAK. Furthermore, overexpression of PDE4D protein is also associated with resistance to MAPK pathway-targeted therapy. Its inhibition blocks melanoma cell proliferation ex vivo and in vivo in a murine model, suggesting that inhibition of PDE4 proteins represents a novel therapeutic option for the treatment of melanoma patients.

The PI3K/AKT/mTOR signaling pathway is essential for tumor cell growth, survival, and plasticity. At the core of this pathway, the mTORC2 complex regulates AKT activation via phosphorylation at S473. Within it, the SIN1 subunit (also known as MAPKAP1) plays a central role by ensuring the stability and substrate specificity of mTORC2. Its expression is frequently elevated in various cancers, and its overexpression is associated with increased proliferation, enhanced invasion, and therapeutic resistance. Furthermore, SIN1 constitutes a signaling node at the interface of the PI3K/AKT/mTOR pathway and other signaling pathways frequently altered in cancers, particularly the MAPK pathway. We have demonstrated that SIN1 acts as a key player in tolerance and therapeutic resistance states in melanoma, sustaining survival signaling under pharmacological stress. We designed an original inhibitory peptide capable of specifically blocking the RAS-SIN1 interaction, which is highly prevalent in resistant cells. This cell-penetrating peptide induces dissociation of the RAS-SIN1 complex and decreases proliferation, increases apoptosis, and potentiates the effect of a BRAF inhibitor. This work highlights the tumorigenic role of SIN1 and proposes an original strategy for targeting the RAS-SIN1 interaction to restore sensitivity to targeted therapies in melanoma and beyond.

Axis 1: Work in Progress