Laurence Bresson-Bépoldin received her PhD in Neurosciences and Pharmacology from the University of Bordeaux in 1994. She was then appointed as a post-doc in Werner Schlegel’s lab at the University of Geneva. In 1997 she obtained a CNRS research position in Bernard Dufy’s lab. She joined François Ichas’s team in Bordeaux in 2002, before moving to the Bergonié Cancer Institute in 2006.
Pierre Vacher received his PhD in Neurosciences and Pharmacology from the University of Bordeaux in 1989. After 1 year as a post-doc in Werner Schlegel’s lab at the University of Geneva, he obtained an INSERM research position in Bernard Dufy’s lab at the University of Bordeaux where he developed electrophysiological and calcium imaging techniques on neuroendocrine cells. He joined François Ichas’s team in Bordeaux in 2002, before moving to the Bergonié Cancer Institute in 2006.
Pierre Soubeyran graduated in medicine from the University of Bordeaux in 1989. After a research position in Haematology and Laboratory Medicine at the MD Anderson Cancer Centre in Houston, he received his PhD in Health Sciences from the University of Bordeaux in 1996. He was appointed as Professor of Medical Oncology at the University of Bordeaux in 2006 and is the Head of Clinical Research and Coordinator of the Haematology Research Group at the Bergonié Cancer Institute.
Role of calcium in apoptosis and sensitization to chemotherapeutic agents in non-Hodgkin lymphomas
Apoptosis is essential for organ and tissue homeostasis. Furthermore, human diseases including cancer and auto-immunity occur when apoptotic processes are impaired. Resistance to apoptosis occurs both during tumorigenesis and tumour relapse following chemotherapeutic treatment. Numerous anti-tumour agents eliminate cancer cells by activation of the death receptor pathways. Hence, the restoration or amplification of these apoptotic pathway is a topic of great interest in oncology. To achieve this, we need to better understand the mechanisms of death receptor activation. In collaboration with Patrick Legembre’s group at the University of Rennes, we have recently shown that calcium ions play an unexpected role in the regulation of apoptosis. Specifically, we have shown that the CD95/Fas and TRAIL death receptor ligands trigger a calcium-mediated negative feedback loop preventing death signalling (Chaigne-Delalande, Bresson-Bépoldin et al., submitted). We have found that a decrease in intra- and extra-cellular Ca2+ potentiates the cytotoxic effects of numerous anti-cancer drugs acting via the death receptor pathway. This work is the subject of a patent as detailed below. Future work will address the identification of the molecular target(s) responsible for these calcium effects.
Radiotherapy and traditional chemotherapies induce major side effects because they target both cancerous and non-cancerous dividing cells. Fortunately, they are being supplemented by a new generation of « targeted » drugs. These are more specific and several have already been approved for use in malignancies, including non-Hodgkin lymphomas (NHL). For example, Rituximab, a monoclonal anti-CD20 antibody targeting B lymphocytes, is currently used alone or in combination with standard chemotherapeutic regimens to treat NHL. We have shown in vitro, using human cell lines and human B lymphoma cells from lymph nodes and in vivo, with xenografted mice, that the pro-apoptotic effect of Rituximab can be significantly increased when intra- or extra-cellular calcium concentration is decreased. It thus appears that combination therapy with a hypocalcemic agent can potentiate the therapeutic effect of Rituximab without triggering major side effects. This reduced toxicity offers a promising approach for the treatment of fragile elderly patients. To take this through to the final proof of concept stage, we will first perform animal experiments to confirm the validity of our hypotheses and then design clinical trials. Future work will explore the association of hypocalcemic agents with other drugs activating death receptor pathways, either directly (eg. TRAIL), or indirectly (eg. antidepressants, proteasome inhibitor or HDAC inhibitors).
Vacher P, Khadra N, Vacher AM, Charles E, Bresson-Bepoldin L, Legembre P. Does calcium contribute to the CD95 signaling pathway? Anticancer Drugs.22 : 481-487, 2011.
Tauzin S, Chaigne-Delalande B, Selva E, Khadra N, Daburon S, Contin-Bordes C, Blanco P, Le Seyec J, Ducret T, Counillon L Moreau J-F, Hofman P, Vacher P and Legembre P. The naturally processed CD95L elicits a c-yes/calcium/PI3K-driven cell migration pathway PLoS Biol, Jun;9(6):e1001090, 2011.
Chaigne Delalande B*, Bresson-Bepoldin L*, Penna A, Cahalan MD, Ducret T, Ségui B, Khadra N, Vacher AM, Reiffers J, Moreau JF, Vacher P¥ and Legembre P¥.*joint first authors, ¥hjoint last authors. Store-operated calcium entry prevents formation of the DISC and contributes to a « cooling-off period » upon engagement of the CD95 receptor. (submitted to EMBO J).
Chaigne-Delalande B, Daburon S,, Ducret T, Counillon L, Contin C,, Blanco P, Moreau J-F, Vacher P and Legembre P. Naturally processed soluble CD95L activates a PI3K/calcium/actin-driven cell migration (submitted to PLOS Biol)
Jaubert A., Ichas F., Bresson-Bépoldin L. TH and DAT expression in lactotrophs from post-lactating rats: involvement in DA-induced apoptosis. Endocrinology, 148: 2698-707, 2007.
Soubeyran P, Mertens C, Bellera C, Mathoulin-Pélissier S, Rainfray M. Management of unfit patients with unfavourable non-Hodgkin’s Lymphomas. Cancer Treatment Reviews; 35: 528-32, 2009 Soubeyran P, Masmoudi A, Blanc-Bisson C, Bellott R, Soubeyran I, Donamaria C, Molimard M, Quénel N, Hœrni B, Robert J. A phase II study for the evaluation of quinine as a modulator of multidrug resistance in non-Hodgkin’s lymphoma. Eur J Cancer 43: 53-4 2007.
Pigozzi D., Tombal B., Ducret T., Vacher P., Gailly P. Role of store-dependent influx of Ca2+ and efflux of K+ in apoptosis in CHO cells. Cell Calcium, 36: 421-430, 2004.
Patent: « Nouvelles compositions et méthodes pour la potentialisation des signaux d’apoptose dans les cellules tumorales » – Brevet français N°FR0858261 4th December 2008 – P Vacher, P Legembre, L Bresson-Bépoldin, B Chaigne-Delalande, P Soubeyran, AM Vacher. US provisional N°US 61/119,767, 4 December 2008. PCT n° 817-PCT, 4th December 2009.