FEDER - UCBN - COACH-IPP Project (fct)
Kohesio
UNIVERSITE DE CAEN NORMANDIE
Ovarian cancer causes around 150,000 deaths each year worldwide, according to figures from the World Health Organization (WHO). In France, it affects around 4,500 women per year, and is responsible for more than 3,500 deaths per year in France; it has the lowest survival rate of all gynecological cancers and every woman can develop ovarian cancer, whatever her age, even if the average age is generally around 69 years. The introduction of new treatments and the evolution of protocols over the last thirty years have only slightly improved overall survival: ovarian cancer recurs and is generally incurable. The identification of chemoresistant patients and the development of new therapeutic strategies likely to overcome chemoresistance therefore constitute major challenges, recognized by health authorities. There is chemoresistance to the extent that the regulation of programmed cell death (or apoptosis) is impaired; the control of apoptosis is complicated and responds to different signals, mediated in particular by proteins, which interact with each other. Thus, the Bcl-2 family proteins are among the key players in the regulation of apoptosis. In this family we find anti-apoptotic members (like Bcl-xL or Mcl-1), and pro-apoptotic members. Thus, targeting anti-apoptotic molecules and neutralizing them is one of the possible strategies to restore apoptosis in cells and cause the death of cancer cells. Recently, our team developed a new molecule, called “pyridoclax,” capable of interacting with the Mcl-1 protein [Gloaguen, C.; Voisin-Chiret, A.S. et al. (2015) J.Med. Chem., 58, 1644; WO/2015/132727]. However, since the regulation of apoptosis is complex, this new molecule is not active alone. It needs to be administered with another molecule to exert its anticancer activity. Thus, it seems wise, for the continuation of our work, to design, using efficient physicochemical tools, new agents capable of interacting simultaneously with several proteins. Indeed, recent work by our partner has shown that the anti-apoptotic proteins Bcl-xL and Mcl-1 cooperate to protect ovarian cancer cells against apoptosis, and that their concomitant inhibition leads to the death of chemoresistant cells [Brotin et al. (2010) Int. J. Cancer, 126, 885]. The anti-apoptotic proteins Bcl-xL and Mcl-1 thus constitute an “essential molecular lock preventing the occurrence of apoptosis. Removing this barrier alone is sufficient to induce the death of chemoresistant tumor cells in response to oncogenic stress or chemotherapy. In this context, the discovery of dual-action inhibitors acting on Bcl-xL and Mcl-1 would be of major interest in the treatment of ovarian cancers that are highly refractory to conventional chemotherapy. Indeed, this concept of dual-action inhibitor offers numerous advantages in terms of therapeutic effectiveness by targeting several proteins of the apoptosis signaling pathways. In oncology, directing a therapeutic agent towards several targets (in limited number) constitutes a strategy for inducing cell death in a context of chemoresistance which is very advantageous compared to combinatorial therapies.
Smarter Europe / Research and innovation / Research and innovation activities in public research centres and centres of competence including networking