Identification and characterization of new anti-melanoma compounds
The melanoma is one of the most lethal cancers among young adults. Melanoma has a high capability of invasion and rapid metastasis to other organs. The prognosis of metastatic melanoma is extremely pejorative. Even if recently encouraging results were obtained with BRAF inhibitors, these responses remain transitory. Regrettably, after a short period of remission, the melanoma acquires in all the cases, a drug resistance and the metastases develop again. Another therapies (anti-CTLA4 or anti PD1) which reactivates the immunity response of the patient, were recently developed. However, these therapies give an objective response in only 15 to 30% of patients. Thus, it appears necessary to develop new drug candidates for specific biotherapy treatment of melanoma.
Using structure/activity relationship studies, we developed and selected a first series of candidates (Thiazole Benzensulfonamides) exhibiting a strong death-promoting effects in melanoma cells with HA15 as the lead compound of this series. Interestingly, HA15 is active molecule on all melanoma cells independently of mutational status and on melanoma cells freshly isolated from patients sensitive or resistant to BRAF inhibitors. HA15 exhibited also a strong efficacy in xenograft mice models without any sign of toxicity in mice. We next performed pan-genomic, proteomic and biochemical studies to decipher the signaling pathway, the mechanism of action. We identified BIP, an endoplasmic reticulum protein, as the specific target of our compound. We demonstrated clearly that the interaction between our compound and BIP increases Endoplasmic Reticulum Stress and leads to melanoma cell death by concomitant induction autophagy and apoptosis mechanisms (Cerezo et al, Cancer cell, 2016). Another part of our researches focuses on Metformin, which is the most commonly used anti-diabetic drug in the world. In melanoma cells, we demonstrated that metformin induces melanoma cell death and also inhibits invasive capacity of melanoma. In this context, a clinical trial has been done to test the efficacy of metformin in metastatic melanoma patients but results were disappointing. We thus recently screened for Metformin-derived compounds to identify new molecules with better pharmaco-kinetic characteristics in melanoma cells than Metformin. Thanks to this screening, we identify a new molecule called CRO15 that we characterized for their anti-melanoma properties. Unpublished interesting results concerning these new biguanide derivate will be presented.
INSERM U1065, team 12, Nice, France
Domain 1 - UMR 3347 / U1021 - Normal and pathological signaling