Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model

Anastassia Karageorgis (1) , Michaël Claron (2) , Romain Jugé (3) , Caroline Aspord (1) , Fabien Thoreau (2, 1) , Claire Leloup (2) , Jérôme Kucharczak (3) , Joël Plumas (1) , Maxime Henry (1) , Amandine Hurbin (1) , Pascal Verdié (4) , Jean Martinez (4) , Gilles Subra (4) , Pascal Dumy (5, 4) , Didier Boturyn (2) , Abdel Aouacheria (3, 6) , Jean Coll (1)

1 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
2 DCM - Département de Chimie Moléculaire
3 LBMC - Laboratoire de Biologie Moléculaire de la Cellule
4 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
5 DCM - I2BM - Département de Chimie Moléculaire - Ingéniérie et Intéractions BioMoléculaires
6 UMR ISEM - Institut des Sciences de l'Evolution de Montpellier

Melanoma is a highly metastatic and deadly form of cancer. Invasive melanoma cells overexpress integrin αvß3, which is a well-known target for Arg-Gly-Asp-based (RGD) peptides. We developed a sophisticated method to synthetize mg amounts of a targeted vector that allows the RGD-mediated targeting, internalization and release of a mitochondria-disruptive peptide derived from the pro-apoptotic Bax protein. We found that 2.5 μM of Bax [109-127] was sufficient to destabilize the mitochondria in 10 different tumor cell lines, even in the presence of the anti-apoptotic Bcl2 protein, which is often involved in tumor resistance. This pore-forming peptide displayed antitumor activity when it was covalently linked by a disulfide bridge to the tetrameric RAFT-c[RGD]4-platform and after intravenous injection in a human melanoma tumor model established in humanized immuno-competent mice. In addition to its direct toxic effect, treatment with this combo induced the release of the immuno-stimulating factor MCP1 in the blood and a decrease in the level of the pro-angiogenic factor FGF2. Our novel multifunctional, apoptosis-inducing agent could be further customized and assayed for potential use in tumor-targeted therapy

Domaines: Chimie; Cancer

Anastassia Karageorgis, Michaël Claron, Romain Jugé, Caroline Aspord, Fabien Thoreau, et al.. Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model. Molecular Therapy, 2017, 25 (2), pp.534-546. ⟨10.1016/j.ymthe.2016.11.002⟩. ⟨hal-02000186⟩