Toward the development of a novel non-RGD cyclic peptide drug conjugate for treatment of human metastatic melanoma.

Boris Redko,Tamar Segal,Gary Gellerman,Gabi Gerlitz,Dror Tobi,Albert Pinhasov,Galia Luboshits,Helena Tuchinsky,Osnat Ashur-Fabian

doi:10.18632/oncotarget.12748

Abstract

The newly discovered short (9 amino acid) non-RGD S-S bridged cyclic peptide ALOS-4 (H-cycl(Cys-Ser-Ser-Ala-Gly-Ser-Leu-Phe-Cys)-OH), which binds to integrin αvβ3 is investigated as peptide carrier for targeted drug delivery against human metastatic melanoma. ALOS4 binds specifically the αvβ3 overexpressing human metastatic melanoma WM-266-4 cell line both in vitro and in ex vivo assays. Coupling ALOS4 to the topoisomerase I inhibitor Camptothecin (ALOS4-CPT) increases the cytotoxicity of CPT against human metastatic melanoma cells while reduces dramatically the cytotoxicity against non-cancerous cells as measured by the levels of γH2A.X, active caspase 3 and cell viability. Moreover, conjugating ALOS4 to CPT even increases the chemo-stability of CPT under physiological pH. Bioinformatic analysis using Rosetta platform revealed potential docking sites of ALOS4 on the αvβ3 integrin which are distinct from the RGD binding sites. We propose to use this specific non-RGD cyclic peptide as the therapeutic carrier for conjugation of drugs in order to improve efficacy and reduce toxicity of currently available treatments of human malignant melanoma.

Highlights

Melanoma is the most deadly skin cancer, frequently associated with metastasis and poor survival prognosis [1]
The newly discovered short (9 amino acid) non-RGD S-S bridged cyclic peptide ALOS-4 (H-cycl(Cys-Ser-Ser-Ala-Gly-Ser-Leu-Phe-Cys)-OH), which binds to integrin avβ3 is investigated as peptide carrier for targeted drug delivery against human metastatic melanoma
Our research proposes to address these concerns by utilizing the newly discovered short (9 amino acids) nonRGD cyclic peptide ALOS4 (H-cycl(Cys-Ser-Ser-AlaGly-Ser-Leu-Phe-Cys)-OH) that binds to a non-RGD site upon integrin αvβ3 [25]

Summary

Introduction

Melanoma is the most deadly skin cancer, frequently associated with metastasis and poor survival prognosis [1]. Systemic therapy for metastatic melanoma has been ineffective, but recent successes in the development of new therapies including mitogen-activated protein kinase (MAPK) pathway inhibitors, anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) and Programmed cell death protein 1 (PD-1)/ Programmed cell death 1 ligand 1 (PD-L1) `blocking antibodies have all yielded promising results, enlarging the variety of therapeutic options for patients [1, 2]. The modest activity of single drug against metastatic melanoma has raised the possibility to use combinations of cytotoxic agents in order to improve outcomes (such as the combination of carboplatin and paclitaxel that is currently an NCCN cited “community standard” for treatment of patients with metastatic disease), but limited success has been achieved [4,5,6,7,8]. New targeted drug delivery approaches are needed to overcome toxicological problems and improve efficacy

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