1. Academic Validation
  2. A Novel RGD-4C-Saporin Conjugate Inhibits Tumor Growth in Mouse Models of Bladder Cancer

A Novel RGD-4C-Saporin Conjugate Inhibits Tumor Growth in Mouse Models of Bladder Cancer

  • Front Oncol. 2022 Apr 11;12:846958. doi: 10.3389/fonc.2022.846958.
Stefania Zuppone 1 Chiara Assalini 1 Claudia Minici 2 Oronza A Botrugno 3 Flavio Curnis 4 Massimo Degano 2 Angelo Corti 4 5 Francesco Montorsi 1 5 Andrea Salonia 1 5 Riccardo Vago 1 5
Affiliations

Affiliations

  • 1 Urological Research Institute, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy.
  • 2 Biocrystallography Unit, Division of Immunology, Transplantation, and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy.
  • 3 Functional Genomics of Cancer Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy.
  • 4 Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy.
  • 5 Faculty of Medicine and Surgery, Università Vita-Salute San Raffaele, Milano, Italy.
Abstract

Although toxin may have some advantages compared to chemotherapeutic drugs in Cancer therapy, e.g. a potent cytotoxic activity and a reduced risk of resistance, their successful application in the treatments to solid tumors still remains to be fully demonstrated. In this study, we genetically modified the structure of the plant-derived single-chain ribosome inactivating protein saporin (SAP) by fusing its N-terminus to the ACDCRGDCFCG peptide (RGD-4C), an αv-integrin ligand, and explored the anti-tumor activity of the resulting protein (called RGD-SAP) in vitro and in vivo, using a model of muscle invasive bladder Cancer. We found that the RGD-4C targeting domain enhances the cytotoxic activity of SAP against various tumor cell lines, in a manner dependent on αv-integrin expression levels. In a subcutaneous syngeneic model of bladder Cancer, RGD-SAP significantly reduced tumor growth in a dose-dependent manner. Furthermore, systemic administration of RGD-SAP in combination with mitomycin C, a chemotherapeutic drug currently used to treat patients with bladder Cancer, increased the survival of mice bearing orthotopic bladder Cancer with no evidence of systemic toxicity. Overall, the results suggest that RGD-SAP represents an efficient drug that could be exploited, either alone or in combination with the state-of-the-art therapies, for the treatment of bladder Cancer and, potentially, of other solid tumors.

Keywords

RGD peptide; RGD-integrins; bladder cancer; recombinant protein; ribosome inactivating proteins; saporin; targeted therapy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P3732
    99.82%, αv-integrin Ligand