Identification of siRNA silencing TGFβ1 and VEGFR2 and utility of the combination in targeting immune modulation and angiogenesis in treating melanoma in vivo

Late-stage melanoma can metastasize to organs beyond the skin, such as lungs, liver, brain, and bone, resulting in reduced patient survival time. The incidence of melanoma is currently growing worldwide, and novel therapeutic options are needed to prevent its dissemination and to improve therapeutic results. This paper describes the use of small interfering RNA (siRNA) to silence expression of TGFβ1 and VEGFR2 as an alternative approach for melanoma treatment. These two therapeutic targets have been well-documented in tumor immune modulation and tumor angiogenesis within the tumor microenvironment (TME). Two potent siRNA candidates targeting TGFβ1 or VEGFR2 were identified with 100% identity to sequences of mouse, non-human primate (NHP), and humans. The combination of the two siRNAs was formulated with a clinically validated polypeptide nanoparticle (PNP) carrier. This PNP-packaged siRNA formulation, STP355, administered intravenously in mice bearing syngeneic melanoma tumors, demonstrated silencing of both targets and a reduction in tumor growth. STP355 also reduced tumor weight significantly, without the toxicity observed with cisplatin, resulting in prolonged survival of mice compared with this small molecule. It increased immune cell penetration into TME and reduced metastases to the lung. STP355 was more efficacious than, and somewhat additive with, immune checkpoint inhibitory monoclonal antibodies.