Pancreatic cancer (PC) is still one of the major challenges in clinical oncology, with an average overall survival shorter than a year that has not improved significantly in the last decades. Silenseed developed novel treatments for cancer diseases based on its LODER™ (LOcal Drug EluteR) platform, combining proprietary technology of local and prolonged delivery of siRNA (short interfering RNA) with specification and optimization of new targeted siRNA drugs. Over 90% of human pancreatic ductal adenocarcinomas involve gain-of function mutations in the KRAS oncogene. The LODER™ enabled the company to select this KRAS target, thus far considered as an ‘undruggable’ target. Moreover, the LODER™ enables a continuous administration along a few months to support diffusion of drug within the entire tumor tissue, while protecting the siRNA from degradation.
The effects of siG12D LODER on KRAS mRNA and protein levels and on cellular facets related to tumorigenesis were tested in vitro. These studies show a marked decrease in KRAS expression upon treatment and consequent decreases in proliferation, viability and migration. In vivo, the retarding effects of siG12D LODER on tumor growth were shown through both subcutaneous and orthotopic xenografts and synograft models. Downstream signaling changes attesting to treatment specificity – a decrease in ERK signaling and proliferation markers - were demonstrated by western blot and immunohistochemistry. Furthermore, the survival of treated mice was prolonged.
Following these successful pre-clinical studies, a Phase I clinical study has been carried out on non-operable non-metastatic patients (NCT01188785). Full tolerability and safety have been confirmed. Moreover, encouraging early evidences show halting of tumor growth, decrease in tumor serum marker CA19-9 and extension of overall survival. Phase II study (NCT01676259) is now in preparation.
