About 20% of all cancer diseases and about 90% of pancreatic cancer cases are involved with mutations that convert a protein called KRAS into an oncogene (a ‘cancer cuasing protien’). However, after 30 years of intensive research, none of the efforts to target KRAS have matured to become a drug. KRAS is a GTPase protein belonging to the family of RAS proteins. RAS proteins are localized in the inner cell membrane, bind GDP and GTP, and possess an intrinsic GTPase activity, implicated in the regulation of their activity. RAS proteins influence proliferation, differentiation, transformation, and apoptosis by relaying mitogenic and growth signals into the cytoplasm and the nucleolus. In a normal cell, most of the RAS molecules are present in an inactive GDP-bound conformation.
In pancreatic ductal adenocarcinoma, the cancer cells are addicted to the expression of the mutated KRAS. KRAS mutations were shown to be an early event in the development of pancreatic cancer. Genetic alterations in the KRAS signaling pathway are involved in over 90% of pancreatic cancer cases. The most common KRAS mutation of the human pancreas adenocarcinoma is a gain-of-function substitution mutation of glycine at codon 12 to aspartate (G12D). Moreover, PDA cancer cell growth was shown to be dependent on the activity of the mutated KRAS and accordingly, silencing KRAS has proven effective in controlling pancreatic cell line proliferation.
The Silenseed’ LODER platform enables harnessing of the advantages of siRNA technology to a therapeutic modality for pancreatic cancer. siRNA against mutated KRAS can lead to apoptosis of cancer cells in vitro and in-vivo in mice and reduce tumor growth. In the cells, the siRNA is loaded into a protein complex called the RNA-induced silencing complex (RISC), which unwinds the siRNA, retaining the antisense strand, thus silencing the target gene and preventing protein production. Moreover, anti-mutated KRAS treatment can potentially slow epithelial-to-mesenchymal transition (EMT) and thereby slow the progression of PC disease from local to metastasis. Local and prolonged delivery of siRNA-based drugs can overcome the many existing challenges of systemic delivery, including enzymatic degradation and renal clearance of the siRNA, while enabling targeting of previously non-druggable targets, dramatic dose reduction, and reduction/elimination of toxicity effects including stimulation of the immune system.
siG12D is synergistic and strongly enhances the effect of chemotherapy in pancreatic cancer (A) Gemcitabine (Gemzar), (B) FOLFIRINOX
KRAS-LODER inhibits growth of pancreatic tumors in-vivo in mice from cells of human origin, (A) shown here the size of tumor based on Luciferase imaging and (B) KRAS-LODER extends survival of mice bearing Panc1 pancreatic tumors from the different treatment groups: untreated, injected with siG12D, or implanted with empty LODERs or KRAS-LODERs (From Zorde Khvalevsky et al., Mutant KRAS is a druggable target for pancreatic cancer, PNAS Vol 110, No. 51, 20723-20728, Dec 2013)