Purpose: Usually, 2 out of 3 patients of pancreatic cancer have Kras mutation causing fast progression of the disease. Prior research shows that, flavonoid derived from Cannabis sativa (FBL-03G) demonstrates significant therapy potential in the treatment of murine pancreatic adenocarcinoma, including potential for radio-sensitization and treatment of metastatic tumors through immunemodulation. Here we demonstrate the potential for FBL-03 in targeting the Kras-gene expression in a murine pancreatic cancer model.
Methods: FBL-03G (Mw =368.38 g/mol) was delivered intratumorally loaded in smart radiotherapy biomaterial (SRB) for sustained action. In house SRBs were developed with Poly (lactic-co-glycolic) acid (PLGA) polymer. KPC cells were derived from a LSL-Kras;p53+/floxed,Pdx-cre mouse used for generating orthotopic pancreatic tumors in C57BL/6 background mice. Tumors were treated with SRB-FL-03 or 6 Gy of radiation or in combination. Post-vivo tumors were collected on day 10 post treatment and tumor weight and intratumor immune cell population were analyzed. To further evaluate the role of these treatment models in Kras-gene expression, western blot analysis was performed on same treated tumor tissue using Kras antibody.
Results: We observed significant reduction of tumor weight with the treatment of SRB-FBL-03G and in combination treatment with RT+SRB-FBL-03G. Radiation was shown to further enhance the antitumor activity of SRB-FBL-03G. Further investigation with flowcytometry also demonstrates increase infiltration of T helper cells (CD45+CD3+CD4+) in both SRB-FL-03 (p<0.01) and RT+SRB-FL-03 (p<0.001) treated groups. Similarly, most important cytotoxic T cells (CD45+CD3+CD8+) was also increased in SRB-FBL-03G (p<0.01), and RT+SRB-FBL-03G (0.001) treated groups, confirming the antitumor immune response with these treatments. Western Blot analysis of the treated tumor tissue also confirmed the suppression of Kras-gene expression in both SRB-FBL-03G (p<0.05) and RT+SRB-FBL-03G (p<0.01) treated groups.
Conclusion: Significant suppression of Kras expression was observed along with immune-modulation and reduction of tumor growth in the FBL-03G treatment, which was further enhanced by radiation.
Funding Support, Disclosures, and Conflict of Interest: There is no conflict of interest.
Radiation Therapy, Radiobiology