Flavonoid Derivative of Cannabis Demonstrates Therapeutic Potential in Preclinical Models of Metastatic Pancreatic Cancer
Michele Moreau, Udoka Ibeh, Kaylie Decosmo Noella Bih, Sayeda Yasmin-Karim, Ngeh Toyang, Henry Lowe5 and Wilfred Ngwa
Frontiers in Oncology, July 2019, Vol. 9, article 660.
Pancreatic cancer is particularly refractory to modern therapies, with a 5-year survival rate for patients at a dismal 8%. One of the significant barriers to effective treatment is the immunosuppressive pancreatic tumor microenvironment and development of resistance to treatment. New treatment options to increase both the survival and quality of life of patients are urgently needed. This study reports on a new non-cannabinoid, non-psychoactive derivative of cannabis, termed FBL-03G, with the potential to treat pancreatic cancer. In vitro results show major increase in apoptosis and consequential decrease in survival for two pancreatic cancer models- Panc-02 and KPC pancreatic cancer cells treated with varying concentrations of FBL-03G and radiotherapy. Meanwhile, in vivo results demonstrate therapeutic efficacy in delaying both local and metastatic tumor progression in animal models with pancreatic cancer when using FBL-03G sustainably delivered from smart radiotherapy biomaterials. Repeated experiments also showed significant (P < 0.0001) increase in survival for animals with pancreatic cancer compared to control cohorts. The findings demonstrate the potential for this new cannabis derivative in the treatment of both localized and advanced pancreatic cancer, providing impetus for further studies toward
Keywords : pancreatic cancer, flavonoids, cannabis, metastasis, radiotherapy, smart biomaterials
Pancreatic ductal adenocarcinoma is an antagonistic internecine ailment of the exocrine pancreas with < 8% of patients surviving within a 5-year period (1, 2). A major challenge shared by pancreatic cancers is its aggressiveness, which often metastasizes to other organs before the patient is even diagnosed (3, 4).
Current treatment options for pancreatic cancer include: surgery, chemotherapy, targeted therapy, immunotherapy, and radiation therapy. Curative treatment is available only if the tumor is found early and can be removed by surgery before metastasis. If the cancer has metastasized, the standard of care is chemotherapy, or radiotherapy. However, pancreatic cancer is notoriously defiant to current therapies including chemotherapy, radiotherapy and immunotherapy (1, 5).
Cannabis sativa and their derivatives, have been investigated as both anti-cancer agents and for managing the side effects of conventional cancer treatments like chemotherapy and radiotherapy (6). Previous studies have indicated that medical cannabis derivatives could enhance survival in pancreatic cancer animal models, when used in synergy with radiotherapy (7). Smart materials for drug delivery like the smart radiotherapy biomaterials (SRBs) system have also been investigated for delivering cannabinoids into tumors to enhance radiotherapy treatment for pancreatic cancer (8). A major benefit of the SRB approach is their ability to be employed in place of currently used inert radiotherapy biomaterials (e.g., spacers, or fiducialmarkers) and hence their use could come at no additional inconvenience to patients.
In this study, we investigate a new non-cannabinoid, nonpsychoactive derivative of cannabis, called FBL-03G, to assess its potential for the treatment of pancreatic cancer. We hypothesize that the use of FBL-03G will have therapeutic potential and can enhance radiotherapy during the treatment of pancreatic cancer. To investigate this hypothesis, in vitro studies were first carried out with and without radiotherapy (RT). In vitro studies, in vivo studies were also conducted in small animals employing FBL-
03G sustainably delivered from smart radiotherapy biomaterials, allowing continual exposure of the tumor to the cannabis derivative payloads over time.
Apart from the antineoplastic properties of cannabis derivatives, the immune system modulative properties of these extracts have been well documented (8–12). Different volumes and concentrations of FBL-03G payloads were also investigated for their potential to generate systemic tumor responses. In particular, we investigated the abscopal effect, whereby radiotherapy (RT) at one site may lead to regression of metastatic cancer at distant sites that are not irradiated (13). The abscopal effect has been connected to mechanisms involving the immune system (14). However, the abscopal effect is rare because at the time of treatment, established immune-tolerance mechanisms may hamper the development of sufficiently robust abscopal responses. Today, the growing consensus is that combining radiotherapy with immuno-adjuvants provides an opportunity to boost abscopal response rates, extending the use of radiotherapy to treatment of both local and metastatic disease (15). With in this context, the cannabis derivative FBL-03G was also investigated as a potential immuno-adjuvant to radiotherapy.