Cancer of the pancreas is a particularly deadly cancer, claiming over 90% of its victims within 5 years from diagnosis. It resists most standard therapies, including surgery, chemotherapy, radiation therapy, immunotherapy and targeted therapy, and metastasizes early, often before being diagnosed. A cure is possible only with very localized tumors.
Now, however, a new cannabis-derivative called FBL-03G, loaded into tumor-targeted smart radiotherapy biomaterials systems (SRBs systems), shows great promise in killing cancer cells within a treated tumor as well as in other distant parts of the body, with a survival advantage.
FBL-03G is a cannabis flavonoid, a synthetic derivative of Cannflavin B. It is not a cannabinoid, and lacks psychoactive properties. This new study uses SRB-loaded FBL-03G introduced into the tumor to test its ability to improve the tumor response to radiation therapy. This is called radiosensitization. It also seeks to explore the immunomodulatory properties of this compound at varying concentrations and volumes.
Harvard researchers are testing cannabinoids, which are derived from the plant Cannabis sativa, for their anti-cancer properties and to alleviate the often harsh adverse effects of chemotherapeutic agents and radiation therapy. One novel approach to the use of cannabinoids incorporated them into smart radiotherapy biomaterials systems (SRBs systems) for direct delivery to the tumor.
Cultivation of marijuana (Cannabis sativa). Image Credit: Kojin / Shutterstock
SRBs, also called “microscopic drones”, are a new form of therapy using biomaterials to deliver radiation to the tumor instead of foreign material implants. They are found to deliver 90% to 100% of the drug into the tumor. Compared to the earlier average of 5% for conventional drug delivery systems, this is incredibly high, and may facilitate rapid progression into clinical trials.
The researchers were particularly interested in the systemic response to FBL-03G delivered via SRBs, and especially the abscopal effect of the treatment – the shrinking of a metastatic tumor following radiation therapy at another site. This is mediated via the immune response, but is rare due to the ability of the tumor to produce immune tolerance of its cells within a short time of initial growth. If FBL-03G enables abscopal effects, it would enhance its role as an immunoadjuvant.
In the first step, FBL-03G was loaded in SRBs which were introduced into the tumor cells in vitro. This produced increased tumor cell death when compared to radiation therapy alone, with synergistic effects being seen with the use of 1 µM of the drug with 4 Gy radiation. This may be due to the inhibition of cancer cells by FBL-03G along with radiation-induced DNA damage.
Moreover, the use of 4 µM of FBL-03G killed pancreatic tumor cells more effectively than 4 Gy radiation therapy, probably through induced apoptosis and by preventing the proliferation of the cancer cells.
The experiment was then repeated in vivo. The results were compared with the effects of direct injection of the same amount of FBL-03G into the tumor. The results showed that tumor growth was reduced much more significantly by the SRB-associated FBL-03G than with intra-tumor administration. Moreover, metastases in the vicinity which had not been treated also showed an abscopal response, with inhibition of tumor growth. Mouse survival was prolonged following treatment with SRB systems containing FBL-03G.
The next step was to test the effect of the same compound at different concentrations, of 100, 200 and 300 µg, in SRB systems, with and without radiation therapy. There was no obvious advantage to the use of radiation therapy. However, both treated and untreated tumors shrank more in the SRB-FBL-03G cohorts than with those treated with 6 Gy radiation or the controls.
Thus FBL-03G acts as a radiosensitizer. Its use in SRBs causes tumors to shrink both locally and in distant sites not exposed to treatment, irrespective of the independent use of radiation therapy. The SRBs allow the FBL-03G to be in contact with the tumor cells for prolonged periods, thus enhancing its efficacy. The SRB system also delivers the drug to the tumor with precision, and thus allows the use of many orders less of the drug than would be otherwise required. The current study used only a single dose of radiation therapy, which again contributes to lower toxicity. Thus this flavonoid appears to be a highly promising compound in the treatment of both local and metastatic tumors in pancreatic cancer.
The impact of this finding is higher when the early metastatic tendency of this malignancy is considered. The fact that FBL-03G increased the survival period is very significant. More work is required to find the optimal dosage combining maximum efficacy with minimum toxicity.
This experiment offers the possibility of rapid translation into clinical practice since it doesn’t require any additional device, and is completed with a single delivery of the immunoadjuvant. Most contemporary immunoadjuvants must be delivered by multiple injections. The single radiation therapy fraction also precludes the need for repeated sessions of radiation, reducing the cost, duration and toxicity of treatment. This could be a huge benefit in countries and communities with relatively low healthcare resources.
The mechanism of the immunoadjuvant activity of FBL-03G on local and metastatic tumor cells with prolonged exposure is still unclear. It could be that FBL-03G is an immunotherapeutic agent, and is therefore equally effective against local and metastatic tumor. Another theory is that FBL-03G delivered via an SRB allows the drug to have prolonged exposure to the tumor, which accounts for its greater efficacy. Since metastasis is among the most serious challenges to cancer cure, and is the factor associated with most of the cancer symptoms and cancer mortality, its management is extremely important.
Thus, this compound needs to be investigated further for its role in pancreatic cancer. The researchers hope to complete the preclinical phase by 2020. The study was published in the journal Frontiers in Oncologyon July 23, 2019.
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 Lowe and Wilfred Ngwa. Frontiers in Oncology. https://doi.org/10.3389/fonc.2019.00660, https://www.frontiersin.org/articles/10.3389/fonc.2019.00660/full