Pancreatic cancer is a devastating disease, with a five-year survival of less than 6%. Despite years of intensive research, pancreatic cancer remains one of the deadliest cancers worldwide, with mortality nearly mirroring incidence (Ilic, World J Gastroenterol, 2016). This is due, in part, to late detection of the disease, but also the lack of effective therapeutic strategies to combat the disease.
Many in vitro and in vivo studies have reported the antitumorigenic effects of cannabinoids; however, there has yet to be clinical translation into practice. Given that cannabinoids appear to have anticancer potential, both as a monotherapy and in combination with other therapies, such as clomiphene, these compounds warrant further study to determine if they have the potential to advance the standard of care.
Diagram of a pancreas.
About Pancreatic Cancer
The pancreas is an organ of the digestive and endocrine system located in the abdominal cavity behind the stomach. It helps to regulate several important hormones in the blood including insulin, glucagon, and somatostatin, and aids in digestion of carbohydrates, proteins, and lipids. Pancreatic cancer is a highly lethal disease, for which mortality closely parallels incidence. It is one of the leading causes of cancer mortality in developed countries and one of the most lethal malignant neoplasms across the world. Based on WHO estimates, pancreatic cancer causes more than 430,000 deaths each year, accounting for 4.5% of all cancer deaths. It ranks as the seventh most common cause of cancer death. Rates of death are greater in more high-income countries. The estimated five-year survival rate of pancreatic cancer is thought to be about 6% worldwide and less than 3% in England (GLOBOCAN, 2018; Ilic, World J Gastroenterol, 2016). To date, the causes of pancreatic cancer are still insufficiently known, although certain risk factors have been identified which include smoking, obesity, advanced age, pancreatitis, heavy alcohol drinking, genetics, and diet (Bosetti, Mol Carcinog, 2012).
Part of the reason pancreatic cancer is so lethal is because most patients remain asymptomatic until the disease reaches an advanced stage. When patients do present with symptoms they include weight loss, abdominal pain, jaundice, nausea and vomiting, back pain, lethargy, new-onset diabetes, and thrombophlebitis. Signs of the cancer include jaundice, hepatomegaly, and new right upper quadrant mass. The initial presentation of pancreatic cancer varies according to the tumor location. Tumors at the pancreatic head present more often with jaundice, steatorrhea, and weight loss compared to tumors of the body and tail (Keane, BMJ Open, 2014; Porta, Clin Transl Oncol, 2005). There is no standard screening protocols for patients, making the disease even more difficult to detect (Kamisawa, Lancet, 2016).
The two main tumor types of pancreatic cancer are ductal adenocarcinoma (accounting for about 85% of cases) and pancreatic endocrine tumors (which make up less than 5% of all cases) (Ilic, World J Gastroenterol, 2016). Pancreatic ductal adenocarcinomas (PDAC) are mucin-producing, gland-forming neoplasms that elicit an intense stromal desmoplastic reaction. An accumulation of somatic mutations in oncogenes and tumor suppressor genes cause non-invasive precursor lesions (pancreatic intraepithelial neoplasias) to transform into cancerous adenocarcinomas. The four major driver genes identified in pancreatic ductal adenocarcinoma are KRAS, CDKN2A, TP53, SMAD4. KRAS mutations and alterations in CDKN2A are two of the most common early events in pancreatic tumorigenesis. Somatic mutations in KRAS, a gene which encodes a small GTPase that mediates downstream signaling from most growth factor receptors, occur in more than 90% of tumors. CDKN2A, which encodes an essential cell-cycle regulator, is the most frequently altered tumor suppressor gene, with loss of function in more than 90% of ductal adenocarcinomas (Kamisawa, Lancet, 2016).
If pancreatic cancer is suspected, patients receive a full lab workup, including an analysis of liver, gallbladder, and pancreatic function. Patients with jaundice will receive a transabdominal ultrasound, endoscopic retrograde cholangiopancreatography (ERCP) or a magnetic resonance cholangiopancreatography (MRCP) to evaluate for obstruction of the common bile duct. If a pancreatic mass is seen on initial imaging, an abdominal computed tomography (CT) is obtained to confirm the presence of the mass and assess disease extent. Abdominal CT is the preferred initial imaging test in patients with epigastric pain and weight loss, but without jaundice. Endoscopic ultrasound-guided or percutaneous biopsies of the mass can be obtained if histologic confirmation is needed. The tumor marker CA 19-9 is often used an indicator of disease activity, but not for initial screening (Hidalgo, Clin Transl Oncol, 2017).
Treatment of pancreatic cancer includes surgery, chemotherapy, radiation therapy, and palliative care. Surgical resection is regarded as the only potentially curative treatment for pancreatic adenocarcinoma, however, because of the late presentation of the disease, only 15-20% of patients are candidates for pancreatectomy. Patients cannot undergo resection if they have metastases in the liver, peritoneum, omental or any extra-abdominal site or if there is occlusions of key arteries and veins. Adjuvant chemotherapy with gemcitabine or S-1, an oral fluoropyrimidine derivative, is given after surgery. FOLFIRINOX (fluorouracil, folinic acid or leucovorin, irinotecan, and oxaliplatin) and gemcitabine plus nanoparticle albumin-bound paclitaxel are the treatment of choice for patients who are not surgical candidates but have good performance status (Kamisawa, Lancet, 2016). Despite surgical and medical advancements, the life expectancy for pancreatic cancer patients has seen no substantial changes in the past 40 years. Palliative treatment is often the only available option for patients (Ferro, Nature, 2018). There is an unmet need for more effective treatment strategies to improve prognosis.
Cannabidiol (CBD) as an Adjunct to Standard of Care Treatment
There is a growing body of evidence supporting the role of cannabinoids in the management of cancer due to their antineoplastic, anticachectic and analgesic potential. Anticancer activities of cannabinoids have been demonstrated for various malignant tumors including brain, breast, skin, blood, and recently, pancreatic cancer (Michalski, Int J Cancer, 2008).
Although there has been limited research on the topic, several studies have suggested a relationship between changes in the endogenous endocannabinoid system and pancreatic cancer. A 2006 study of tumor tissue in Spain found higher levels of both CB1 and CB2 receptors on human pancreatic tumor biopsies. Expression of cannabinoid receptors was detected clearly in tumor nodules, but hardly found in surrounding healthy pancreatic tissue (Carracedo, Cancer Res, 2006). A German study on the relationship between cannabinoid receptors, endocannabinoid metabolizing enzymes, and pancreatic ductal adenocarcinomas (PDAC) in post-mortem tissue samples demonstrated that the levels of these receptors and enzymes on pancreatic cancer cells may actually effect prognosis of PDAC patients. Compared to healthy controls, the levels of cannabinoid receptors were generally upregulated in pancreatic cancer, suggesting an active role of these receptors in pancreatic carcinogenesis. Moreover, researchers found a negative correlation between the amount of cannabinoid receptors, specifically CB1, and patient survival. The median survival in the group with low CB1 staining in cancer cells was 16 months, versus six months for the group with a high CB1 staining (p=0.0011). Researchers were also able to show that lower levels of endocannabinoid metabolizing enzymes were associated with shorter survival (Michalski, Int J Cancer, 2008). This body of research points to a relationship between changes in the endocannabinoid system and the lethality of pancreatic cancer, suggesting that a cannabinoid-based therapy may activate cell-death pathways primarily in tumor cells.
Given the relationship that appears to exist between changes in the endocannabinoid system and PDAC, it follows that cannabinoids may have a role in the treatment of pancreatic cancer. Research have demonstrated that cannabinoids can induce apoptosis of pancreatic cells both in vitro and in vivo. Based on examination of in vitro pancreatic tumor cells, researchers have postulated that activation of CB2 cannabinoid receptors induced apoptosis of pancreatic tumor cells, based on dose-dependent decreases in cell viability in the lines tested. Researchers were also able to selectively induce apoptosis of pancreatic tumor cells in vivo in murine models (Carracedo, Cancer Res, 2006; Carracedo, Cancer Cell, 2006).
Another in vitro study suggests that cannabinoid derivatives can induce cell death in pancreatic cancer cell lines independent of cannabinoid receptor presence, possibly due to their lipophilic nature allowing them to cross cell membranes and disrupt cellular networks (Fogoli, FEBS, 2006). More recent in vitro research has suggested that cannabinoids induce autophagy through AMP-activated kinase (AMPK), a sensor of energy status and homeostasis in cells. Research suggests that cannabinoids increase oxidative stress, activating AMPK in malignant pancreatic cells, ultimately promoting cell death (Dando, Cell Death Dis, 2013). While the mechanism of action still needs to be fully elucidated, evidence suggests that there are anti-tumor effects of cannabinoids in pancreatic adenocarcinomas.
Merits of a Cannabinoid Combination Therapy
Prior preclinical research has shown that the anti-tumor effects of cannabinoids can be improved when combined with other therapies. Recent research on combination therapy for pancreatic cancer has also shown similar, promising results. Combining cannabinoids with other therapies may allow for the simultaneous targeting of tumor progression at different levels, while minimizing toxicities for these therapies relative to toxicities from higher doses when used as monotherapies (Yasmin-Karim, Front Oncol, 2018).
Monotherapy with gemcitabine has been the standard treatment for PDAC during the last decade, although it only has a response rate of <20% (Burris, J Clin Oncol, 1997). There has been some modest improvement in survival with different drug combinations, including gemcitabine and platinum salt, but there is still substantial room for improvement. Recent investigations into the impact of gemcitabine combined with cannabinoids have yielded promising results. One study demonstrated that the in vitro combination therapy synergistically inhibited pancreatic adenocarcinoma cell growth and increased the production of reactive oxygen species in pancreatic cancer cells, causing increased cell stress and ultimately increased autophagy of the cancer cells. Cannabinoids also potentiated the effects of the gemcitabine 5- to 10-fold in traditionally resistant cell-lines. Moreover, there were minimal off-target effects as normal fibroblast cells were significantly less sensitive to cannabinoid therapy and their growth was not further inhibited by GEM addition. This was thought to be due, in part, to the overexpression of cannabinoid receptors in pancreatic cell lines. In in vivo mouse models, the researchers found the tumor burden of the mice treated with combination therapy remained essentially unchanged, while it increased in the monotherapy and control groups. The body mass of the mice did not change during the experiment, suggesting the treatment did not produce any apparent toxicity (Donadelli, Cell Death Dis, 2011).
Another recent in vivo study in mouse models looked specifically at the synergistic effects of cannabidiol (CBD) and gemcitabine when targeting a novel receptor, GPR55, in PDAC progression. GPR55 is a G protein-coupled receptor, and increasing evidence shows that it plays an important role in the progression of many cancer types. CBD is an antagonist to the receptor. The researchers found that, following combination therapy, there was a significant increase in survival. Compared to controls, the mice treated with combination therapy survived three times longer compared to those treated with gemcitabine alone (mean 52.7 days vs 18.6 days). The combination therapy inhibited tumor cell production and slowed the development of resistance to gemcitabine both in vivo and in vitro (Ferro, Nature, 2018).
An area that has yet to be fully explored is the relationship between PDAC and estrogen receptor modulator therapy. Recent research suggests androgen receptor signaling may have a critical role in the development of pancreatic cancer (Kanada, World J Gastroenterol, 2014). If these receptors can be targeted, it could have high therapeutic potential for this difficult-to-treat cancer.