Cancer: a disease of the body’s endocannabinoid system
PART I - THE ERRORS
YEAR: 1620
LOCATION: LONDON, BRITAIN
A young medical student accompanies his mother to the city hospital, complaining of shortness of breath, chest pain, and discomfort radiating to her arm and throat. The attending physician does a routine check-up and theorizes that her lungs were not pumping sufficient blood throughout the body. He proceeds to recommend a series of tests to the patient to check for irregular lung function.
The young student has his doubts - lungs pumping blood? Something does not sound right. Nevertheless, he agrees with the physician and escorts his mother to administer the prescribed tests. A few months later, she passes away suddenly, causes: unknown.
As it turns out, in 1620, physicians believed that the lungs were responsible for moving the blood around throughout the body. They proposed that blood was formed new from digested food, dissipated, and consumed by the body. The only function of the heart, in their opinion, was the production of heat.
It wasn't until eight years later that William Harvey (physician extraordinary to King James I) published his famous "de Motu Cordis" where he hypothesized that the heart is responsible for pumping blood throughout the body.
"It must, therefore, be concluded that the blood in the animal body moves around in a circle continuously and that the action or function of the heart is to accomplish this by pumping. This is [the] only reason for the motion and beat of the heart." - [William Harvey and the discovery of the circulation of the blood]Four hundred years later, the scientific community recognizes William Harvey as the man who discovered and published the first accurate description of the human circulatory system.
YEAR: 1975
LOCATION: RICHMOND, VA, USA
A team of researchers at the Medical College of Virginia publish a seemingly obscure paper titled "Anti-neoplastic activity of cannabinoids." They had received funding and an exclusive license from the Drug Enforcement Agency (DEA) to study the Cannabis plant. Their mission: to report on how THC might bedetrimental to immunosuppressed mice with cancer. THC is one of the natural compounds found in Cannabis, called a phytocannabinoid. It is known to cause psychotropic effects. So the researchers injected THC into mice that had tumors and waited. To their surprise, they found that the tumors shrank!
Immediately after they reported this data in their study, the DEA stripped them of their license to study Cannabis and terminated the funding.
Why did this happen?
During the 1960s and 1970s, Cannabis had evolved into a socio-political drug. In 1970, under President Richard Nixon, the US Congress classified Cannabis as a Schedule 1 drug through The Controlled Substances Act. To curb the influence of Cannabis, the DEA had systematically restricted access to the plant, including in research. They provided access and funding to institutions selectively. They did this with the hopes that further research might support the claims of its deleterious effects (which, as is evident from the MCA study above, backfired).
This story is essential, and we will revisit it later.
YEAR: 2019 (DECEMBER)
LOCATION: GOA, INDIA
My mother, Canti, has just been diagnosed with a malignant brain tumor called glioblastoma multiforme, the most aggressive type of cancer known to humans. There is no known cause, no known cure and no known method of preventing this cancer. All current treatments are, at best, palliative.
My family has never had a history of cancer (including distant family relatives). When I ask the medical oncologists what could have caused the tumor, they redirect my attention to the treatment.
it does not matter what caused this cancer, it is more important that we treat it. While acknowledging that they cannot cure it, they remind my family that she would only live 3 months without immediate treatment. After the treatment, she could get 12 months. My family accedes, and my mother goes through the current standard-of-care treatment of glioblastoma, which is abysmal, brain surgery followed by radiation therapy followed by chemotherapy. This treatment has not changed much for the past 30 years, and consequently, neither has the outcome.
My mother is wheelchair-bound within 2 months of diagnosis, having lost most of her cognitive and motor functions. Yet, only a few months earlier, she was expertly balancing herself during yoga while visiting me in Lisbon, Portugal.
I am perplexed, and I revisit the question of causation.
By now, the doctors are busy managing the side effects - of which there are many (radiation after-effects and chemotherapy side-effects). For chemotherapy, the doctors have prescribed temozolomide, approved in 2005, and only works for 1/3 of GBM patients. MGMT, a biomarker found in her tumor sample, is "fortunately" methylated. This finding suggests that temozolomide could give her an additional 2 months.
The doctors spend their time poring over MRI scans that cannot tell us if the disease is stable or progresses. I insist on my question.
Cancer is caused by mutations in the DNA.What causes the mutations?
Anything. It could be the environment. It could be ionizing radiation. It can happen at any time to anyone.I am beginning to identify with that young man from 1620 who accompanied his mother to the London city hospital (in case you were wondering, she was most likely experiencing congestive heart failure, which, if left undiagnosed, can be fatal)
We are missing something big.
PART II - THE ENEMY
Like most high school kids who played PC games during the late '90s, I would rush home after school to kill demons in a first-person shooter called Quake. The game's rules were simple - stay alive and work your way to the next level. In the final level, the player encounters the "enemy boss" - Shub-Niggurath - a massive demonic tentacled creature, with three tendril-like limbs extending upwards from her central bleeding mass, surrounded by a lake of lava.
None of the hero's weapons can inflict damage on her, and somewhat surprisingly, she has no attacks of her own. Shub-Niggurath's only 'combat' ability is her impossible defense. She relies purely on the power of her children, and the only way to win the game is to kill all her children. That was unexpected.
Imagine that you were asked to "design" an enemy. How would you go about it? One approach is to imagine the form of the enemy first and then give it monster "functions" such as speed, aggression, special abilities. Another approach is to reverse engineer this process by asking the question, "what do we want the enemy to represent in the game." In other words, imagine the "abstract function" of the enemy before giving it "form."
Let me attempt to use the second approach to build a new enemy with the following "abstract functions."
function (of origin): mysterious, i.e., of unknown origin
function: capable of invisibly signaling, i.e., recruiting "good" soldiers to join the evil army
function: capable of self-healing, i.e., ability to re-spawn and further agonize the hero
Now imagine you are the hero of this game. How would you defeat this enemy?
Mercilessly attacking the enemy would be fruitless and temporary since it would eventually self-heal. Furthermore, the attack would leave the hero's health diminished.
We are left with two other choices.
understand the enemy's origins
uncover the "invisible signaling" process
Only the pursuit of one of these two choices could give us a clue on how we can defeat an enemy with a self-healing capability. I am tempted to understand the enemy's "invisible signaling" before I tackle its origins.
Let us now return to the 1975 MCA research study.
After the study was published, researchers in the field contemplated the reasons for the extraordinary response of the mice to THC. Perhaps:
the mice had cannabinoid receptors in the brain (think of these as "locks") and
THC was mimicking an "endo"-cannabinoid. (think of these as "keys")
It was not until 20 years later that both these theories were proven right.
In the early 1990s, researchers discovered the presence of cannabinoid receptors in the brain (receptors CB1 & CB2). On 24 March 1992, Lumír Hanuš, a Czech analytical chemist working with William Devane, an American pharmacologist, isolated the human brain's first known endocannabinoid. They named it anandamide, after the Sanskrit word for joy or bliss.
With the discovery of both the receptors (locks) and the endocannabinoids (keys), researchers had uncovered proof of a complex system hitherto unknown to humans. This system works within our body alongside all other previously-known systems (including the "recently discovered" circulatory system).
Initial research suggested that endocannabinoid receptors were only present in the brain and nerves. However, additional research showed that the receptors were present throughout our body: in our skin, immune cells, bone, fat tissue, liver, pancreas, skeletal muscle, heart, blood vessels, kidney, and gastrointestinal tract. In short, everywhere.
This complex system is known as the Endocannabinoid System or ECS.
It is defined as a sophisticated signaling system within our body that maintains bodily homeostasis and natural harmony in response to changes in the environment. Research shows that ECS is involved in regulating pain, memory, mood, appetite, stress, sleep, metabolism, immune function, and reproductive function. It is also incredibly old, having evolved over 500 million years ago. Moreover, it is present in all vertebrates — mammals, birds, reptiles, amphibians, and fish all produce endocannabinoids.
Scientists have begun to recognize endocannabinoids as one of the most widespread and versatilesignaling molecules known to humans.
The discoveries did not stop there. In 2007, a group led by Jan Lötvall in Sweden discovered messenger RNA and microRNA inside "exosomes." Exosomes are minute lipid vesicles secreted by a variety of cells. They were initially assumed to provide cells with the means to dispose of unneeded proteins, nucleic acids, and lipids. Today, we know that exosomes play a role in intercellular communication.
Exosomes aid in cancer proliferation and chemo-resistance through the active transfer of pro-oncogenic factors.
The ECS system could also help explain the recent mystery findings at the Fred Hutchinson Cancer Research Center and Alvord Brain Tumor Center in Seattle. The researchers observed an unintended abscopal effect of a ULBP3-armed oncolytic herpes simplex virus (oHSV) used to treat GBM. An abscopal effect occurs when therapy shrinks not only the targeted tumor but also leads to the shrinkage of untreated tumors elsewhere in the body. Oncolytic viruses, by design, should only induce local tumor destruction and inflammation. However, in the absence of viral spreading away from the local site, the oHSV inhibited distant tumor growth.
With the discovery of the ECS and exosomes as "signaling" mechanisms, I feel electrified. Could this be the "invisible signaling" that my enemy has been using?
PART III: THE EXPLORATION
I must admit that I only had a superficial understanding of cancer when my mother was diagnosed with GBM.
More than a decade ago, I lost a high school buddy of mine, Daryl, to acute lymphoblastic leukemia. He preferred "command & conquer" games to first-person shooters. When he introduced me to Red Alert, I was hooked and never looked back. When I do look back, I remember that Daryl maintained a positive spirit throughout his cancer therapy. I recognize that I never internalized the real depth of his disease. Amongst many debilitating "treatments," he lost half a lung, damaged the nerves in his feet from chemotherapy, and underwent a bone marrow transplant.
Despite the brutal toll that the treatment takes on my mother's body, it is not the regime that bothers her - it is the question "why."
During the 65 years that she has been alive, she has never smoked, rarely ever drank alcohol and ate from a "food as medicine" mindset. She maintained an active lifestyle and daily climbed multiple flights of stairs at our family-run hotel in Goa.
Immediately after surgery, she asked me again, "why" this happened to her. I felt helpless without an answer.
I explore the question of causation yet again.
However, this time, I take my question to cancer research centers and to biotech companies - individuals who are closer to the science.
I make progress.
Researchers point me to a virus, cytomegalovirus of the herpesvirus family. I am surprised to discover that a few cancers are caused by viruses. Harald zur Hausen went against existing dogma and postulated that the human papillomavirus (HPV) caused cervical cancer, the second most common cancer among women. Many researchers at the time scoffed at this idea. However, they were left speechless when he walked away with the 2008 Nobel Prize in Medicine for proving his theory. His work eventually led to the development of prophylactic vaccines against HPV acquisition. (Thank you, Harald, for not giving up).
I add an anti-viral, valacyclovir, to my mom's drug regime in the hopes that it might help.
It doesn't.
Other researchers point me back to the "mutations." However, unlike the doctors that I have spoken to so far, they encourage me to sequence my mother's genome. I track down a reputable sequencing lab in India, and I send them my mother's tumor and blood samples. As I await the report, I discover the work done by The Cancer Genome Atlas (TCGA).
The TCGA was built over 12 years, tracking 11000 cancer genomes across 33 types of cancers, at the cost of $275 million. It followed upon the success of the Human Genome Project, which cost $3 billion over 13 years to sequence the first human genome. The TCGA data is publicly available to analyze at the GDC Data Portal, so I investigate. Of the 594 available GBM-cancer-genomes, I am disappointed to find that only 3 cases belong to "non-white Asian women." I don't need to be a researcher to understand that a more diverse cancer database could help us gain a broader understanding of cancer.
Other researchers point to clinical trials.
I contact around 50 clinical trials around the world that are recruiting for newly-diagnosed GBM patients.
The timing is horrible. In addition to new travel restrictions imposed by the coronavirus pandemic, I am told by each of these centers that my mom's rapidly deteriorating condition is not a "good fit" for their trials (ironically research centers need "fit" terminal cancer patients to test their synthetic drugs)
Frustrated, I build my own "drug landscape tool." This tool helps me identify drugs currently in phase II & phase III trials, using data from the UK-based OpenTargets platform. I keep my fingers crossed that one of these drugs will soon become the magic pill that can save my mother's life, but I'm not holding my breath.
On the side, I read The Emperor of All Maladies by Siddhartha Mukherjee. Except for an epic history of doctors' failures in defeating cancer, I do not receive much value.
Finally, my research leads me to a clue:
"cancer pathways."
Over the past few decades, cancer researchers have uncovered about a dozen cancer pathways that aid in cancer development and proliferation. A pathway is a mechanistic way that cancer evolves and survives.
Of these pathways, "immune checkpoint signaling pathways" have shown the most promise in the past decade. The FDA approved the first immunotherapy drug, Ipilimumab, in 2011, and has since approved an additional six drugs for various cancers. This approach has revolutionized cancer treatment by targeting the body's immune system to detect and destroy cancer cells. Right now, immune checkpoint inhibitors are the number 1 treatment therapy for lung cancer and melanoma (surpassing chemotherapy).
Unfortunately, GBM is the worst.
Immunotherapy is not effective against GBM. It remains unapproved in the US, Europe, and India.
I am disheartened but not defeated. The recent success with immunotherapy as an anti-cancer treatment tells me that we are on the right track. If targeting the immune system has yielded these results, then perhaps we need to target its source.
I return full circle to the endocannabinoid system, the regulator of the immune system.
PART IV: THE END GAME
I have learnt that medical oncologists are afraid to use the C-word when they talk to patients. One might think that word is "cancer," but that would be incorrect.
In a twisted cry to J.K. Rowling's character Voldemort ("he-who-shall-not-be-named"), the word that oncologists dread using is, in fact, "cure."
Instead, they prefer to use the words "long-term remission."
(Remission: "a decrease in or disappearance of signs and symptoms of cancer. In complete remission, all signs and symptoms of cancer have disappeared, although cancer still may be in the body.)
I do not want to glorify cancer. I am looking for a cure.
Encouraged by the success of researchers from targeting cancer pathways, I build a heat map. It tracks different compounds against established pathways. Think of the compounds as weapons and the pathways as the targets.
My goal: To find a weapon that acts against multiple pathways AND utilizes the immune system AND agonizes the ECS system
With these filters, there is only one weapon that jumps out from the research (both published and unpublished) - and it is a natural product.
cannabidiol (CBD) from the cannabis plant
*new weapon unlocked!*
Specifically, research shows that CBD:
up-regulated the active (phosphorylated) JNK1/2 and MAPK p38 levels. MAPK p38 was one of the main drivers of CBD-induced cell death. https://pubmed.ncbi.nlm.nih.gov/29088769/
increased ROS (reactive oxygen species), which led to the inhibition of cell survival, phosphorylated (p)-AKT, self-renewal and a significant increase in the survival of mice bearing GSC (glioma stem cells) https://pubmed.ncbi.nlm.nih.gov/25590811/
down-regulated ERK and Akt prosurvival signaling pathways in U87-MG and T98G cell lines. https://pubmed.ncbi.nlm.nih.gov/24204703/
decreased hypoxia-inducible factor HIF-1α expression in U87-MG cells (HIF activity is involved in angiogenesis required for cancer tumor growth and the research community has been searching for HIF-1 inhibitors since 2006) https://pubmed.ncbi.nlm.nih.gov/24204703/
inhibited activity of the Wnt/β-catenin pathway in a dose-dependent manner https://pubmed.ncbi.nlm.nih.gov/30871771/
increased cell apoptosis confirmed by the overexpression of p53, caspase 3 and bax https://pubmed.ncbi.nlm.nih.gov/27586579/
significantly reduced exosome release in three cancer cell lines (prostate cancer, hepatocellular carcinoma, and breast adenocarcinoma) https://pubmed.ncbi.nlm.nih.gov/30150937/
These "signals" (up, down, increase, decrease, inhibit, reduce) that CBD simultaneously exhibits tell me that CBD is directly agonizing the ECS system. The ECS then restores the appropriate signaling through the relevant pathways.
Instead of targeting individual pathways, then (and each pathway requires multiple drugs), we should use one drug, CBD, to target one system, the ECS.
In a landmark study by GW Pharmaceuticals, patients received orally a maximum of 12 sprays per day, delivering 100 ml of a solution containing 27 mg/ml THC and 25 mg/ml CBD. The control group that received TMZ (temozolomide) only and had a 44% 1-year survival rate. In contrast, the THC:CBD plus TMZ group showed an 83% 1-year survival rate with a median survival of over 662 days compared with 369 days in the control group.
The results of this study (nearly doubling the median survival) are nothing short of extraordinary compared to synthetic drugs in current GBM trials (which only extend survival by 1-2 months). If "THC:CBD" were a synthetic compound "discovered" by the pharmaceutical industry, the FDA would have approved it as a blockbuster drug for "first-line" treatment for GBM. Alas, it is a natural product, and there isn't much money to be made from developing this "drug."
Incredibly, CBD also appears to be much more potent than temozolomide (IC50 of 0.5–0.7 uM for CBD vs. 200uM-950 uM for TMZ) at destroying cancer cells. Since it mimics our endocannabinoids, CBD can safely cross the blood-brain-barrier to reach the tumor (which, by the way, is one of the most challenging hurdles for synthetic drugs to cross, in clinical trials for GBM)
On 25 May, I am happy to read positive results from the Australians. They have taken the lead in testing CBD with recurrent GBM patients. In a large phase-II double-blind, randomized clinical trial assessing the tolerability of two different ratios of Cannabis they report:
"A single nightly dose of THC-containing cannabis was well tolerated in patients in both groups with rGBM (recurrent GBM) and significantly improved sleep and functional wellbeing and QoL (Qualify of Life)in a sample of patients compared to baseline. From this trial, the 1:1 CBD:THC ratio has been identified as the better-tolerated product with superior QoL outcomes".
Is that light that I see at the end of this tunnel?
PART V - THE ASK
A few months before my mother's diagnosis, I took her to visit the Arc de Triomphe in Paris at the top of the Champs- Élysées. The sight is truly splendid at sunset, but only if you can manage to ignore the traffic.
If you have never been, imagine a traffic intersection. Except, instead of the typical 4-way intersection, imagine a 12-way intersection with a roundabout and no signaling system.
It is only natural that there would be a higher frequency of car accidents within the roundabout (especially when you consider the higher proportion of tourist-driven vehicles). Penalizing drivers, then, would be an ineffective use of traffic police resources. It would be far more effective to zoom-out of the accident scene and address the real problem - improper signaling.
my theory
Cancer is a disease of our body's signaling system - the endocannabinoid system. Several factors can disrupt our signaling system (including viruses, mutations, and yes, even "ionizing radiation"). These disruptions could lead to an over-expression or under-expression of our endocannabinoid receptors/ligands. If not addressed, these disruptions could eventually cause a "cancer" of the ECS system. Since the ECS system is present throughout our body, these cancers can present themselves in different organs of the body. Treating the organs is akin to penalizing the Parisian drivers. Instead, we need to address or attempt to - "factory-reset" the ECS system. If we can do that, I think we can cure cancer.
Today there are around 140 different cannabinoids discovered in the cannabis plant, but we have only studied the two famous players (CBD & THC). A handful of studies on these two cannabinoids have already reaped significant medicinal benefits. Imagine what we could achieve with a sizeable concerted approach to study the rest?
Where do we go from here?
I ask researchers around the world to investigate the remaining 140+ cannabinoids of the marijuana plant and their effects on cancer through their interactions on the ECS.
On 30 May 2020, I watched the SpaceX Crew Dragon spacecraft carrying NASA astronauts Bob & Doug to the International Space Station as it streamed live on YouTube. Later, in his post-launch speech, Elon Musk spoke again about his vision of interplanetary travel, beginning with Mars.
If this reality comes to be, we must admit that it would be pretty silly to travel all those 147.5 million kilometers from Earth to Mars just to find ourselves fighting, not with aliens, but with an enemy that has become familiar to us all.
Thank you for reading all the way. If you think that this article might inspire someone please share. If you have any clues for me please leave a comment below or get in touch with me at nikhil@apitchdeck.com