Targeting cancer cell metabolism, growth signaling pathways and enhancing anti-cancer immunity are among the hottest topics being explored in oncology, today. It has become increasingly clear that many natural compounds, supplements and FDA-approved medications possess these anticancer properties and look quite promising in both preclinical and clinical studies. In fact, over 200 non-cancer drugs have shown some evidence of anticancer effects. Of these, 50% are supported by relevant human data and 16% are supported by data from at least one positive clinical trial. Some of these drugs include: mebendazole, cimetidine, nitroglycerin, diclofenac, itraconazole, clarithromycin, metformin, aspirin and hydroxychloroquine – all common, generic drugs with excellent safety records and a wide range of data sources showing potent anticancer effects.
An exciting research initiative and collaboration between MIT, Harvard and Dana-Farber Cancer Institute reported a new 2020 study, in which they systematically analyzed thousands of already developed drug compounds and found nearly 50 non-cancer drugs, including those initially developed to lower cholesterol or reduce inflammation, that killed some cancer cells while leaving others alone.
Instead of waiting for years for new drugs that exploit these anticancer mechanisms to be developed, studied for safety and efficacy and approved by the FDA, patients are taking matters into their own hands and treating themselves with thoughtful combinations of these agents to hopefully improve their cancer outcomes. This is often called “repurposing” when existing and well-characterized non-cancer drugs are used as treatments for cancer – either as additions to existing drug protocols or in novel combinations with multiple repurposed drugs.
Drug repurposing of inexpensive generics has been gaining interest over the years for two major reasons: 1) Repurposed, generic cancer drugs have the potential to significantly reduce the financial burden on patients and health care systems from high-cost pharmaceuticals. 2) The time to bring repurposed, non-cancer drugs through the clinical trials and FDA approval process (which typically takes 10+ years) should be much faster than with newer cancer compounds, since these are well-known and well-characterized drugs. Much of the hard work of conducting the preliminary studies (i.e. pharmacodynamics, pharmacokinetics, bioavailability, toxicities, established protocols and dosing) has already been done.
What Are “Off-Label” Drugs?
These are prescription drugs that are approved by the Food and Drug Administration for specific uses to treat specific conditions or diseases. This can mean that the drug is:
- Used for a different disease or medical condition
- Given in a different way (such as by a different route)
- Given in a different dose than in the approved label
Physicians may prescribe a drug for a use that’s not described in the approved labeling if it seems reasonable or appropriate to them. This is what’s called “off-label use.” For example, it is not uncommon for physicians to prescribe low doses of beta blocker drugs to help people overcome jitters before public speaking. Beta blockers are not formally approved for this use. The FDA advises doctors in such circumstances that “they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects.”
Why Are Drugs Used “Off-Label”?
Older, generic (non-brand name) medicines are the ones most often used off label. New uses for these drugs may have been found and there’s often medical evidence from research studies to support the new use. But it’s often too costly for the makers of the drugs to put them through the formal, lengthy, and expensive process required by the FDA to officially approve the drug for new uses. Many patients, especially those with diagnoses of aggressive or advanced malignancies, express that they do not have the luxury of waiting for well-designed clinical trials to prove/disprove the effectiveness of a compound that looks very promising in preclinical, pilot clinical and retrospective studies.
Barriers To “Off-Label” Drug Use:
The biggest problem is getting insurance plans to reimburse for off-label drug use. Many insurance companies will not pay for a drug that’s used in a way that’s not listed in the approved drug label. They do this on the grounds that its use is “experimental” or “investigational.” Another problem is that off-label drug use often does not reflect “standard of care” treatment. This could raise concerns about the legal risk to the health care provider should a patient have an unwanted or bad outcome from the treatment. Finally, there is also a lack of information about how to best use the drug other than for what it was approved. Lack of information on off-label drug use and outcomes may put patients at a higher risk for medication errors, side effects, and unwanted drug reactions. It’s important that the patient and doctor talk about the possible risks of using the drug and weigh them against the possible benefits.
There are thousands of plant-derived and nutrient compounds that have been shown in preclinical and clinical studies to exhibit similar pharmacologic properties with many of the “off-label” non-cancer drugs. Unfortunately, the majority of these compounds have not been studied with similar rigor compared with FDA-approved pharmaceuticals and the lack of standardization in dosing, manufacturing and other quality and safety concerns adds more questions than answers on their potential use in cancer treatment protocols. Regardless, the use of anticancer supplements by patients is prolific.
Use Of Multiple Compounds:
Due to the complexity of cancer metabolism, development of resistance and an individual’s physiology (i.e. immune system, tumor microenvironment, etc.), many conventional oncology treatments employ combination therapies to target these variables. This is the same rationale for the use of multiple “off-label” drugs and supplements, which are thoughtfully selected based on their purported effects on inhibiting important drivers of cancer growth and enhancing anticancer systems in the host.
Blocking Cancer Cell Metabolism:
There has been a tremendous interest by researchers to identify drugs that specifically block important cellular metabolic pathways in cancer cells without significantly impacting the functioning of normal cells. Since cancer cells grow more quickly than normal cells, they require higher amounts of nutrients and building blocks. Therefore, using drugs that impair these metabolic pathways or reduce the availability of these building blocks will have a greater impact on cancer cells. Cancer cells are very adaptable to the availability of these compounds, and they will find other routes of obtaining fuel and building blocks to survive. The following diagram (Metabolic Metro Map) illustrates the complexity of cellular metabolism (aside from plant-specific pathways, such as photosynthesis).
For more fine detail, below is the latest human metabolic “subway map” (Stanford University, School of Medicine, 2018)
The figure, below, (McLelland ‘Metro Map’, from the book: How to Starve Cancer, by Jane McLelland. Used with the author’s permission) serves as a great example of how one might use an evidence-informed approach to combine various “off-label” non-cancer drugs and supplements to simultaneously target key metabolic pathways used by cancer cells for growth and survival. Blocking one metabolic pathway (i.e. glucose metabolism) at a time is not effective, as most cancers are able to use other energy sources for their survival (i.e. fatty acids, ketones, amino acids.)
Blocking Cancer Cell Signaling:
As complex (or more) as cancer cell metabolism is, so are the cellular signaling pathways. Manipulation of these pathways enable cancer cells to thrive by taking advantage of any or all of the “hallmarks” of cancer, which include: (1) sustained proliferation, (2) evasion of growth suppressors, (3) death resistance, (4) replicate immortality, (5) angiogenesis, (6) invasion ± metastability, (7) reprogrammed energy metabolism, and (8) immune evasion.
Activating or inhibiting these pathways with targeted drugs is commonly employed in oncology. Patients are also taking matters in their own hands by trying to block these pathways with off-label drugs and supplements.
The Additional Complexity Of Heterogeneity:
To make matters even more complex, your cancer is not the same as someone else’s, even amongst the same cancer types. Furthermore, every one of your cancer cells is slightly different than its neighbor. This is called “heterogeneity,” which means that the targets, metabolic pathways, genetics, epigenetics and the expression of proteins are not all the same…and one more thing…these variables are constantly changing over time as the cancer cells divide. Oy vay!
So, What Are The Most Effective Drugs For Your Cancer?
I wish I could tell you that there is a non-invasive, inexpensive and simple way to figure this out. Unfortunately, there isn’t. What I typically see the vast majority of patients doing is to take different compounds and hope:
- That they don’t develop side effects from the drugs/supplements, and
- That they see a favorable response to treatment on imaging, clinical exam or follow-up.
Eventually, we will have assays (such as the EVA-PCD assay) that will be able to test hundreds of compounds on a sample of your cancer to see which combinations work the best.
So, what does one do if they want to pursue this off-label and supplement approach? First, you need to acknowledge:
- Your cancer is not the same as anyone else’s.
- Response to any treatment will not be same as that of anyone else.
- The signaling targets and metabolic preferences you read about in your cancer are constantly evolving over time and have cell-to-cell heterogeneity.
- You may develop side effects and toxicities that others may not.
- Taking any drug or supplement off-label is an experiment (you are an “n-of-1”, a metaphorical laboratory guinea pig) that may have no effect, improve or worsen cancer-related outcomes.
- As you combine these compounds with each other or other drugs your physicians have prescribed, interactions (known or unknown) are possible. (I always check drug interactions: https://www.webmd.com/interaction-checker/default.htm)
- Many generic drugs and supplements do not contain what is listed on their label.
- While these drugs and supplements may look promising, standard of care (SOC) oncological therapies have higher level evidence supporting their use in peer-reviewed studies. Combining SOC treatments along with these off-label compounds and supplements would be preferred over the latter, alone. Discuss this with your oncologist, first.
- Taking antioxidant supplements may interfere with radiation therapy and chemotherapy: https://integrativeoncology-essentials.com/2019/12/is-it-safe-to-take-antioxidants-during-cancer-treatment/
Once you’ve acknowledged these unknowns, discuss with your oncologist whether they would be open to you trying off-label drugs or supplements. As with any pharmaceutical or supplement, there are concerns about potential side effects, toxicity and harmful interactions between these compounds and other conventional treatments. It is essential that patients understand these issues and discuss their interest in using these compounds with their oncology providers before starting them.
Of course, you can go rogue and do your own thing…many patients do. Thanks to the internet, acquiring off-label drugs (without a doctor’s prescription) and supplements is less of a challenge.
When I counsel patients on using these drugs and supplements, it is based on the understanding of the points I’ve made above. After that, we thoughtfully (based on hypothesis-only, since they are their own experiment) select multiple pathways to address with lifestyle modifications (individualized after functional medicine assay testing) +/- supplements and off-label drugs.
List Of Some Of The More Popular Anticancer Compounds:
TOP TABLE: I have researched dosing information for the metabolic pathway drugs and supplements in the McLelland Metro Map, and have included these in the table below (thank you to one of my patients for sharing the first version of this table with me). BOTTOM TABLE: These compounds are directed at other cell signaling pathways. Dosing information derived from the design and methods sections of published and unpublished clinical studies (main source: ClinicalTrials.Gov)
**4-Drug COC Protocol™ (Care Oncology Clinic):
- Atorvastatin: 40 mg 2 x/day
- Metformin: 500 mg 2 x/day (start with 500 mg 1 x/day x 2-weeks and increase to 500 mg 2 x/day if tolerated)
- Doxycycline 100 mg 1 x/day
- Mebendazole 100 mg 1 x/day
- Clinical trial reference: https://clinicaltrials.gov/ct2/show/NCT02201381
Pre- and Post-Cancer Surgery Protocol #1:
Both study medications will be given orally for an intervention phase of 20 days as follows: 5 days prior to surgery, on the day of surgery, and 14 days postoperatively.
- Etodolac: 800 mg 2 x/day for the entire intervention period
- Propranolol: 20 mg 2 x/day for 5 preoperative days, 80 mg 2 x/day on the day of surgery, 40 mg 2 x/day for the first postoperative week, 20 mg 2 x/day for the second postoperative week
- Clinical trial reference: https://clinicaltrials.gov/ct2/show/NCT00888797
Pre- and Post-Cancer Surgery Protocol #2:
Six total days of treatment: starting 3 days before surgery and until 2 days after surgery
- Propranolol: 10 mg 4 x/day
- Etodolac: 400 mg 2 x/day
- Clinical trial reference: https://clinicaltrials.gov/ct2/show/NCT00502684
Helpful References for More Information:
- The Repurposing Drugs in Oncology (ReDO) project
- AntiCancer Fund: Drug Repurposing
- Medscape: Repurposing Drugs in Your Medicine Cabinet
- How to Starve Cancer: Book (by Jane McLelland)…In my opinion, the BEST resource currently available.
- Jane McLelland Off Label Drugs for Cancer Public Group (Facebook)…over 5,400 members.