Repurposed Drugs for Cancer
"Repurposed drugs" is the name given to pharmaceutical drugs that are FDA approved for one condition where there is evidence of benefit in another condition and therefore scope for repurposing. The most famous example of this is Viagra which was discovered by accident when men participating on a trial for another indication all got erections and the drug company realised they had found something with far more commercial upside (no pun intended). And there are many other drugs , FDA approved for conditions other than cancer, yet have purported uses in cancer. The Anti Cancer Fund curated a spreadsheet of over 250 repurposed drugs for oncology, called the ReDo project, based on peer-reviewed studies, medical case reports, observational studies and clinical trials. All the drugs are off-patent and therefore cheap which explains why pharmaceutical companies are loath to repurpose them, as they would be unlikely to recoup their investment in sales. Aspirin is just a few dollars a packet after all. They could modify the molecule so they are able to repatent it, as has happened in the past, but that can take 5-10 years, which I imagine few of us reading this are able to wait!
There are various organisations and charities increasing awareness of these drugs, such as the Anti Cancer Fund and the Care Oncology Clinics (COC), based in NYC and London, who besides consulting and prescribing these drugs, are raising money to fund trials and studies in this domain.
If you would like to start taking some of these repurposed drugs for cancer, you can consult with one of the COC clinics who can advise you on whether or not they believe you suitable to take the 4 drugs in their protocol, as well as write a prescription for them. The COC in London charges 400 pounds for an initial consultation, 200 pounds for each subsequent quarterly consultation and around 75 pounds for a prescription for the 4 drugs (metformin, atorvastatin, mebendezole and doxycycline). If you live abroad, you can organise a Skype consultation. They have chosen these 4 drugs as they strongly believe there is the most amount of clinical data supporting their benefits to cancer patients with very limited toxicity. This has now been registered as a clinical trial under the acronym METRICS: https://clinicaltrials.gov/ct2/show/NCT02201381
So far, they have had very promising results from a cohort of GBM patients. This text is taken from their website:
A clinical trial performed in the U.K., comprised of a 95-patient cohort, resulted in a median overall survival of 27 months when the COC Protocol was used in addition to standard-of-care. Compared to median overall survival of 15.6 months¹ and 14.8 months² with standard-of-care alone.
Whether or not you take guidance from COC or you merely start self-medicating, it is important to monitor your blood tests to check that the body is tolerating these drugs. Metformin may affect kidney function for example, so it's essential to look at your creatinine levels amongst others. Liver function may be compromised by other drugs, so also important to monitor this. It is often unnecessary to demand additional testing from your doctor if your cancer is fairly advanced, as your oncologist will no doubt test your blood regularly anyway.
You can also add to your research by joining two useful Facebook groups. The first is Jane McLelland's group Off Label Drugs for Cancer the admin of which has now written a book "How to Starve Cancer" which tells her own story of curing metastatic cervical cancer with repurposed drugs in addition to other treatments. There is also a US Facebook group called Repurposed Drugs for Cancer Treatment whose contributors I find extremely knowledgeable and helpful. By following these threads for a few weeks, you quickly get up to speed on recent research, common questions on interactions etc. I also read Beyond the Magic Bullet: The Anti Cancer Cocktail by Raymond Chang who also has a website called Cancer Cocktail. However, I note this site hasn't been updated since 2013 so may be lacking recent studies. Likewise, his book was published in 2012, but does form a good foundation for learning about using off label/repurposed drugs in cancer treatment. Key takeaways from this book are to take celebrex, cimetidine and metformin, and many others also.
I plan to pad out this section below with research relating to these, but here are some drugs I have been researching.
DISCLAIMER - I am not medically qualified and none of the below should be read as advice. I am merely sharing my research.
Dipyridamole
Dipyridamole is the favourite "big gun" from Jane McLelland's book "How to Starve Cancer", which she discusses in detail. It's a platelet inhibitor given to prevent blood clots after heart valve replacement surgery. and this research discusses how it can benefit patients with triple negative breast cancer:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829204/
and may be syngergistic with the chemo 5FU
DCA (sodium dichloroacetate)
This is available on Amazon and commonly used on children with congenital mitochondria disorders:
Not only has DCA shown strong anti-tumour activity across various cancers as monotherapy, it is also synergistic with the chemo, 5FU and targets TP53 (where I am mutated):
https://www.nature.com/articles/s41388-019-1035-8
Tetrathiomolybdate (TM)
The drug works by chelating copper from your body, on which tumours depend, and is largely side effect free, but for this to be effective one needs to have one's ceruloplasmin levels monitored, the level of protein in the blood that binds to copper, and kept in an optimal range.
This paper details the phase II results of 10 of 15 stage 4 patients who are cancer-free after 6.9 years while taking TM.
http://abstracts.asco.org/199/AbstView_199_194978.html
This article discusses the relationship between copper and cancer:
https://dailyreckoning.com/the-link-between-copper-and-cancer/
Until I can source it, I have read it to be beneficial to up my zinc dose, which can also help chelate copper from the body.
http://www.sciencedirect.com/science/article/pii/S0047637415000068
https://www.ncbi.nlm.nih.gov/m/pubmed/16570028/
https://www.ncbi.nlm.nih.gov/m/pubmed/2914279/
Also, the combination of zinc with disulfiram (Antabuse given to alcoholics) may also be helpful.
https://www.cancertreatmentsresearch.com/unlocking-zincs-potential-to-fight-cancer/
On ceruloplasmin levels as a prognostic indicator in bile duct cancer:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438709/
TM must be sourced from a compounding pharmacy and is not a registered drug in Hong Kong.
Itraconazole
This is an antifungal medication that as well as being a potent angiogenesis inhibitor (like Avastin), has the ability to raise plasma levels and increase the strength of TKIs (e.g. Tagrisso) . This could make the drug more effective, but of course, could increase the side effects.
Even the Daily Mail (!) has reported on itraconzole:
But if you prefer to read from other sources (!), I highly recommend the website cancertreatmentsresearch.com for its well written and researched pieces on cancer treatments including repurposed drugs in oncology:
https://www.cancertreatmentsresearch.com/itraconazole
This is where I found a link to the report suggesting itraconazole with chemo in biliary tract cancers (BTC) could be interesting:
https://www.ncbi.nlm.nih.gov/m/pubmed/23546045
I also found that itraconazole could be interesting for BTC when combined with chemotherapy.
https://www.ncbi.nlm.nih.gov/pubmed/26254389
And here is an interesting report where using cholangiocarcinoma patient derived organoids they screened hundreds of drugs to conclude that anti fungals were potential therapeutic targets for BTC.
https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30427-9
This report from Pubmed focuses on its angiogenic properties and a phase 2 trial in lung cancer patients combining it with chemo.
https://www.ncbi.nlm.nih.gov/m/pubmed/23546045
Disulfuram : otherwise known as Antabuse, this is a pill given to recovering alcoholics as one sip of alchohol will induce nausea and ill feeling. There is a mouse model showing it may make Folfirinox more effective:
https://www.sciencedirect.com/science/article/pii/S0304383517305153
And a lung cancer trial from 2015 where combined with chemo, the only long term survivors were those taking the Disulfiram (40mg 3 times a day):
https://www.ncbi.nlm.nih.gov/pubmed/25777347
They are now recruiting pancreatic cancer patients on Folfirinox whose CA 19.9 has started to rise, for a trial adding Disulfiram with copper gluconate to their Folfirinox regime: https://clinicaltrials.gov/ct2/show/NCT03714555
On the pathogenetic treatment of primary and metastatic melanoma with disulfiram, CuSO4 and ZnSO4
http://www.drturumin.com/en/Melanoma_en.html
Mebendezole - this is an anti worming tablet with a long safety record and significant research supporting cancer treatments. Absorption is poor but can be improved by adding ranitidine or cimetidine. Based on your blood tests, the COC may advise 100mg per day for one month (before rotating it with doxycycline). There is the potential to increase the mebendezole to 100mg twice a day once you can see via blood tests that your liver tolerates it well. However, there are far higher doses being taken in trial with very limited toxicity such as this John Hopkins trial for paediatric patients with recurring brain tumours taking 500mg a day:https://clinicaltrials.gov/ct2/show/NCT02644291
Note this particular paper on MBZ and cholangiocarcinoma which shows that in cell and mouse lines, MBZ can inhibit cholangio growth but not stop it.
Febendezole - this is a canine worming tablet that passed human safety studies and there are various anecdotal accounts of this putting aggressive cancers into remission. See this blog for example of a 60 year old finance CEO who believes it cured his terminal lung cancer, although it remains unclear at this point whether or not the clinical trial he was also on involving Keytruda may have also been a contributor:
He has a Facebook group which is useful to join if you wish to follow his protocol https://www.facebook.com/groups/mycancerstoryrocks/
Contact your vet or go online at Amazon or Ebay to get hold of febendezole, or I believe it is also available at Waitrose in the UK.
Why to combine FBZ with vitamins
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687140/
According to the protocol, this is the recommended form of vitamin E: https://www.amazon.com/Life-Extension-Tocopherols-Tocotrienols-Softgels/dp/B000VHV3BM
Niclosamide - another anti-helminthic drug used to treat tapeworm disease. This report suggests that alkalinising the gut while taking this medicine maybe beneficial:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777479/
Studies have shown this drug is particularly useful in targeting the TP53 mutation:
https://www.straitstimes.com/singapore/fda-approved-drug-found-to-kill-some-cancer-cells
Metformin this is a prescribed diabetic drug with significant research showing it may have anti cancer properties. Based on your blood tests, in particular kidney function, the COC may recommend a starting dose of 500mg building up to 2000mg a day if side effects are tolerated. Typical side effects include nausea, weight loss and diarrhoea. It is often recommended to take it with a large glass of water after breakfast and supper, to protect the kidneys, and ensure you abstain from metformin for 2-3 days before and after a PET CT scan, to ensure the kidneys have adequate time to process the radioactive dye. Some not wishing to take pharmaceutical drugs choose berberine which has a similar mechanism of action.
According to studies, diabetics who take metformin have a lower incidence of getting cancer and longer survival times if they do get cancer: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308971/
Similarly, at the cholangiocarcinoma conference in Bangkok March 2018, an epidemiological study showed those on metformin had a lower incidence of getting intrahepatic bile duct cancer: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565026/
However, one study on cholangio patients (although it’s a a small study so might not be representative) from the Mayo Clinic showed that diabetic patients taking metformin with cholangio showed no survival advantage: https://aasldpubs.onlinelibrary.wiley.com/.../hep.27821
Metformin is also shown to work synergistically with other treatments. For example this research shows that metformin could sensitise cells to chemo, specifically 5Fu: https://www.spandidos-publications.com/10.3892/or.2014.3151 and also this research on mice showing the improved efficacy of metformin with 5FU: https://medicalxpress.com/news/2018-01-metformin-day-malignant-tumors.html
And at ASCO 2018 they presented data from a phase II study showing it improved survival times in lung cancer when taken with another drug: http://abstracts.asco.org/214/AbstView_214_230373.html
This study shows how metformin along with several other repurposed drugs can increase efficacy of capecitebine in metastatic breast cancer: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513700
Metformin Exerts Antiproliferative and Anti-metastatic Effects Against Cholangiocarcinoma Cells by Targeting STAT3 and NF-ĸB
http://ar.iiarjournals.org/content/37/1/115.short
Statins (cholesterol lowering drugs) are an important part of many cancer patients' protocol, and block GLUT1 and PPAR gamma.
Not only is simvastatin a lipophilic statin that crosses the BBB (so best for anyone like me with brain mets), but it has specific research supporting its use in cholangio:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071437/
http://europepmc.org/article/PMC/4780463
Plus there is lots of research supporting their use in preventing cholangio in the first place (less useful for us already with it, unless NED?)
https://www.ncbi.nlm.nih.gov/pubmed/25808421
One can get it prescribed by COC in London (they are also in the US) who do Skype calls globally.
Depending on your personal situation and blood tests, the COC may recommend an initial 40mg per day of atorvastatin/simvastatin which should be taken with fat for optimal absorption and before bed to allow the liver a low level of cholesterol over night. Once you know from a few months of blood tests checking the liver (AST and ALT for example), that the liver can tolerate 40mg, you may be able to increase the dosage to 80mg.
This article suggests a statin may be helpful for those with a mutation in TP53 and this piece suggests statins may prevent breast cancer recurrence: https://www.oncologynurseadvisor.com/breast-cancer/effect-of-statins-breast-cancer-recurrence/article/735097/
Ranitidine/Cimetidine/Tagamet - ranitidine increases the absorption of the mebendezole. Cimetidine is available OTC in many countries, known as Tagamet.
On repurposing cimetidine for cholangiocarcinoma: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403332/
Note that these drugs may be contraindicated if you are taking a TKI as may make them less effective.
Dukoral (cholera vaccine): This is available OTC in Canada and has shown in a Swedish study to vastly increase overall survival in colorectal cancer patients when taken, regardless of the stage of their disease.
Some have been known to acquire it from their doctor on the pretext of overseas travel to countries with a cholera risk. Side effects are minimal and it is apparently still fine to combine it with chemo, since the vaccine is inactivated. Some repeat the vaccine every 6 months.
NSAIDS - all NSAIDs are potentially beneficial for cancer, and it may be that those with the PIK3CA alteration may benefit more than most, as per this study of head and neck cancer patients: https://www.ncbi.nlm.nih.gov/pubmed/30683736
The COC has developed their own NSAID called Flarin. Aspirin and ibuprofen easily obtainable OTC.
Celecoxib/Celebrex - Of all the NSAIDS, Celecoxib seems to have the most amount of clinical data supporting its benefits in cancer. I have personally met a long term survivor or cholangiocarcinoma who believes his long term survival can be attributed to combining celecoxib with sorafenib.
Low Dose Naltrexone - Nausea is sometimes a side effect and it can keep you awake so best taken in the morning. It may also help pain. Shouldn't be taken with opiates as it's an opiate blocker.
Doxycycline - this is an antibiotic, commonly used for acne when is often taken for 6 months at a time. Depending on your bloodwork, the COC in London recommends starting off with one month of daily 100mg followed by one month of 100mg mebendezole and so on, in order to not overwork the liver. Doxycyline has also been shown to be supportive in inhibiting bone cancer as per this article. It is also shown in vitro to be synergistic with high doses of vitamin C, liposomal or intravenous: https://www.ncbi.nlm.nih.gov/pubmed/28978032 although as yet I cannot find research recommending dosage here. Side effects of doxycline include nausea. However, there are concerns of the long term effects of antibiotics on the gut biome, and its possible adverse impact on immunotherapy results.
