The COC Protocol™ and Blood Cancers
This document is a summary of the rationale and some of the current scientific evidence which supports the use of the COC Protocol medications alongside standard-of-care treatments for blood cancers – including leukemia, lymphoma and myeloma. We understand that cancer is a very personal condition, and every patient has a unique set of challenges. For more information regarding your own personal situation please get in touch with the Care Oncology Clinic at +44 20 7580 3266 in the UK or 800-392-1353 in the United States, or visit the website at https://careoncology.com.
The COC Protocol and blood cancers: Key points
- The COC Protocol is a combination of four commonly prescribed medications (atorvastatin, metformin, mebendazole, and doxycycline) with the potential to target blood cancers and help improve the effectiveness of standard anticancer therapies.
- A number of observational studies have linked metformin or statin use to improved outcomes in patients with different types of blood cancer, including lymphoma, leukaemia, and myeloma.
- Laboratory studies on blood cancer cells grown in the lab show that metformin and statins can directly target and damage blood cancer cells – weakening them and making them more vulnerable to standard treatments.
- Some small early-stage clinical studies in patients with blood cancers have reported that statins given alongside standard treatments may help to improve the effectiveness of the treatment. Other trials are negative. More clinical studies are underway.
- Laboratory studies show that doxycycline can reduce the survival of blood cancer cells grown in the lab.
- Mebendazole has been shown to kill cancer cells grown in dishes by disrupting special structures inside the cell, called microtubules. Clinical studies to test the effectiveness of mebendazole in patients with cancer are ongoing.
The COC Protocol and blood cancers: Published evidence
The COC Protocol is a combination regime of four commonly prescribed medications, each with evidence of metabolically-based anticancer activity, and well understood safety profiles. These medications are: metformin, atorvastatin, doxycycline, and mebendazole.
Some of the studies which support the use of the COC Protocol as an adjunctive therapy alongside current standard treatments for blood cancers are presented below. This evidence mainly comes from laboratory studies, large epidemiological studies (which investigate links between taking medications and blood cancer outcomes in groups of individuals), and early stage clinical trials.
You may notice that many of the studies below only focus on individual COC Protocol medications. We are the first to design an adjunct therapy which combines all four. We do believe that combining these medications will achieve the greatest results, and our own research program, called METRICS, is already producing more of the evidence needed to show this. You can read more about why we believe these medications work together so well to help target cancer, and about the METRICS program itself, in further sections below.
Metformin and blood cancers
Some large scale population studies indicate that taking metformin may help patients with blood cancers (Alkhatib et al., 2017; Wu et al., 2014). These studies also suggest that standard anticancer therapies may sometimes be more effective in patients with blood cancer who are taking metformin. For example, in one population study of patients with diffuse large B‑cell lymphoma who were being treated with standard rituximab-based chemo-immunotherapy, diabetic patients who were also taking metformin had a longer time before their lymphoma progressed compared to non-diabetic patients and diabetic patients on other glucose lowering medications (Singh et al., 2013). Further investigations in the lab found that metformin is more effective at killing lymphoma cells sensitive to rituximab, but not those resistant to rituximab (Singh et al., 2013). This finding might explain some of the differences in the effects of metformin reported in lymphoma patients being treated with rituximab (Hicks et al., 2017; Koo et al., 2011).
In a different population study in patients with multiple myeloma who had undergone stem cell transplant, metformin use was associated with a better response to stem cell transplant and a longer time until disease progression (Duma et al., 2017).
Various laboratory studies support these clinical findings. Many studies have found that metformin blocks growth and induces death in a number of lymphoma and myeloma cell types grown in the laboratory or taken from patients (Gu et al., 2015; Rizzieri et al., 2019; Rosilio et al., 2013; Shi et al., 2012; Zi et al., 2015). Other studies have also found that the metabolic and molecular changes induced by metformin in lymphoma and myeloma cells help to improve the potency of anticancer treatments (Chukkapalli et al., 2018; Jagannathan et al., 2015; Patel et al., 2015; Zi et al., 2015).
Laboratory studies also suggest that metformin can benefit patients with leukemia, both by directly acting on cancer cells, and by helping to lower high blood glucose levels, which are sometimes associated with treatment of leukemia (Rosilio et al., 2014; Wang and Wetzler, 2015). This mode-of-action evidence shows that metformin can target, block growth, and destroy leukemia cells through similar anti-metabolic and molecular mechanisms as it uses to damage lymphoma and myeloma cells (Kirito, 2013; Rodríguez-Lirio et al., 2015). It may also have the power to improve the effectiveness of other therapies used to treat leukemia (Sabnis et al., 2016; Velez et al., 2016; Yi et al., 2017). These effects appear wide ranging across a number of different types of leukemia; one study on cells grown in the lab found that metformin was able to block oxygen uptake in 6 different types of leukemia cell (Scotland et al., 2010).
Clinical trials for metformin in blood cancers are slowly starting to get under way, but more are needed. Andresen and Gjertsen have just published an excellent scientific review paper outlining the current status and challenges of running clinical trials for repurposed medications, including metformin and statins, in acute myeloid leukemia (Andresen and Gjertsen, 2019).
Statins and blood cancers
Statins have been widely prescribed for decades, and a large number of population studies provide evidence suggesting that statins may provide anticancer benefits for some people. These studies consistently seem to show that statin use can reduce the risk of developing any blood cancer (Yi et al., 2014); including lymphoma (Cerhan et al., 2007; Cho et al., 2015; Fortuny et al., 2006; Wallace et al., 2013; Ye et al., 2017), leukemia (Pradelli et al., 2015), and multiple myeloma (Chiu et al., 2015; Epstein et al., 2017). Some studies also directly link statins to improved survival in blood cancer patients (although this evidence is more mixed) (Brånvall et al.; Ennishi et al., 2010; Sanfilippo et al., 2016).
This ‘observational’ evidence is supported by many laboratory studies, which show that some types of statin can actively target and damage blood cancer cells grown in the lab (Burke and Kukoly, 2008; Clutterbuck et al., 1998; Crosbie et al., 2013; Dimitroulakos et al., 2000; Matar et al., 1999; Qi et al., 2013; Sassano et al., 2007), and these findings in turn are supported by some early studies in patients.
For example, in one case study from 2001, lovastatin was given to a 72 year old patient with relapsed acute myeloid leukemia who did not want further induction therapy. The researchers found that the patient’s cells grown in the laboratory were sensitive to lovastatin, a statin similar to atorvastatin, and lovastatin was offered to the patient. Lovastatin appeared to control the patient’s leukemic blast cells, and the author’s suggested lovastatin could potentially provide a new way of controlling leukemic cell growth in acute myeloid leukemia patients (Minden et al., 2001).
High cholesterol levels in and around cancer cells can help them thrive and survive attack by anticancer treatments (Codini et al., 2016; Kuzu et al., 2016). Laboratory studies show that statins (which reduce cholesterol levels) can help keep blood cancer cells sensitive to chemotherapy and other treatments, and reduce resistance to these drugs (Lee et al., 2018; Li et al., 2003). Patient studies are now also beginning to support this. A Phase 1 study where patients with acute myeloid leukemia were given increasing doses of pravastatin alongside a standard chemotherapy regimen had encouraging results, particularly in newly diagnosed patients with unfavorable prognosis due to the molecular makeup of their cancer. A total of 80% of these patients achieved a complete response, compared to just 40% for similar patients used as historical controls who had only a standard chemotherapy regimen (Kornblau et al., 2007).
A subsequent Phase 2 study in patients with relapsed acute myeloid leukemia also achieved good results, with 75% of patients achieving an adequate response (Advani et al., 2014). A second Phase 2 trial in patients with untreated acute myeloid leukemia and high-risk myelodysplastic syndrome was stopped early, as although results were still encouraging, they were unlikely to achieve a predefined level of success specified by researchers as an acceptable level of effectiveness (Shadman et al., 2015). Reasons for this are unclear and could in part be related to patient characteristics or trial methodology. Further, larger trials are ongoing .
Early-stage clinical trials in multiple myeloma have also shown positive results. In one small trial of six patients with refractory (i.e. treatment resistant) lymphoma, cancer resistance to standard treatments of bortezomib or bendamustine was reduced when simvastatin was added alongside (Schmidmaier et al., 2007). In another trial with 91 patients with relapsed or refractory multiple myeloma who were being treated with stem cell transplantation therapy, those who were treated with lovastatin alongside thalidomide and dexamethasone (49 patients) had improved responses and better survival compared to those who were given only thalidomide and dexamethasone without lovastatin (Hus et al., 2011). Subsequent studies in the lab showed that a combination of thalidomide and lovastatin was more toxic to cancer cells than either one alone, underlining the importance and potential benefits of using statins as an adjuvant therapy alongside standard treatments.
Despite the benefits, it is still important these medicines are given by specialists who can tailor dosages and regimens to each individual patient and their situation. For example, two small early stage trials in heavily pretreated patients with myeloma found that high doses of a statin may not be beneficial for some patients (Sondergaard et al., 2009; van der Spek et al., 2008).
Doxycycline and blood cancers
Laboratory studies from as far back as 1985 suggested that doxycycline could stop tumor growth and eradicate tumors in rats with leukemia (van den Bogert et al., 1985). Later studies which have since delved deeper into the mode-of-action of doxycycline and other tetracyclines have found doxycycline can directly target blood cancer cells, over and above the traditional anti-bacterial and anti-inflammatory effects (Bahrami et al., 2012; Ferreri et al., 2006). A small unpublished laboratory study (presented at a conference) has also shown that doxycycline can help improve the ability of lenalidomide (a standard therapy for multiple myeloma) to kill multiple myeloma cells. The researchers suggest that addition of doxycycline alongside lenalidomide could potentially help to reduce the therapeutic dose of lenalidomide required, and so help improve side-effects linked to this treatment (Dorjsuren et al., 2019).
In one clinical trial where doxycycline was shown to help patients with a type of MALT lymphoma associated with certain bacterial infections, researchers initially believed the beneficial effects of doxycycline in this context was mostly down to its antibiotic, bacteria‑eradicating properties (Ferreri et al., 2006). But growing evidence suggests that tetracyclines, and specifically doxycycline, are doing more than that. Numerous studies in the laboratory have now shown that doxycycline can directly damage, kill, or initiate processes which can lead to death (i.e. apoptosis) in a number of different types of cancer, including blood cancers (Alexander-Savino et al., 2016; Bahrami et al., 2012; Lamb et al., 2015a; Pulvino et al., 2015; Song et al., 2014; Wang et al., 2015).
Intriguingly, a recent case study in a patient with B-cell lymphoma linked to a bacterial infection found that the patient’s lymphoma activity (which was being treated with chemotherapy, doxycycline, and hydroxychloroquine) aligned with their blood levels of doxycycline, and relapsed when doxycycline was stopped (Melenotte and Raoult, 2017). The authors state that this phenomenon emphasizes the ‘pro-apoptotic’ benefits of doxycycline. Clinical research is ongoing to establish just how and when doxycycline use can benefit patients with blood cancers.
Mebendazole and blood cancers
Scientific interest in mebendazole as a potential anticancer treatment is relatively new, and is mostly based on promising mode-of-action studies and compelling reports from case studies in cancer patients (Nygren and Larsson, 2014; Pantziarka et al., 2014).
Emerging evidence also suggests that mebendazole may have particularly high levels of activity against blood cancers. This is all down to how mebendazole works. Mebendazole is thought to kill cancer cells by disrupting special structures inside the cell, called microtubules. Vincristine, a chemotherapy treatment often used to treat leukemia, lymphoma, and myeloma, works in a similar way. These mechanistic similarities, combined with mebendazole’s relatively low levels of side-effects and good safety record has led to suggestions that mebendazole could actually be used to replace vincristine for treatment of some cancers (De Witt et al., 2017). Numerous clinical trials are now underway to investigate this possibility.
In addition, two separate large scale screening studies have also independently picked up the potential potency of mebendazole against leukemia (Matchett et al., 2016; Nygren et al., 2013). In one of these studies (Nygren et al., 2013), the leukemia panel was the most sensitive to mebendazole out of all cancer types tested. Both screening studies then went on to show that mebendazole can potently and selectively target animal and human leukemia cells in the lab. Flubendazole, which is from the same family as mebendazole and works in a similar way, has also been shown to kill leukemia and myeloma cells in the lab (Spagnuolo et al., 2010).
Our own evidence: The METRICS Study
What is METRICS?
METRICS is our own in-house research program. A great deal is already known about the safety and effectiveness of the COC Protocol medications in cancer. But it is also our responsibility to acknowledge that we don’t have all the answers, and that we still need to generate good quality clinical research investigating the COC Protocol in patients with cancer, to ensure the COC Protocol is as effective and safe as it can be.
To enable us to fund this research, we have developed a novel, affordable system where our clinical study, METRICS, is essentially ‘patient-funded’. Every consenting patient who enters the clinic is enrolled into METRICS, and these fees are helping to fund the study. This is a new model of clinical research, aimed at bridging the funding and data gaps which are currently hindering the repurposing and further clinical development of already licensed medications.
METRICS first results
In a first success for METRICS, results from our initial pilot study were recently published in the peer-reviewed scientific journal Frontiers in Pharmacology. The paper can be accessed freely online here.
The METRICS pilot study was an observational retrospective study, which means that our researchers looked back and analyzed patient clinical records to find out what happened. They collected data and recorded the outcomes from 95 patients with an advanced type of brain cancer called glioblastoma who attended the Care Oncology Clinic and who took the full COC Protocol alongside their usual standard treatments. This study did not have a control group, so our researchers compared the results from METRICS with previously published results from earlier studies in patients with the same type of cancer, and who also took standard-of-care treatments.
Initial results suggest that patients who attended our clinic and took the COC Protocol as part of their usual care were much more likely to survive at least 2 years (64.0% of patients in our study survived at least 2 years, compared to 27-29% for patients included in previously published studies), and tended to have longer survival times overall than would usually be expected for patients with this type of cancer (patients survived an average of 27 months in our study, compared to 15-16 months in earlier studies)(Agrawal et al., 2019).
These results are extremely promising, but they are also still preliminary. We don’t yet know exactly how the COC Protocol may have impacted survival times for example, or how other factors such as certain patient characteristics may have also influenced these results. But this first, initial evidence is certainly encouraging, and it suggests to us that we are heading in the right direction. Our next planned stage is to conduct a larger, well-designed study. You can find out more about future METRICS plans by looking online or contacting the clinic.
More about the COC Protocol
What is the COC Protocol?
The COC Protocol is a combination treatment regimen comprised of licensed medications, specifically designed by Care Oncology for adjunctive use alongside a patient’s usual treatments (i.e. standard-of-care).
The four medications included in the COC Protocol regimen are: metformin, a very common anti-diabetes drug; atorvastatin, a type of statin used to manage cardiovascular conditions; doxycycline, a type of antibiotic often used to treat chronic infections like acne; and mebendazole, a medicine commonly used to treat parasite infections in children and adults.
We chose these four medications from thousands of potential candidates specifically because they fit our predetermined selection criteria. These criteria include solid evidence of effectiveness against cancer, a coherent mechanism of action, and importantly, a good safety profile. These three central tenets have shaped our approach from the very beginning.
Safety is paramount
Cancer is a complex disease with complex treatments, and we believe that the addition of further therapies alongside standard treatments should be very carefully evaluated. Not just from the perspective of effectiveness, but also, importantly, in terms of safety. This is why our whole approach is based on evidence – mostly published scientific studies, and also, increasingly, our own data.
Many different medications on the market have at least some published evidence supporting their relatively effective use in cancer, but few of these medications have the level of evidence of both safety and effectiveness that we require for the COC Protocol. Large amounts of detailed data already exist for each of the protocol medications, garnered from years of use in the general population – and this helped to give us a crucial head-start during development.
We have painstakingly searched through decades of published data on each of the COC Protocol medications, exploring how they work in different patient populations (including patients with cancer), and on cell and animal models in the lab. These data, alongside our own clinical experience, help to ensure that we have a good understanding of how these medications will behave in patients with differing stages and types of cancer, both in combination with each other and also in combination with numerous other cancer therapies. This knowledge is paramount, and from our studies, this type of evidence is just not there yet for many other off‑label anticancer drug candidates – especially when given in combination.
An anti-metabolic therapy which can potentially target any cancer
The COC Protocol is designed to work by restricting the overall ability of cancer cells to take up and use (i.e. ‘metabolize’) energy.
Cancer cells need huge amounts of energy to survive, and the vast majority of cancers use an adaptive process called aerobic glycolysis to generate the excessive energy they need (Kroemer and Pouyssegur, 2008). Each of the medications in the protocol can target the various molecular metabolic processes involved in and surrounding aerobic glycolysis, and this can help lower the overall metabolic rate of the cancer cell (Jang et al., 2013).
We believe the COC Protocol medications can work in combination consistently to restrict energy supply and use, while simultaneously preventing cancer cells from adapting and using other pathways to take up energy (Jagust et al., 2019). As a result, cancer cells become increasingly weaker and less able to take in and use the nutrients (e.g. such as glucose and essential amino acids glutamine and arginine) they need from their surroundings (Andrzejewski et al., 2018; Liu et al., 2016). This makes it more difficult overall for cancer cells to survive, grow, and spread in the body. Gradually, the weakened cells (including more resilient and previously treatment-resistant cells) become more vulnerable to attack from other cell‑killing cancer therapies such as radiotherapy, chemotherapy, hormonal therapy, and targeted therapies (Bradford and Khan, 2013; Chen et al., 2012; Lacerda et al., 2014; Lamb et al., 2015b; Pantziarka et al., 2014).
By targeting the adapted metabolic mechanisms which are common to most cancers (but not usually healthy cells), we believe that the COC Protocol can be effective and selective for virtually any cancer regardless of specific type, stage, or location of cancer. Published epidemiological and lab studies increasingly support the potentially broad range of this therapy (Chae et al., 2015, 2016; Iliopoulos et al., 2011; Lamb et al., 2015a; Pantziarka et al., 2014).
Mechanistic coherence in action – the power of combination
The true power of the COC Protocol lies in the specific combination of medications we use. We developed the protocol not just as a regimen of four individual treatments each with anticancer activity, but also to work as a single combined treatment- with the potential to produce powerful synergistic effects (Mokhtari et al., 2017).
Each medication in the COC Protocol targets cancer cell metabolism in a distinct and complementary way, and we have termed this action ‘mechanistic coherence’. Put simply, mechanistic coherence describes how each medication can attack the cancer cell from a different angle. For example, cancer stem cells are a particularly resilient type of cancer cell, and each medication targets these cells in a different way: metformin targets the cell’s ‘batteries’ (called mitochondria) by making it very difficult for mitochondria to run the molecular reactions they need to produce energy, doxycycline blocks the cell-DNA machinery that mitochondria need to replicate and repair (Skoda et al., 2019), statins can alter cancer stem cell gene expression, making the cells more sensitive to other cancer therapies (Kodach et al., 2011), and mebendazole can interrupt numerous molecular processes involved in cell division to help block cancer stem cell growth (Hothi et al., 2012; Hou et al., 2015).
By combining all four agents together, the COC Protocol can hit cancer stem cells (and other cancer cells) across multiple ‘weak spots’, and like a one-two punch, this leaves the cells less able to dodge and recover.
Increasingly, evidence from lab studies are beginning to support the effectiveness of our own combinatorial approach. Mechanistic studies have shown that combining statin and metformin greatly decreases the growth of prostate and endometrial cancer cells more than either agent alone (Kim et al., 2019; Wang et al., 2017). And observational studies have also reported potentially ‘synergistic’ effects of these medications against various cancers (Babcook et al., 2014; Danzig et al., 2015; Lehman et al., 2012; Nimako et al., 2017). A clinical trial investigating metformin and doxycycline in breast cancer is now underway (NCT02874430), and our own research program, METRICS, is now also beginning to produce promising data.
A long-term adjunctive therapy
The COC Protocol is primarily designed to be a long-term ‘adjunctive’ therapy, to help optimize standard treatments. However, as metabolic treatment with the COC Protocol is intended to run long-term, patients may also take the protocol as a maintenance regime after standard treatment has been completed or during breaks from standard treatment and as part of a long-term strategy to mitigate the risk of recurrence or metastases. For this reason, it is also worth noting that each of the COC Protocol medications also has reported beneficial mechanisms of action in cancer which are not dependent on the co-administration of standard therapies, and which may independently help to reduce the risk of relapse and metastatic spread.
The Care Oncology model
Active medical supervision of each patient
Although the COC Protocol medications have been used safely in the general population for many years, they are not without side-effects. In addition, every patient’s situation is both complex, and unique- requiring careful, personalized assessment. This is why every patient who attends the Care Oncology Clinic is placed under the direct care of clinicians with specialist knowledge of prescribing the COC Protocol medications in the context of cancer. Our clinicians individually assess the potential benefits and risks involved in taking the COC Protocol with each patient. They will only recommend the COC Protocol to patients when they believe it will be safe and beneficial to do so. Each COC Protocol prescription is tailored to the needs of the patient, and doses and regimens are carefully reviewed and adjusted based on how the patient progresses.
It is therefore essential that patients are carefully monitored at our clinic throughout the course of their treatment.
Purpose of this article
This article is an overview of some of the scientific and medical published literature concerning the medications which comprise the patented Care Oncology protocol. Care has been taken to select relevant articles supporting the off-label use of these medicines in a clinical setting for the adjunct treatment of cancer. This article does not purport to be a comprehensive review of all the evidence, nor does it capture all of the potential side-effects of such treatment.
This article is for information purposes only and it does NOT constitute medical advice. The medicines discussed herein are available on prescription-only and should not be taken without consultation with your doctor or other professional healthcare provider. Care Oncology doctors will discuss the suitability of these medicines with you and will liaise with your doctor or oncologist to discuss their suitability for you.
You must NOT rely on the information in this article as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter you should consult your doctor or other professional healthcare provider. If you think you may be suffering from any medical condition you should seek immediate medical attention. You should never delay seeking medical advice, disregard medical advice, or discontinue medical treatment because of information contained in this article.
The copyright in this article is owned by Health Clinics Limited and its licensees.
The Care Oncology (“COC”) Protocol is protected by United States patent US9622982B2 and by various additional international patents.
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