The COC Protocol™ in Lung Cancer
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 lung cancer. 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 lung cancer: Key points
- The COC Protocol is a combination of four commonly prescribed medications (atorvastatin, metformin, mebendazole, and doxycycline) with the potential to target lung cancer 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 lung cancer.
- Laboratory studies on lung cancer cells grown in the lab show that metformin and statins can directly target and damage lung cancer cells – weakening them and making them more vulnerable to standard treatments.
- In a study using a mouse model of lung cancer, metformin given alongside chemotherapy helped to accelerate lung cancer remission and improve relapse times.
- Some small early-stage clinical studies using metformin or statins in patients with lung cancer have reported encouraging disease response results. Other studies show no change. Larger trials are needed, and are now underway.
- Laboratory studies show that doxycycline can reduce the survival of lung cancer cells grown in the lab.
- Mebendazole has been shown to kill lung cancer cells grown in dishes by disrupting special structures inside the cell, called microtubules. In an experimental mouse model of human metastatic lung cancer (i.e. lung cancer which has spread), mebendazole blocked lung cancer cell survival, and reduced both the number and size of tumours. Human studies are now needed.
The COC Protocol and lung cancer: 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 lung cancer are presented below. This evidence mainly comes from laboratory studies, large epidemiological studies (which investigate links between taking medications and lung 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 lung cancer
Metformin use linked to potential lung cancer benefits
Metformin has long been used to treat type 2 diabetes, and observational studies in groups of patients with diabetes who develop lung cancer tend to show that those who take metformin have better chances of an improved outcome. Metformin use has been linked to improved survival in diabetic patients with lung cancer (Chuang et al., 2018; Hung et al., 2018; Wan et al., 2016; Xin et al., 2018), and potentially also improved response to lung cancer treatment (Hung et al., 2018; Wink et al., 2016).
Some of the beneficial effect of metformin reported by these observational studies may partly be due to the fact that metformin can control the patients’ underlying diabetes, which is itself a risk factor for a worse outcome in lung cancer. However, studies suggest that this is not the whole story (Dhillon et al., 2014).
Numerous laboratory studies using lung cancer cells grown in petri dishes or on small animal models of lung cancer show that metformin can actually directly target and damage lung cancer cells through reducing the cell’s ability to take up and use energy. This makes the cell weaker and less able to survive. (these studies are extensively reviewed in the open-access article: (Yousef and Tsiani, 2017)). Metformin is active against both small cell lung cancer cells and non-small cell lung cancer cells (including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma types). Metformin therefore has the potential to work effectively alongside standard treatments for any lung cancer, regardless of the cancer subtype.
Laboratory studies using cells grown in the lab also show that addition of metformin has can improve the effectiveness of standard lung cancer therapies, either by re-sensitizing cancer cells which have become resistant, or by making cancer cells more sensitive to these treatments in the first place (Bruycker et al., 2019; Riaz et al., 2019; Troncone et al., 2017). In one study using a mouse model of lung cancer, metformin given alongside chemotherapy helped to accelerate lung cancer remission and improve relapse times (Iliopoulos et al., 2011). This is how we believe metformin can bring the most benefit to patients with lung cancer- by helping to improve the effectiveness of their usual treatments.
Metformin in lung cancer clinical trials
As observational and laboratory data increasingly supports the use of metformin in lung cancer, clinical trials in patients are slowly beginning to get underway. At least 15 clinical trials have now begun- most of them investigating metformin in combination with other lung cancer therapies (Yousef and Tsiani, 2017).
Clinical trials can take a notoriously long time to yield results, but initial results are promising (Marrone et al., 2018; Morgillo et al., 2017). A collective analyses (meta-analysis) of the results of two of these early-stage trials suggest that metformin alongside standard chemotherapy is well tolerated in patients with lung cancer. Encouraging anticancer activity was also noted in patients with different molecular subtypes of cancer (Parikh et al., 2019). In one pilot (i.e. small) clinical study in patients with very advanced non-small cell lung cancer, patients who took metformin alongside their usual chemotherapy regimen survived for an average of 12 months, compared to 6.5 months for those who did not (Sayed et al., 2015). Statistical analysis showed that these impressive results may not be to do with addition of metformin, and could just have happened by chance, however they are clearly very encouraging.
Statins and lung cancer
Statins target lung cancer cells
Statins have been around for many years, and are still in regular use as a long-term treatment to help manage chronic cardiovascular conditions. This has helped researchers gather a large amount of data and begin to understand how statins might work in different patient populations.
A large number of laboratory studies show that statins, particularly fat-soluble ‘lipophilic’ statins like atorvastatin (Kato et al., 2010), block growth and division of cancer cells and reduce cancer cell survival for many different types of cancer, including lung cancers. (Hwang et al., 2011; Li et al., 2014; Pelaia et al., 2012; Yu et al., 2012) (also reviewed extensively in (Do et al., 2018)).
Importantly, studies also show that statins can help sensitize lung cancer cells and overcome treatment resistance to standard lung cancer treatments, including radiotherapy and chemotherapy (Chen et al., 2012; Sanli et al., 2011).
Similar to metformin, statins can produce these anticancer effects across different lung cancer types, even those with specific mutations which can affect how they respond to treatment (Chen et al., 2013; Hwang et al., 2014; Park et al., 2010).
Clinical studies link statins to better lung cancer outcomes
Recent observational studies on large groups of people who take statins for cardiovascular conditions have found that some individuals with lung cancer who take statins may have a better chance of improved disease response to anticancer treatments (Iarrobino et al., 2018; Xia et al., 2019), and potentially also improved survival rates (Chen et al., 2019; Ung et al., 2018). Results from other observational studies disagree with these findings however (Oh et al., 2018), or find that patients with some types of lung cancer may benefit more than others (Nishikawa et al., 2019).
Clinical trials which can directly investigate the effects of taking statins alongside standard chemotherapies to help treat lung cancer are just beginning to get underway. Although these trials have consistently found the addition of statin to lung cancer therapy to be safe, they disagree over how much benefit can be gained in doing so. Some trials show promising improvements in treatment effectiveness with the addition of a statin (Fiala et al., 2015; Han et al., 2011), while other found no benefit (Lee et al., 2017), including a large randomized Phase 3 trial called LUNGSTAR (Seckl et al., 2017). Although these mixed results must not be ignored, they are also partly to be expected as researchers work out the most appropriate trial methods to use, including dosage, type of statin, and patient population. For example, the LUNGSTAR trial did not use a fat-soluble type of statin, mostly because the trial was designed before relevant evidence about the varying effectiveness of different types of statin in cancer was published (Facchinetti and Tiseo, 2018). We also believe (and our own evidence is beginning to support) that statins can have the most powerful anticancer effect when used in combination with other metabolic medicines.
Clearly, more well-designed studies are needed to help provide a better idea of just how statins might help patients with lung cancer, and researchers in the field recognise this (Facchinetti and Tiseo, 2018). An upcoming ‘meta-analysis’ review of results from all observational studies and clinical trials for statins in lung cancer will hopefully help (Li et al., 2018), as will our own research, and further clinical trials which are underway.
Mebendazole and lung cancer
Mebendazole. a member of the benzimidazole drug family, is widely and safely used to treat parasitic infections in both children and adults. Interest in mebendazole as a potential anticancer treatment is relatively new, and mostly based on promising mechanistic studies and compelling reports from case studies in cancer patients (Nygren and Larsson, 2014; Pantziarka et al., 2014). Based on this preliminary evidence, a number of clinical trials are now underway investigating mebendazole as an adjunctive treatment for cancer.
In laboratory studies, mebendazole has been shown to block the growth and survival of lung cancer cells partly by disrupting special structures inside the cell, called microtubules (Pantziarka et al., 2014; Sasaki et al., 2002). It has also been shown to stimulate powerful immune cells to target and kill lung tumour cells grown in dishes, and potentially block the growth of blood vessels around lung tumours in mice. This suggests that mebendazole can effectively target lung cancer using a number of different, interrelated, mechanisms (Mukhopadhyay et al., 2002; Rubin et al., 2018). In an experimental mouse model of human metastatic lung cancer (i.e. cancer which has spread), mebendazole blocked lung cancer cell survival, and reduced both the number and size of tumours (Mukhopadhyay et al., 2002).
Emerging evidence also suggests that, as expected, benzimidazoles can enhance the activity of standard lung cancer treatments. In one drug library screening of over 1200 small molecule drug candidates, benzimidazoles were identified as being particularly potent against lung cancer cells with the common mutation KRAS. In subsequent lab studies, addition of benzimidazole to standard chemotherapy treatments potently improved the ability of these treatments to supress KRAS lung cancer cell growth (Shimomura et al., 2019).
Doxycycline and lung cancer
Aside from being an effective antibiotic, doxycycline also possesses other extremely valuable properties, including anti-inflammatory and anticancer activity. This gives doxycycline real therapeutic potential in treating cancer (Bahrami et al., 2012).
Lab studies and animal studies have long shown that doxycycline can block cancer cell growth, division, and movement (Duivenvoorden et al., 2002; Fife and Sledge, 1995, 1998). In lung cancer, lab studies show that doxycycline can block the processes lung cancer cells need to divide and spread to other parts of the body, and can also reduce their ability to survive (Qin et al., 2015; Wang et al., 2016).
Other studies also show that doxycycline can stop cancer cells from repairing their DNA when it becomes damaged, for example, by chemotherapy (Peiris-Pagès et al., 2015). Indeed, studies have shown that doxycycline can help improve the effectiveness of chemotherapy activity against cancer cells grown in the lab (Foroodi et al., 2009; Lamb et al., 2015a). Emerging evidence also suggests that doxycycline can potently target cancer stem cells from a range of different cancers (Ozsvari et al., 2017; Zhang et al., 2017), including lung cancer (Lamb et al., 2015b).
Doxycycline has just reached early clinical trials in cancer patients. Results from a first small study, published in October 2018, show that patients with early-stage breast cancer who took doxycycline for just 14 days before surgery reduced levels of molecular markers for presence of cancer stem cells by an average of around 40%. Beneficial effects were noted for all but one of the patients treated (8/9) (Scatena et al., 2018). Larger clinical trials are now underway.
There are as yet no specific trials
investigating doxycycline as an anticancer therapy in lung cancer, although a
number of trials are investigating doxycycline alongside standard lung cancer
chemotherapies to help treat rash (a common side-effect of chemotherapy). This
helps to highlight how well doxycycline is usually tolerated by lung cancer
patients who are taking other standard therapies.
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).
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 to consistently 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., 2015a; 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., 2015b; 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.
Lab studies are beginning to highlight the effectiveness of this approach using COC Protocol medication combinations. In mechanistic studies, 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). 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 programme, 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 optimise 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 licensors.
The Care Oncology (“COC”) Protocol is protected by United States patent US9622982B2 and by various additional international patents.
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