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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 in 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.  

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Introduction

What is the COC Protocol?

Care Oncology specializes in using already-licensed (off-label) medications with known anticancer activity to help treat and control cancer. The COC Protocol combines what we believe to be the most effective metabolically-targeted off-label medications available for adjunctive use alongside a patient’s usual treatments (i.e. standard-of-care). These medications are metformin, atorvastatin, doxycycline, and mebendazole. We chose these four medications from thousands of potential candidates specifically because they fit our predetermined selection criteria, which 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. ‘metabolise’) 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, was also set up to drive forward research into combinatorial use of these agents in cancer.  

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. For lung cancer, some of these most recent published studies are summarized in the next section. 

The COC Protocol in Lung Cancer

There are a number of different types of lung cancer, and treatment can vary, depending on the stage and molecular type of the disease. Current standard treatment options include surgery, chemotherapy, radiation, and targeted therapies. Much current lung cancer research is also focused on introducing additional (adjunctive) treatments alongside standard treatments in the hope of improving results for patients. 

Below is a brief overview of outlining some of the studies which particularly support the use of the COC Protocol as an adjunctive treatment in lung cancer. 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. 

This section is divided into the separate medications because until now, this is how most research on these medications has been done (although, as mentioned above, some studies are now beginning to catch up and investigate combinations of these medications). We do believe that combining these medications will achieve the greatest results, and we are conducting our own research programme to produce more of the evidence needed to show this. You can read more about our research programme below. 

Metformin

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 show that metformin can actually directly target and damage lung cancer cells (these studies are extensively reviewed in the open-access article: (Yousef and Tsiani, 2017)). These studies, carried out on cells grown in petri dishes, or on small animal models of lung cancer, show that metformin can actively work directly against lung cancer cells, reducing their ability to take up and use energy, and blocking their ability to grow, divide, and survive. They also show that 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

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

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

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. 

The Care Oncology model

The Care Oncology Clinic

Although the COC Protocol medications have been used safely in the general population for many years, every patient who comes to us is unique. 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 only take the COC Protocol while being carefully monitored at our clinic for the duration of their treatment. 

The METRICS study

At Care Oncology, our aim is to ‘repurpose’ or ‘reposition’ already licensed medications to help treat cancer. There are thousands of licensed drugs on the market, and many of them are thought to have benefits outside their licensed area. However, these benefits are often left unexplored, in many cases because it is economically unviable to run expensive full clinical trials on medications usually already out of patent (Pantziarka et al., 2017). 

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 a great deal of 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 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 clinical development of already licensed medications. 

Our valuable patient community is continuously helping us to improve the COC Protocol, and the first research report presenting extremely promising data from our METRICS study is now in submission for publication in a peer-reviewed scientific journal. 

Important Disclaimer

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.

Copyright

The copyright in this article is owned by Health Clinics LLC and its licensors. 

Patent

The Care Oncology (“COC”) Protocol is protected by United States patent US9622982B2 and by various additional international patents.

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