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The COC Protocol in Prostate 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 prostate cancer. We understand that prostate 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 in prostate cancer: Key points                       

  • The COC Protocol is a combination of four commonly prescribed medications (atorvastatin, metformin, mebendazole, and doxycycline) with the potential to target prostate cancer and help improve the effectiveness of standard anticancer therapies.
  • A number of observational studies have linked metformin and statin use to improved outcomes in prostate cancer. Statin use is particularly associated with reduced risk of aggressive prostate cancer in some studies.
  • Observational and cell-based studies also suggest that statins and metformin can work together, to produce a ‘dual effect’ targeting prostate cancer, both by helping to improve dietary and disease risk factors for the disease, and also potentially by directly targeting prostate cancer cells directly.
  • Laboratory studies suggest that metformin and statins can stop prostate cancer cells taking up and using the energy they need – weakening the cancer cells and making them more vulnerable to standard treatments.
  • Some small early-stage clinical studies suggest that metformin or statin use may be associated with decreased PSA levels (a marker of prostate cancer risk and aggressiveness). Other trials are negative. More clinical studies are underway.
  • Laboratory studies show that doxycycline can potentially target MMP enzymes responsible for prostate cancer spread (metastasis), and a small number of cell and animal studies indicate doxycycline may help target and reduce bone metastasis in prostate and breast cancer. This has not yet been shown in humans.
  • Mebendazole has also been found to target prostate cancer cells and help to improve the effectiveness of the chemotherapy drug docetaxel in an animal model of prostate cancer.

The COC Protocol in prostate 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.

This section briefly outlines some of the published studies which particularly support the use of the COC Protocol as an adjunct therapy, alongside standard prostate cancer treatments. Existing evidence mainly centers on laboratory studies in cells and animal models; along with observational studies and some clinical studies in patients. A number of larger clinical trials  investigating the individual benefits of the COC Protocol medications in prostate cancer are also currently underway.

You may notice that many of the studies below only focus on individual 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 statins in prostate cancer

Like many cancer cells, prostate cancer cells need to take up and use large amounts of energy to grow, divide, and survive. To cope with this increased demand in energy, they have developed special metabolic processes which are vulnerable to targeting by some medications, including statins (which can reduce levels of blood cholesterol and other fats) and metformin (a diabetes drug which can help control blood sugar levels)(Ferro et al., 2019).

In addition, metformin and statins can also help manage obesity and metabolic syndromes (i.e. diabetes, high blood pressure, increased weight and high levels of blood cholesterol etc.) which are associated with increased risk and worse outcomes for prostate cancer (Gacci et al., 2017; Jamnagerwalla et al., 2018; Liss et al., 2019; McGrowder et al., 2012).

Laboratory studies show that both statins and metformin can act directly to reduce the growth and survival of prostate cancer cells, by targeting numerous molecular process both in and surrounding prostate cancer cells. This also has the effect of weakening the cancer cell – making it more vulnerable to standard therapies (Alfaqih et al., 2017; Vallianou et al., 2014; Whitburn et al., 2017; Zaidi et al., 2019).

Metformin may also be particularly efficient at targeting prostate cancer stem cells (a particularly resilient type of cancer cell), making them more sensitive to standard treatments like chemotherapy and radiotherapy (Iliopoulos et al., 2011; Mayer et al., 2015). In studies using mouse models of prostate cancer and other cancers, metformin decreased the dose of chemotherapy required to shrink tumours, and also helped to prevent relapse when given in combination with the standard treatment (Iliopoulos et al., 2011).

A ‘dual effect’ targeting prostate cancer cells

There is also evidence that metformin and statins in combination can produce a ‘dual effect’ against cancer. In cell and animal studies, statin plus metformin together were able to directly kill aggressive prostate cancer cells, and reduce tumour growth and spread with a stronger effect than either medication alone (Babcook et al., 2014a, 2014b; Wang et al., 2017). This finding is also supported by a number of observational studies. One such study reviewed the outcomes for over 700 men with diabetes who underwent surgical treatment for prostate cancer. Their data suggested that patients who had taken both metformin and statins seemed to have a lower risk of their cancer returning following surgery (as indicated by biochemical markers) than those men who did not take these medications, or who took just one or the other medication (Danzig et al., 2015).

Two other observational studies (recently published in conference reports) analysed the clinical records of thousands of patients who had high-risk (i.e. more aggressive) prostate cancer, and found that patients who used of a combination of statins and metformin were less likely to die of prostate cancer during the study, compared to patients who did not take either drug. This effect was even more pronounced for patients with metabolic syndromes (Lu-Yao et al., 2015, 2018). Interestingly, one of the studies linked some brands of statins to better outcomes than others – with atorvastatin (i.e. the brand used in the COC Protocol) being the most effective (Lu-Yao et al., 2018).

Many observational studies have also singularly linked statin use or metformin use alone with improved outcomes in prostate cancer, including benefits in survival, and lower risk of relapse or progression to more advanced cancer, and better response to standard treatments (Alfaqih et al., 2017; Bonovas et al., 2008; Coyle et al., 2016; He et al., 2019; Hutchinson and Marignol, 2017; Murtola et al., 2017; Zhong et al., 2015).

Observational studies can at best only give a general snapshot indication of what is really going on, and some studies have not found any benefit of these medications for prostate cancer. Nevertheless, the positive findings from observational and mechanistic studies have been sufficient to initiate small and early-stage clinical trials in this area (Alfaqih et al., 2017; Whitburn et al., 2017).

Clinical studies show promise

Clinical studies have generally found that men who take statins or metformin may have decreased levels of prostate-specific antigen (PSA a molecular marker for prostate cancer risk and aggressiveness) (Khosropanah et al., 2011; Mener, 2010; Rothermundt et al., 2014).

A small pilot study in men with prostate cancer who were about to undergo surgery to treat the disease found that metformin for up to 1.5 months prior to surgery appeared to reduce markers of cancer cell division, and a trend towards decreased PSA was also noted (Joshua et al., 2014). A different randomised study in newly diagnosed men with prostate cancer reported that atorvastatin use for at least 28 days prior to surgery also appeared to reduce markers of cancer cell growth and division (Murtola et al., 2018), compared to placebo.

In another small exploratory study, some patients with aggressive prostate cancer who took metformin also had decreased PSA levels, and metformin also appeared to help stabilise disease progression for some of these patients (Rothermundt et al., 2014). PSA decreases were also seen in a small Phase 1 study investigating metformin in combination with another treatment in men with aggressive and previously treated prostate cancer (Parikh et al., 2019). And in a related trial, metformin alongside exercise was also shown to help counteract potential increased cardiovascular and metabolic problems which has been linked to androgen-deprivation therapy – a standard treatment option for men with some types of prostate cancer (Nobes et al., 2012).

The results of the above studies are promising; however, one weakness is that few had comparison control groups. In contrast, a fully randomized controlled trial in patients with very advanced prostate cancer which investigated metformin alongside their usual chemotherapy regime found that although metformin was well tolerated, no significant clinical benefit was noted in these patients (Martin-Castillo et al., 2018). A different study, also in men with heavily advanced prostate cancer also found no real benefit of adding metformin to standard therapy (Mark et al., 2019). These results show that more studies are still need, to help refine exactly how and when metformin and statin use may have most benefit against prostate cancer. Larger randomised controlled trials are ongoing and will help to further establish the evidence (Crawley et al., 2017).

Mebendazole and prostate 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). Mebendazole is thought to kill cancer cells partly by disrupting special structures inside the cell, called microtubules (Lai et al., 2017). There is also some evidence that mebendazole can help to ‘starve’ a tumor by blocking the growth of blood vessels the tumor needs to supply oxygen and nutrients (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 prostate cancer, a recent conference report presented initial results of a laboratory study which tested a number of repurposed drugs in combination with the commonly used chemotherapy drug docetaxel on prostate cancer cells grown in the lab. They found that mebendazole in combination with docetaxel was highly effective in inducing the cancer cells to undergo pre-programmed death (apoptosis), and that the two drugs together produced a dual effect greater than either drug alone (Rushworth et al., 2018). In a different study, a compound in the same drug family as mebendazole was also able to block the growth of prostate cancer cells cultured in the lab, and to reduce PSA levels and tumor growth in a mouse model of prostate cancer (Chen et al., 2018).

Doxycycline and prostate cancer

Aside from being an effective tetracycline antibiotic, doxycycline also possesses other extremely valuable properties, including anti-inflammatory and anticancer activity (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 order to grow and spread, tumor cells must first cut through the structural matrix of molecules and proteins that surrounds them. They do this in part by producing enzymes called matrix metalloproteinases, or MMPs, which can chop through the surrounding matrix, helping the cancer cells to escape. Evidence suggests that high levels of some MMP molecules produced by cancer cells are sometimes associated with more aggressive types of cancer, including prostate cancer (El-Chaer et al., 2018; Gong et al., 2014).

MMPs have also been shown to help mediate cancer spread (metastasis) to the bone- a common site of metastasis for patients with prostate cancer and breast cancer. In lab studies, doxycycline has been shown to decrease levels of MMPs produced by various cancer cells, including in prostate cancer cells (Ogut et al., 2016), and can reduce cancer spread to the bone in mouse models of breast cancer (Duivenvoorden et al., 2002). This makes doxycycline a potentially important component of any combinatorial treatment for both breast cancer and prostate cancer (Saikali and Singh, 2003).

Doxycycline has also been shown to help enhance the activity of chemotherapy drug doxorubicin and block the growth of castration-resistant prostate cancer cells grown in the lab (Zhu et al., 2017). And emerging laboratory evidence also suggests that doxycycline can potently target various types of cancer stem cells, including prostate cancer stem cells (Lamb et al., 2015a).

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). Other clinical trials, including one investigating the combined effects of metformin and doxycycline the treatment of some types of cancer (trial no. NCT02874430) are now underway.

More about the COC Protocol

What is the COC Protocol?

The COC Protocol is a combination treatment regimen 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. ‘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., 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 type of 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., 2014b; 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.

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 tells 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.

The Care Oncology model

The Care Oncology Clinic

Care Oncology specializes in using already-licensed (off-label) medications with known anticancer activity to help treat and control cancer. 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, and 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.

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Important Notice

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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