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The Care Oncology Protocol and Melanoma

This document is a summary of some of the current scientific evidence which supports the use of the COC Protocol medications alongside standard-of-care treatments for melanoma.

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 800-392-1353 in the United States, or +44 (0) 20 3855 5939 in the UK, or visit the website at https://careoncology.com.  

The COC Protocol and melanoma: Key points

  • The COC Protocol is a combination of four commonly prescribed medications (atorvastatin, metformin, mebendazole, and doxycycline) with the potential to target melanoma and help improve the effectiveness of standard anticancer therapies.
  • Research suggests that metabolic-targeted treatments may help to improve melanoma outcomes.
  • Studies investigating the benefits of COC Protocol medications for melanoma are mostly still at the cell and animal level, more patient studies are needed.
  • However some studies on groups of patients with melanoma who happen to be taking metformin or statins point to potential benefits of these medications in some circumstances.
  • Both metformin and statins are suggested to beneficially interact with certain anti-cancer immune system activities- and help to improve standard therapies via a number of different mechanisms
  • Doxycycline may also target harder to treat melanoma stem cells.
  • Two separate screening studies have also identified mebendazole as a viable candidate for use in the treatment of melanoma.

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The COC Protocol and melanoma: 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 (mostly cell- and animal- based) studies which support the use of the COC Protocol medications as adjunctive therapies alongside current standard treatments for melanoma are presented below.

You may notice that the studies we discuss below only focus on individual COC Protocol medications. We are the first to design an adjunct therapy which combines all four. We believe that combining these medications will achieve the greatest results. Our own research program, called METRICS, is already producing some 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 the further sections below.

Metformin and melanoma

Metformin is widely used to lower blood glucose levels in patients with type 2 diabetes. The drug can also target the glucose-based molecular processes cancer cells use to generate energy (called glycolytic metabolism).

A freely available recent review of the research investigating metformin in melanoma by Jaune and Rocchi (2018) provides a good overview of this topic:

Briefly, Jaune and Rocchi and other researchers have found evidence that metformin can directly target melanoma cells through various molecular mechanisms, including cell-metabolism pathways and via cell parts such as mitochondria, which are involved in energy generation and use. Pathways which involve a molecule called AMPK seem to be particularly important. AMPK is a strong target for metformin. Studies report that metformin can slow growth, survival and spread of melanoma cells grown in the lab, and can also reduce the volume of melanoma tumors in both diabetic and non-diabetic mice (Li et al., 2018). Melanoma cell death processes possibly induced by metformin include autophagy and apoptosis- two important programmed forms of cell destruction.

Other studies suggest that metformin may target melanoma via activation and optimization of the microenvironment around the tumor, and anticancer immune responses (Jin and Jin, 2020; Pereira et al., 2018). In Pereira et al (2018) for example, the anticancer activity of metformin in mice was shown to be partly reliant on immune response, and was greatly reduced in mice with impaired immune systems.

Other cell-based studies have investigated metformin and its potential usefulness as an ‘adjunctive’ treatment alongside standard melanoma therapies such as chemotherapy, BRAF inhibitors and immunotherapies. Positive results have been reported, suggesting metformin may work well together with these therapies in humans (Jaune and Rocchi, 2018). For example, a mouse study suggests that metformin could partly help to improve immunotherapies by improving the low-oxygen state around some melanoma tumors, which may interfere with immunotherapy (Scharping et al., 2017).

Some preclinical (i.e., cell based) studies have reported otherwise (Martin et al., 2012), and although in our view the early-stage cell and animal data is overall positive for metformin in melanoma, these conflicting results highlight that the research is still (and always will be) evolving. It also underlines the importance of a multi-targeted antimetabolic approach (such as the COC Protocol) alongside standard therapies.

Patient studies investigating metformin in melanoma are also starting to yield data. Retrospective studies which look back at outcomes for patients with melanoma who happened to be taking metformin (for diabetes) during or prior to their diagnosis report encouraging results. For example, a retrospective study of patients with advanced melanoma which had spread, found that those who happened to be taking metformin alongside a type of immunotherapy called immune checkpoint inhibitors were possibly more likely have slightly better treatment outcomes (Afzal et al., 2018). And a recent study also found evidence that patients with diabetes and melanoma who were treated with metformin had a better chance of melanoma survival compared to those without diabetes, who were not treated with metformin (Urbonas et al., 2020).

Jaune and Rocchi’s own patient clinical trial which investigated metformin treatment for a small group of patients with heavily advanced melanoma did not show any benefit of metformin use for these patients (Montaudié et al., 2017). However, they remain optimistic and cite several reasons why this could be, such as the very advanced nature of the disease in these particular patients, who had already progressed beyond standard therapy options (Jaune and Rocchi, 2018). They suggest more trials in patients with earlier disease are needed. Further clinical trials are ongoing.   

Statins and melanoma

Statins are usually prescribed to patients as a long-term treatment to help manage heart and blood vessel-related conditions. The potential anticancer properties of statins have also been studied for many years. Laboratory studies show that statins, particularly fat-soluble ‘lipophilic’ statins like atorvastatin (Kato et al., 2010) can block growth, division, and spread of cancer cells grown in dishes, and slow tumor growth in mice.

Some melanoma cancer cells may have increased production of cholesterol, an important fat molecule used by cells as a building block (Kuzu et al., 2016). This has led some researchers to think that statins, which block cholesterol synthesis pathways, may therefore be useful alongside standard treatments for these cancers. Many lab studies do suggest that statins may help to inhibit melanoma cell growth and survival, through a number of mechanisms (Ivanov and Hei, 2011; Licarete et al., 2017; Maj et al., 2016; Teisseyre et al., 2021).

A recent computational study also reports evidence that statins might target melanoma cell genes involved in metastasis (spread). This finding is backed up by further analysis in the same paper which analyzed cancer outcomes for patients with melanoma, and found a link between a reduced chance of melanoma spreading and statins in this group (Yu et al., 2021).  

Some other retrospective studies also suggest that taking statins might help to improve outcomes for some patients with melanoma (Feng and Qin, 2021; Livingstone et al., 2014; von Schuckmann et al., 2020). For example, a study in patients with ulcerated primary melanoma has reported that statin use might help to reduce risk of recurrence for male patients (von Schuckmann et al., 2020). Gender specific differences were also noted by Livingstone et al (2014).

Statins show the greatest potential for use in melanoma alongside standard therapies. Similar to metformin, statins have been reported to have immune-targeted effects which may help improve effectiveness of immune-based therapies as well as chemotherapy and other therapies (Jin and Jin, 2020; Sarrabayrouse et al., 2017). One cell-based study found that statin in combination with a drug that blocks tumor blood vessel growth enhanced its activity and reduced melanoma cell growth and spread. This effect was linked to beneficial interaction with immune cells and factors in the immediate environment surrounding the melanoma cells (Rauca et al., 2018).

Statins have also been reported to potentially work with other standard therapies in melanoma (Ghasemi et al., 2019). Another cell-based study reported that statin combined with standard melanoma chemotherapy dacarbazine can effectively kill melanoma cells, partly by activating programmed autophagy processes (Al-Qatati and Aliwaini, 2017). This finding was supported by a different study that found combined statin and dacarbazine also improved survival rate for mice with melanoma that has spread (Tsubaki et al., 2019).

Together these preclinical studies offer promising results. Patient studies are now needed to help establish benefits of statins alongside standard therapy in different patient populations. Our own research in this area should help us understand further.

 

Mebendazole and melanoma

Mebendazole, a member of the benzimidazole drug family, is widely 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 (Bai et al., 2011; Nygren and Larsson, 2014; Pantziarka et al., 2014). Based on this preliminary evidence, a number of clinical trials are now currently investigating mebendazole as an adjunctive treatment for cancer.

Two separate screening studies have each independently identified mebendazole as a promising candidate for repurposing, with the potential to help treat melanoma. The first study, which took a partly computer-based approach, predicted that mebendazole could be active against cancers with certain changes in a gene called NRAS. The researchers then showed that mebendazole in combination with standard melanoma treatment trametinib was effective in mice with this type of melanoma which can be resistant to some standard therapies (Simbulan-Rosenthal et al., 2017).

A different screening study investigated over 2000 different compounds for activity against treatment-resistant melanoma cells grown in the lab. This study also found that mebendazole and related molecules could stop melanoma cell growth and induce cell death (apoptosis), possibly by blocking the activity of an important cell molecule called Bcl-2 (Doudican et al., 2008). Further research by the same team then found that oral mebendazole was able to slow melanoma tumor growth in mice (Doudican et al., 2013).

One or two other studies have also reported similar findings in melanoma cells with flubendazole (Li et al., 2019; Rudolf and Rudolf, 2020), a compound related in structure to mebendazole.

Doxycycline and melanoma

The tetracycline antibiotic doxycycline may have real therapeutic potential in targeting cancer (Bahrami et al., 2012).

Various lab studies report that doxycycline can target and suppress melanoma cancer cell growth and movement- possibly via a number of different molecular mechanisms (Shieh et al., 2010; Sun et al., 2009).

For example, in an early mouse study of melanoma, doxycycline appeared to modulate levels of important enzymes called MMPs, and alter tumor blood vessel formation, leading to reduced melanoma tumor growth (Sun et al., 2007). And an interesting cell screening study from 2015 reported that doxycycline (along with various other antibiotics) was able to ‘eradicate’ melanoma stem cells grown in the lab. Perhaps by targeting the ability of the cell to generate mitochondria, which it needs to produce energy (Lamb et al., 2015). A very recent study also suggests that doxycycline may act via disruption of mitochondria in melanoma cells, as well as causing DNA damage (Rok et al., 2020).

Cell and animal data is promising for doxycycline use in melanoma, and we now need more definitive data for humans.

Immunotherapies such as immune-checkpoint inhibitors are increasingly being used to treat a range of cancers, including melanoma. In light of this rapid expansion in use, recent studies have begun investigating the potential impact of antibiotic-induced alteration of the gut microbiome on immunotherapies such as checkpoint inhibitors and CTLA-4 inhibitors (Kapoor et al., 2020).

Indeed, a 2019 paper by Pinato et al. discussed introducing a higher threshold for antibiotic prescribing for cancer patients due to receive immunotherapy (Pinato et al., 2019). While this research paper has author-acknowledged limitations (including the small number of patients, lack of direct observations of changes to the gut microbiome, potential impact of any other health conditions the patients may have had), this topic will also certainly benefit from further research.

In line with Care Oncology’s cautious approach, and acknowledging, our team is closely following the evolving research and will carefully assess each patient who is on immunotherapy or likely to start immunotherapy in future. Doxycycline is not negatively implicated in current research, and  it does not appear to disrupt gut microbiota as extensively as other antibiotics (Nord and Edlund, 1991). It is also an antibiotic which is bacteriostatic (inhibits growth of bacteria) rather than bactericidal (kills bacteria), nevertheless, in certain cases, a decision may still be taken for doxycycline to be omitted or paused for a period.

Our own evidence: The METRICS Study

What is METRICS?

METRICS is our own in-house research study. Although our own experience combined with the level of existing research for the individual COC Protocol medications means we are confident prescribing and managing the Protocol for patients with cancer, more good quality clinical research in this area is needed. METRICS helps us to meet this need. Data from METRICS is helping to ensure that our clinicians understand how these medications work in combination, and how best to prescribe the COC Protocol in the context of cancer.

There is a well acknowledged ‘funding gap’ which currently slows down the repurposing and further clinical development of licensed medications for other conditions. We bridge this gap by using patients’ fees to help fund our research. This means METRICS is essentially ‘patient-funded’. This is a new way of funding clinical research.

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 FAQs

Why do we only prescribe the COC Protocol?

Cancer is a complex disease with complex treatments, and we believe that the potential benefits and risks of adding any further therapies into this mix should be very carefully evaluated. This is why our whole approach is based on cautious evaluation of evidence. This is also why we only prescribe the COC Protocol, and do not prescribe any other off-label medications.

Our knowledge of the existing research, plus our own clinical experience means we are confident that we have a good understanding how the protocol medications will behave in patients with differing stages and types of cancer, and also in combination with other types of cancer treatments. Although many different medications on the market have at least some published evidence supporting their relatively effective use in cancer, they are not our specialty. Having a solid understanding is extremely important to us. We believe this type and level of evidence is just not there yet for many other off‑label anticancer drug candidates – especially when given in combination.

We chose the four medications included in the COC Protocol from thousands of potential candidates specifically because they fit our predetermined selection criteria. Each medication in the protocol is supported by:

  • solid published evidence of effectiveness against cancer. This evidence mainly comes from cell and animal lab studies, observational patient studies, and some small clinical trials (mostly for metformin and statins) and case studies (mebendazole).
  • additional evidence of potential ability to work well with the other protocol medications (i.e. a coherent mechanism of action). This evidence is mostly based on cell and animal mechanistic studies, and some observational patient studies (metformin and statins).
  • a good overall safety profile in patients. This evidence is mostly based on years of clinical trial and patient study data generated as the medications were originally developed and studied for other conditions. Also some more recent patient data in the context of cancer, including our own recently published research data.

How does the COC Protocol work?

The COC Protocol is designed to work primarily 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., 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., 2015c; Pantziarka et al., 2014).

Why these four medications together?

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 (Mokhtari et al., 2017).

Evidence suggests that each medication in the COC Protocol can target 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 from standard treatments.

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 program, METRICS, is now also beginning to produce promising data. 

Can I take the COC Protocol long-term?

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, and requires 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. We will only recommend the COC Protocol to patients when we 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 USA Corp 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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