The COC Protocol™ in Glioma
This document is a summary of the rationale and some of the current scientific evidence which supports the use of the Care Oncology (COC) Protocol medications alongside standard-of-care treatments for glioma. 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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The COC Protocol and glioma: Key points
- A glioma is a type of tumor that starts in the glial cells of the brain or the spine. The term “Glioma” can include several types of tumor, including ependymomas, astrocytomas and oligodendrogliomas.
- Glioblastoma is a malignant, high-grade astrocytoma and is the most common primary brain tumor amongst adults.
- The COC Protocol is a combination of four commonly prescribed medications (atorvastatin, metformin, mebendazole, and doxycycline) with the potential to target glioma and help improve the effectiveness of standard anticancer therapies.
- Our own observational research study has found that a group of patients with glioblastoma who attended our clinic and took the COC Protocol as part of their usual care tended to have longer survival times overall than would usually be expected for patients with this type of cancer.
- A number of other observational studies have also linked metformin or statin use to improved outcomes in patients with glioma. Clinical trials investigating metformin or statins in glioma are still inconclusive, and more studies are needed.
- Laboratory studies using animal models and glioma cells grown in dishes show that metformin and statins can directly target and damage glioma cancer cells using several different mechanisms- weakening them and making them more vulnerable to standard treatments.
- Mechanistic studies also show that doxycycline treatment could make glioma stem cells more susceptible to other treatments like radiotherapy and less able to regrow after temozolomide treatment. These findings have not yet been shown in humans.
- Mebendazole is thought to kill cancer cells partly by disrupting special structures inside the cell, called microtubules. It can inhibit glioma tumor cell growth in the lab and has been shown to improve survival in preclinical mouse models of glioblastoma. More human studies are needed, and are now underway.
The COC Protocol and glioma: 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.
Glioma tumors grow from glial cells in the brain and are the most common type of brain tumor. Low-grade benign gliomas are slower growing and less dangerous than high-grade, aggressive (malignant) gliomas. Glioblastoma multiforme (GBM), a type of malignant astrocytoma, is the most common high-grade brain tumor in adults.
Some of the studies which support the use of the COC Protocol as an adjunctive therapy alongside current standard treatments for glioma are presented below. This evidence mainly comes from laboratory studies, large epidemiological studies (which investigate links between taking medications and breast 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.
Statins and glioma
High-grade gliomas like GBM are thought to be very dependent on the cell processes primarily targeted by statins for survival, and fat-soluble ‘lipophilic’ statins like atorvastatin can cross the human blood-brain barrier (BBB) relatively easily (Wood et al., 2010). These qualities, along with the demonstrated ability of statins to slow and suppress glioma cancer cell growth in the lab and in preclinical mouse models makes atorvastatin a good candidate as a repurposed glioma treatment (Rundle-Thiele et al., 2016).
Several studies show that statins can target and damage glioma cells in a number of different ways, including by increasing programmed and unprogrammed cell death (e.g. apoptosis and necrosis) (Bababeygy et al., 2009; Bayat et al., 2016; Yanae et al., 2011), and reducing cancer cell growth, division, and movement (proliferation and migration) (Bouterfa et al., 2000; Oliveira et al., 2018; Yanae et al., 2011; Yongjun et al., 2013).
Other lab studies have also shown that statins can help to reduce tumor resistance to other glioma treatments (Cemeus et al., 2008; Chang et al., 2017; Hamm et al., 2014). One lab study using pitavastatin, a statin similar in profile to atorvastatin, showed that MDR-1, a molecule which is excessively produced in glioma cells in response to treatment and which helps these cells become resistant, is blocked by statins. In this study, statins helped to improve the effectiveness of chemotherapy (Jiang et al., 2014). In a separate lab study, combining statins with an additional metabolically-targeted drug also appeared to increase potency on glioblastoma cells (Tapia-Pérez et al., 2016).
Most clinical studies for statin use in glioma patients are still ongoing or awaiting results (see Table 1 below). But completed clinical studies show promise. Early-phase studies from the 1990s, where adult and child patients with solid central nervous system (i.e. brain) tumors and high-grade gliomas took lovastatin or fluvastatin in 3 or 4 weekly cycles, showed that statins were well tolerated. Promising tumor responses were noted in patients with GBM and anaplastic astrocytoma, and study investigators suggested a less cyclical and more constant treatment regime could be more effective (Larner et al., 1998; Thibault et al., 1996). Patient population studies monitoring survival in large numbers of people who took statins before and during glioblastoma diagnosis and treatment have had inconclusive results, possible due to different study designs (Bhavsar et al., 2016; Gaist et al., 2014).
Mebendazole and glioma
Scientific interest in mebendazole as a potential anticancer treatment is mostly based on promising mechanistic studies and compelling reports from case studies in cancer patients (Nygren and Larsson, 2014; Pantziarka et al., 2014).
Emerging evidence also suggests that mebendazole may have particularly high levels of activity against cancers of the brain. This is partly because mebendazole is a small, fat-soluble molecule which can easily cross the BBB. It is also thought to work in a similar way to vincristine, a chemotherapy drug currently used for treatment of some types of cancer, including some gliomas (Tan et al., 2018). Mebendazole is thought to kill cancer cells partly by disrupting special structures inside the cell, called microtubules (Lai et al., 2017). It can inhibit glioma tumor cell growth in the lab and has been shown to improve survival in preclinical mouse models of glioblastoma (Bai et al., 2011). In addition, some forms of mebendazole (including the form which is prescribed as part of the COC Protocol) are thought to cross the BBB more readily than vincristine (Bai et al., 2015), which has led to suggestions that mebendazole could replace vincristine in the treatment of brain tumors (De Witt et al., 2017).
In a computer modelling study which looked at 51 different drugs including all chemotherapies used or previously used for treatment of a childhood glioma called DIPG, mebendazole was one of just 8 drugs which was predicted to reach effective concentrations in the brain following systemic (i.e. by mouth or injection) administration (El-Khouly et al., 2017). Evidence from lab studies also suggests that simultaneous use of microtubule disruptors like mebendazole can help to improve the effectiveness of radiotherapy and temozolomide, two standard glioma treatments (Kipper et al., 2018; Markowitz et al., 2017). Numerous clinical trials are now underway to investigate this possibility (see Table 1 below).
Metformin and glioma
An impressive number of lab studies show metformin can block glioma and glioblastoma cell and tumor growth via a number of different mechanisms, including suppressing growth, division and movement of glioma cells (Gerthofer et al., 2018; Seliger et al., 2016; Sesen et al., 2015), increasing programmed glioma cell death (Isakovic et al., 2007; Songthaveesin et al., 2018), and blocking growth of new blood vessels (angiogenesis) to glioma tumors (Elmaci and Altinoz, 2016). Metformin can also target and disrupt glioblastoma stem cells (Gritti et al., 2014; Najbauer et al., 2014; Würth et al., 2013). This is important, because scientists believe control of these cells is key for ensuring long-term survival for patients with glioblastoma (Najbauer et al., 2014; Würth et al., 2014). Although metformin is not fat soluble, it is still predicted to cross the BBB using special transporter molecules (Łabuzek et al., 2010; Liang and Giacomini, 2017; Molenaar et al., 2017).
Metformin’s real potential in glioma is revealed when metformin is tested in combination with standard therapies or newly-developed anticancer medications. These studies repeatedly show that metformin’s multi‑targeted activity against cancer cells and cancer stem cells can potentially improve potency of a combinatorial anticancer treatment regimen. In lab studies, improved anticancer activity against glioma cells (Aldea et al., 2014; Bradford and Khan, 2013; Lee et al., 2018; Sesen et al., 2015; Valtorta et al., 2017) and/or reduced resistance of glioma cells and glioma stem cells to standard therapies (such as temozolomide) has repeatedly been demonstrated using metformin in combination with other drugs (Sesen et al., 2015; Yang et al., 2016; Yu et al., 2015).
Patient population studies also demonstrate promising links between taking metformin and better survival outcomes for some patients with glioblastoma (Seliger et al., 2019). But more robust patient data are needed, and a number of clinical trials are now underway investigating metformin in combination with other therapies in the treatment of advanced glioblastoma (Table 1). In one early‑stage clinical study, newly diagnosed patients with glioblastoma were treated with a combination of temozolomide and up to three other repurposed medications, including metformin. Metformin in combination with these other agents was well tolerated, and patient survival times were potentially encouraging. Larger trials are needed to establish just how effective these combinations may be, and are now underway (Maraka et al., 2019).
Doxycycline and glioma
Doxycycline is an antibiotic with other extremely valuable properties, including anti-inflammatory and anticancer activity. This gives doxycycline real therapeutic potential in treating a range of other diseases, including cancer (Bahrami et al., 2012).
In glioma lab studies, doxycycline has been shown to help block tumor cell growth and division, and to reduce glioma cells’ potential to move and invade other areas of the body (Wang-Gillam et al., 2007). A recent mechanistic lab study has also helped to further confirm our own rationale, that doxycycline can effectively target glioma cells as part of a metabolically-targeted combinatorial treatment (Petővári et al., 2018). Importantly, doxycycline also appears to be particularly good at targeting tumor stem cells. Lab studies show that doxycycline treatment could make glioma stem cells more susceptible to other treatments like radiotherapy (Lamb et al., 2015a), and less able to regrow after temozolomide treatment (William et al., 2018). The results of these lab studies are now starting to be replicated in patients – a very recent clinical study has just reported that doxycycline was able to effectively reduce cancer stem cells in patients with early-stage breast cancer (Scatena et al., 2018).
Doxycycline is also well absorbed by the body and is known to cross the BBB effectively (Karlsson et al., 1996). These qualities combine to make doxycycline a potentially very powerful anticancer treatment for brain tumors such as glioma (Lamb et al., 2015a).
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 glioblastoma
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 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.
Ongoing clinical research
Table 1 summarizes current ongoing or recently completed clinical trials investigating individual metabolically targeted off-label COC Protocol medications in the treatment of brain tumors, including gliomas of all types, glioblastoma, and childhood brain tumors such as medulloblastoma.
It is notable that whereas most studies are testing just one or two of these medications in combination with standard treatments, Care Oncology’s own METRICS study (NCT02201381) is currently the only study to investigate the tolerability and effectiveness of a combination of four off-label metabolic treatments (i.e. atorvastatin, mebendazole, metformin, and doxycycline) alongside standard treatments in glioma and other cancers.
Table 1: Clinical trials for COC Protocol medications in brain tumors
|NCT number||Cancer type||Summary||Completion date|
|Phase 1/2 trial in approx. 20 adults investigating tolerability and effectiveness of metformin and chloroquine in IDH1/2 positive solid tumors||Dec 2016; Results NA|
|NCT02149459||Brain neoplasms||Phase 1 trial in approx. 18 adults investigating safety and effectiveness of treatment of recurrent brain tumors using metabolic manipulation (metformin and low carb diet) combined with radiotherapy||Jul 2018; Results NA|
|NCT02040376||Brain tumor treated with cranial or cranial-spinal radiation||A Phase 3 trial in approx. 24 children with medulloblastoma treated with cranial-spinal radiation investigating effectiveness of added metformin for brain repair||Mar 2018
|NCT02780024||Glioblastoma multiforme||A Phase 2 trial in approx. 50 adults investigating the effectiveness and tolerability of metformin, neo-adjuvant temozolomide and hypo-accelerated radiotherapy followed by adjuvant temozolomide||Dec 2021|
|NCT03243851||Recurrent or refractory glioblastoma||A Phase 2 trial in approx. 108 adults investigating safety and effectiveness of low dose temozolomide plus metformin or placebo||Dec 2019|
|NCT03151772||Glioblastoma||An early Phase 1 trial in approx. 40 patients investigating the bioavailability (activity in the body) of disulfiram and metformin in glioblastoma||Mar 2021|
|NCT01430351||Glioblastoma multiforme||A Phase I/II trial in approx. 144 adults investigating the safety and effectiveness of temozolomide plus various combinations of memantine, mefloquine, or metformin for post-radiation therapy of glioblastoma multiforme||Sep 2019|
|NCT01528046||Relapsed or refractory solid tumors and primary brain tumors||A Phase 1 trial in approx. 25 children investigating safety and effectiveness of metformin in combination with vincristine, irinotecan and temozolomide||Dec 2020|
|NCT02115074||Glioma||A Phase 1 trial in approx. 21 children investigating the safety and effectiveness of fluvastatin and celebrex in low-grade and high grade optico-chiasmatic gliomas||Oct 2022|
|NCT02029573||Glioblastoma multiforme||A Phase 2 trial in approx. 36 adults investigating the efficacy and safety of atorvastatin in combination with radiotherapy and temozolomide in glioblastoma||Dec 2016
|NCT02104193||Brain metastases||A Phase 2 trial in approx. 50 adults investigating the efficacy and safety of simvastatin with radiation therapy of brain metastases||Dec 2015;
Trial terminated, results NA
|NCT01729260||Newly diagnosed high-grade glioma||A Phase 1 trial in approx. 24 adults investigating the tolerability of mebendazole in glioma patients receiving temozolomide||Sep 2020|
|NCT01837862||Childhood glioma||A Phase I/2 trial in approx. 36 children investigating the safety and effectiveness of mebendazole in combination with vincristine, carboplatin and temozolomide or bevacizumab and irinotecan for the treatment of childhood gliomas||Apr 2020|
|NCT02644291||Recurrent/progressive childhood brain tumors||Phase I study in approx. 21 children investigating the safety and effectiveness of mebendazole therapy||Jun 2021|
NB: Table accurate according to www.Clinicaltrials.gov website as of May 2019.
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 protocol medication was chosen because evidence suggests that when taken together, they will have ‘mechanistic coherence’ in the way they can target cancer. Put simply, this means each of the COC Protocol medications can target cancer cells from different, complementary, angles. And this multi‑targeted approach makes it much harder for the cancer cell to adapt and survive.
For example, all four medications can target cancer stem cells, but they each block a different, essential pathway used by the cell. Metformin makes it very difficult for the cell’s ‘batteries’ (called mitochondria) to run the molecular reactions they need to produce energy, while doxycycline blocks the cell-DNA machinery that mitochondria need to replicate and repair (Skoda et al., 2019). Statins can then alter cancer stem cell gene expression, making the cells more sensitive to other cancer therapies (Kodach et al., 2011), and mebendazole can interrupt numerous other molecular processes involved in cell division to help block cancer cell growth (Hothi et al., 2012; Hou et al., 2015). By combining all four agents together, the COC Protocol can hit these particularly difficult to treat cells across multiple ‘weak spots’. Like a one-two punch, this leaves the cells less able to dodge and recover, or develop resistance.
Lab studies are beginning to highlight the effectiveness of this approach using COC protocol medication combinations. In one mechanistic study, combining statin and metformin greatly decreased the growth of prostate cancer cells more than either agent alone (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, 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 optimize standard treatments. However, as metabolic treatment with the COC Protocol is intended to run long-term, patients may also take the protocol as a maintenance regime after standard treatment has been completed or during breaks from standard treatment and as part of a long-term strategy to mitigate the risk of recurrence or metastases. For this reason, it is also worth noting that each of the COC Protocol medications also has reported beneficial mechanisms of action in cancer which are not dependent on the co-administration of standard therapies, and which may independently help to reduce the risk of relapse and metastatic spread.
The Care Oncology model
Active medical supervision of each patient
Although the COC Protocol medications have been used safely in the general population for many years, they are not without side-effects. In addition, every patient’s situation is both complex, and unique- requiring careful, personalized assessment. This is why every patient who attends the Care Oncology Clinic is placed under the direct care of clinicians with specialist knowledge of prescribing the COC Protocol medications in the context of cancer. Our clinicians individually assess the potential benefits and risks involved in taking the COC Protocol with each patient. They will only recommend the COC Protocol to patients when they believe it will be safe and beneficial to do so. Each COC Protocol prescription is tailored to the needs of the patient, and doses and regimens are carefully reviewed and adjusted based on how the patient progresses.
It is therefore essential that patients are carefully monitored at our clinic throughout the course of their treatment.
Purpose of this article
This article is an overview of some of the scientific and medical published literature concerning the medications which comprise the patented Care Oncology protocol. Care has been taken to select relevant articles supporting the off-label use of these medicines in a clinical setting for the adjunct treatment of cancer. This article does not purport to be a comprehensive review of all the evidence, nor does it capture all of the potential side-effects of such treatment.
This article is for information purposes only and it does NOT constitute medical advice. The medicines discussed herein are available on prescription-only and should not be taken without consultation with your doctor or other professional healthcare provider. Care Oncology doctors will discuss the suitability of these medicines with you and will liaise with your doctor or oncologist to discuss their suitability for you.
You must NOT rely on the information in this article as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter you should consult your doctor or other professional healthcare provider. If you think you may be suffering from any medical condition you should seek immediate medical attention. You should never delay seeking medical advice, disregard medical advice, or discontinue medical treatment because of information contained in this article.
The copyright in this article is owned by Health Clinics LLC 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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