COC - Care OnCology

Dit doen we niet, het zijn namelijk medicijnen op recept en die krijg je hier echt niet zomaar als je bijvoorbeeld geen hoog cholesterol hebt...

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 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 many 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.

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 findings which suggest a potentially ‘synergistic’ effect of these medications against cancer in some cases (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 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 COC Protocol is a combination of four commonly prescribed medications (atorvastatin, metformin, mebendazole, and doxycycline) with the potential to target colorectal cancer and help improve the effectiveness of standard anticancer therapies.

• A number of observational studies in patients taking metformin or statins to treat diabetes or cardiovascular conditions have linked the use of these medications to improved outcomes in colorectal cancer.

• Laboratory studies on cells grown in dishes, along with some small animal studies, suggest that metformin and statins can stop colorectal cancer cells taking up and using the energy they need – weakening the cancer cells and making them potentially more vulnerable to standard treatments.

• A Phase 3 trial in patients at high-risk of developing colorectal cancer who had recently had surgery to remove colorectal polyps found that those who took low-dose metformin for 1 year had a reduced chance of polyps reoccurring compared to those who took placebo.

• Mebendazole has been found to target colorectal cancer cells grown in the lab and also tumors in rodent studies. In a published case study, a single patient with very advanced colorectal cancer who was treated with mebendazole was reported to have a temporary improvement in cancer signs and symptoms in areas where the cancer had spread.

• Laboratory studies also show that doxycycline can block the growth and division of colorectal cancer cells grown in dishes in the lab. This has not yet been shown in humans.

• More clinical trials are needed to investigate the individual and combined use of these medications in cancer.

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 colorectal cancer treatments. Existing evidence mainly centers on laboratory studies in cells and animal models; along with observational studies and some early clinical studies in patients. Laboratory and observational studies can help provide encouraging findings, but only well-designed studies in cancer patients will help us really understand just how these medications could help patients with cancer. It is promising that several clinical trials investigating the individual benefits of the COC Protocol medications in colorectal cancer are now underway. Our own research program, called METRICS, is also investigating how these medications in combination could help patients with cancer.

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 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 our METRICS program, in further sections below.

Metformin use linked to potentially better colorectal cancer outcomes

Numerous observational studies in patients who were taking metformin to treat type 2 diabetes have linked metformin use with reduced occurrence of cellular and tissue changes that can sometimes lead to colorectal cancer (Cho et al., 2014; Rokkas and Portincasa, 2016), and decreased risk of developing colorectal cancer (Zhang et al., 2013a).These studies have also found that in patients who did develop colorectal cancer, metformin use was linked to better survival and reduced cancer spread (Mei et al., 2014; Tian et al., 2017; Zhang et al., 2013b). However, it’s also worth noting that (as is often the case) not all research studies agree on this (Singh et al., 2016; Vernieri et al., 2019).

It’s likely that some of the beneficial effect of metformin found in many observational studies is due to metformin’s ability to improve a patient’s diabetes and/or weight by reducing glucose levels, which can help reduce the risk of developing some types of colorectal cancer. Colorectal cancer cells require high levels of glucose to grow and spread (Lin et al., 2015; Vasconcelos-dos-Santos et al., 2017), and metformin has been shown to reduce inflammation and protect against the colorectal cancer-promoting effects of high-energy ‘western-style’ diets in mice (Chung et al., 2017). Laboratory studies also show that metformin can actively work directly against colorectal cancer cells, blocking their ability to take up and use energy, and reducing their capacity to grow, divide, and survive (Bekusova et al., 2016; Mogavero et al., 2017; Sena et al., 2018).

Metformin can improve chemotherapy potency against colorectal cancer cells

Metformin has the most anticancer potential when used in combination with standard treatments, and a number of studies on colorectal cancer cells grown in the lab have found that metformin can help to improve the effectiveness of different standard chemotherapies (Bradford and Khan, 2013; Mussin et al., 2017). For example, one lab study found that the addition of metformin alongside the chemotherapy drug fluorouracil increased the proportion of colorectal cancer cells killed from just 17% to over 90% (Bradford and Khan, 2013).

Metformin can also sensitize colorectal cancer cells to radiotherapy, possibly by blocking their ability to take up oxygen. In mice, metformin combined with radiotherapy delayed tumor growth, and enhanced tumor response to radiotherapy (de Mey et al., 2018). Colorectal cancer stem cells, which can sometimes be responsible for cancer relapse following treatment, may also become more sensitive to standard chemotherapies in the presence of metformin (Zhang et al., 2013b).

Early clinical studies suggest potentially beneficial effects of metformin in colorectal cancer

The large amount of existing laboratory and observational evidence in favor of using metformin to help treat colorectal cancer has led to the initiation of a number of clinical trials in patients. These studies are beginning to indicate that metformin may benefit patients with colorectal cancer in certain contexts.

The strongest clinical evidence so far comes from a series of trials investigating the potential of metformin in patients who have either very early colorectal cancer, or a very high risk of developing colorectal cancer. In the first small pilot trial, just one month of low-dose metformin significantly reduced the number of potentially pre-cancerous cellular changes (called ‘aberrant crypt foci’) in patients, while patients who had no metformin treatment showed no change (Hosono et al., 2010). Tissue analysis suggested that cell division (i.e., proliferation; a necessary requirement for cancer to develop) was reduced in the patients who took metformin.

A subsequent larger and better controlled Phase 3 trial investigated the benefits of low-dose metformin over 1 year in 151 patients at high-risk of developing colorectal cancer, and who had previously had colorectal polyps removed. This trial found that metformin reduced the chance of polyps reoccurring within the year. Just 38.0% of patients who took metformin had polyps after 1 year, compared to 56.5% of patients who took placebo (Higurashi et al., 2016).

Early studies in patients already diagnosed with colorectal cancer, including those with advanced colorectal cancer which has already spread, have also reported encouraging results. In one study (which had no control group), 50 patients with advanced disease which was no longer responding to other treatments were treated with metformin in combination with the chemotherapy drug fluorouracil. Over 1 in 5 of these patients (22%) responded to treatment, and in these patients, metformin plus fluorouracil afforded them an average (median) extra 5.6 months of disease control (Miranda et al., 2016).

Preliminary results from a different pilot study in patients with gastrointestinal cancers (of which over half had colorectal cancer) who were treated with either metformin plus chemotherapy, or chemotherapy alone, found that metformin treated patients had favorable changes in molecular markers (biomarkers) of the disease, and that this could potentially correlate with control of the disease (Godara et al., 2018).

And a different study in patients who had been successfully treated for colorectal cancer or breast cancer has found that metformin and physical activity improved levels of biomarkers (including insulin) which are linked to cancer relapse (Meyerhardt et al., 2017).

Numerous larger studies investigating the benefits of taking metformin alongside, or immediately following standard cancer treatments are now underway (Chae et al., 2016; Petrera et al., 2018).

Natuurlijke tegenhanger van Metformine en zonder recept te verkrijgen: Berberine

Observational studies link statins to better results following colorectal cancer treatment

A large number of observational studies have found that regular statin use is linked to a reduced risk of dying from any cancer, including colorectal cancer (Dobrzycka et al., 2018; Wang et al., 2016; Yokomichi et al., 2017). And in patients already diagnosed with colorectal cancer, some studies show that those who take statins may have a better chance of survival (Voorneveld et al., 2017) (although again, not all studies have found this (Gray et al., 2017)). In addition, observational studies in patients who are undergoing elective colectomy (i.e. surgery), or who are being treated with chemotherapy and radiotherapy for colorectal cancer have found that statin use is linked to better results, including less chance of relapse (Mace et al., 2013; Singh et al., 2012).

Statins target colorectal cancer cells in many ways

Statins, particularly fat-soluble ‘lipophilic’ statins like atorvastatin, reduce growth and division of colorectal cancer cells in laboratory studies, and may also increase colorectal cancer cell death (Cho et al., 2008; Jang et al., 2016). Other lab studies have found that statins can help to prevent colorectal cancer cells moving and potentially spreading to other organs (metastasis) (Al-Haidari et al., 2014), possibly by reducing the expression of genes in cancer cells which are known to be involved in cancer progression and spread (Juneja et al., 2017; Lakshminarayana Reddy et al., 2010).

In a study in mice, the fat-soluble statin simvastatin reduced colorectal tumor growth and development by reducing cancer cell survival and blocking blood vessel growth around tumors (Cho et al., 2008). Meanwhile other studies have found that statins may also reduce colorectal cancer cell growth by affecting how colorectal cancer cells cause the immune system to respond, and helping to alter production of molecules which mediate inflammation (Bergman et al., 2011).

Similar to metformin, statins can also help to improve the effectiveness of radiotherapy and chemotherapy on colorectal cancer cells grown in the lab, or colorectal cancer tumors in mice (Karagkounis et al., 2018; Kodach et al., 2011; Lee et al., 2018), and may help reduce the development of resistance to standard treatments (Palko-Łabuz et al., 2019). For example, one lab study found that simvastatin helped to improve the effectiveness of the immunotherapy cetuximab in colorectal cancer cells with the DNA mutation KRAS, which normally makes them resistant to this treatment (Lee et al., 2011). Similar to metformin, statins may also help target colorectal cancer stem cells (Zhang et al., 2017).

Early clinical trials investigating statins in colorectal cancer are promising

Early evidence from clinical trials suggests that statins in combination with standard therapies represents the best chance of effectiveness (Chae et al., 2015).

Two early Phase 2 trials, which studied the effectiveness of simvastatin in combination with standard chemotherapy in patients with advanced colorectal cancer, have published promising findings. In one study, the addition of 40 mg daily simvastatin alongside a standard chemotherapy regimen (i.e. fluorouracil, leucovorin, and irinotecan) produced a longer time to disease progression compared to previously published results in a similar patient group. (Lee et al., 2009). In the second study, patients with KRAS mutant colorectal cancer which did not respond to standard chemotherapy (i.e., irinotecan and oxaliplatin) were treated with simvastatin 80 mg once a day, combined with the targeted therapy cetuximab and irinotecan every 2 weeks. Again, patients with this difficult to treat disease showed an improvement in the length of time before their disease progressed, compared to previously published results (Lee et al., 2014).

In contrast, a larger placebo-controlled Phase 3 trial which investigated the effectiveness of standard chemotherapy plus low-dose 40 mg simvastatin in patients with advanced colorectal cancer did not find any difference with the addition of the statin (Lim et al., 2015). The authors are currently planning to investigate higher doses of statin. This and other studies should help establish just how statins in addition to standard treatments may help patients with colorectal cancer.

Natuurlijke statines en zonder recept te verkrijgen: Rode gist rijst

Aside from being an effective antibiotic with anti-inflammatory activity, doxycycline also possesses extremely valuable anticancer properties (Ali et al., 2017).

In colorectal cancer, laboratory studies have shown that doxycycline can block the growth and division of colorectal cancer cells, encourage colorectal cancer cell death, and can also reduce the potential of colorectal cancer cells to move and invade other tissues (Onoda et al., 2004, 2006). In addition, certain molecules called long non-coding RNAs have recently been implicated in the development and spread of colorectal cancer (Chen et al., 2016; YE et al., 2015), and doxycycline has been found to beneficially modulate levels of these molecules in colorectal cancer cells grown in the lab (Zinovieva et al., 2017).

Interestingly, a recent lab study also found that doxycycline could potentially improve the effectiveness of a type of biological therapy which uses immune cells to target and deliver cell-killing viruses to destroy cancer cells. The study found that doxycycline induced molecular changes in colorectal cancer cells which made the cell more ‘visible’ to immunotherapies, and also potentially improved the amount of cell-killing virus delivered to cancer cells (Tang et al., 2013).

In contrast, a study in rats found that doxycycline given at high doses may have potentially problematic inflammatory effects (Nanda et al., 2016). Although the doses given in this study were many times higher than are used in the clinic; the use of any medication requires careful and ongoing assessment of potential risks versus potential benefits, and this is one reason why our specialist clinicians maintain close contact with patients who attend the Care Oncology Clinic.

Nevertheless, laboratory studies do suggest that doxycycline can beneficially target cancer cells in several different ways. For example, doxycycline is also known to interfere with molecules called matrix metalloproteinases, which are used by cancer cells to grow and move to other parts of the body (Bahrami et al., 2012), and can also potentially block cancer stem cell growth, by preventing a process in these cells called mitochondrial biogenesis (Lamb et al., 2015a). Doxycycline has also been found to stop cancer cells from repairing their DNA when it becomes damaged, for example, by chemotherapy or radiotherapy. This means that doxycycline can potentially become very powerful when given alongside standard treatments, and may help to improve their effectiveness (Lamb et al., 2015b; Peiris-Pagès et al., 2015). More clinical studies are needed to explore this further.