The COC Protocol™ in Colorectal Cancer
This document is a brief summary of the rationale and some of the current scientific evidence which supports the use of the COC Protocol medications in colorectal (i.e. colon/rectal) cancer. We understand that colorectal cancer is a very personal condition, and every patient is unique. 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.
Patient Eligibility Form
The COC Protocol in colorectal cancer: Key points
- 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 in colorectal 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 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 and colorectal cancer
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).
Statins and colorectal cancer
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.
Mebendazole and colorectal cancer
Interest in mebendazole as a potential anticancer treatment is mostly based on promising mechanistic studies and compelling reports from case studies in cancer patients (Pantziarka et al., 2014). One of these case studies was in a 74-year old man with advanced colorectal cancer which had spread, and which was no longer responding to standard treatments. Despite the advanced nature of this patient’s cancer, mebendazole was able to induce a period of good remission (i.e. reduction in the signs and symptoms of cancer) in the areas where the cancer had spread, including the lungs, lymph nodes, and liver (Nygren and Larsson, 2014).
Mebendazole was initially identified as a possible colorectal cancer drug when it was included in a large study which screened 1600 already licensed medicines for their ability to stop and kill colorectal cancer cells grown in the lab (Nygren et al., 2013). In this study, mebendazole showed strong activity against all five different types of colorectal cancer cell tested, with a good predicted safety profile. In a different study in mice, mebendazole decreased the size of colorectal cancer tumors by over 60%. It also reduced the number of pre-cancerous polyps in the bowel by 56% in mice who were at high-risk of developing the disease (Williamson et al., 2016).
Mebendazole is known to kill cancer cells partly by disrupting special structures inside the cell, called microtubules. It works in a similar way to vincristine, a chemotherapy drug currently used for treatment of some types of cancer (De Witt et al., 2017). And in small animal models of colorectal cancer, mebendazole has also been shown to help to modulate immune system activity and block the growth of blood vessels which feed tumors (Blom et al., 2017; Williamson et al., 2016). Laboratory studies with other types of cancer have also found that mebendazole and related drugs from the same class (called benzimidazoles) can help to increase the sensitivity of cancer cells grown in dishes to standard cancer treatments including radiotherapy (Markowitz et al., 2017), and chemotherapies (Hou et al., 2015).
Doxycycline and colorectal cancer
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.
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 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.
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.
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 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.
Agrawal, S., Vamadevan, P., Mazibuko, N., Bannister, R., Swery, R., Wilson, S., and Edwards, S. (2019). A New Method for Ethical and Efficient Evidence Generation for Off-Label Medication Use in Oncology (A Case Study in Glioblastoma). Front. Pharmacol. 10.
Al-Haidari, A.A., Syk, I., and Thorlacius, H. (2014). HMG-CoA reductase regulates CCL17-induced colon cancer cell migration via geranylgeranylation and RhoA activation. Biochem. Biophys. Res. Commun. 446, 68–72.
Ali, I., Alfarouk, K.O., Reshkin, S.J., and Ibrahim, M.E. (2017). Doxycycline as Potential Anti-cancer Agent. Anticancer Agents Med. Chem. 17, 1617–1623.
Bahrami, F., Morris, D.L., and Pourgholami, M.H. (2012). Tetracyclines: drugs with huge therapeutic potential. Mini Rev. Med. Chem. 12, 44–52.
Bekusova, V.V., Patsanovskii, V.M., Nozdrachev, A.D., and Anisimov, V.N. (2016). Metformin inhibits development of colon malignant tumors induced by 1,2-dimethylhydrazine in rats. Dokl. Biol. Sci. Proc. Acad. Sci. USSR Biol. Sci. Sect. 468, 97–100.
Bergman, M., Salman, H., Djaldetti, M., and Bessler, H. (2011). Statins as modulators of colon cancer cells induced cytokine secretion by human PBMC. Vascul. Pharmacol. 54, 88–92.
Blom, K., Senkowski, W., Jarvius, M., Berglund, M., Rubin, J., Lenhammar, L., Parrow, V., Andersson, C., Loskog, A., Fryknäs, M., et al. (2017). The anticancer effect of mebendazole may be due to M1 monocyte/macrophage activation via ERK1/2 and TLR8-dependent inflammasome activation. Immunopharmacol. Immunotoxicol. 39, 199–210.
Bradford, S.A., and Khan, A. (2013). Individualizing Chemotherapy using the Anti-Diabetic Drug, Metformin, as an Adjuvant: An Exploratory Study. J. Cancer Sci. Ther. 5.
Chae, Y.K., Yousaf, M., Malecek, M.-K., Carneiro, B., Chandra, S., Kaplan, J., Kalyan, A., Sassano, A., Platanias, L.C., and Giles, F. (2015). Statins as anti-cancer therapy; Can we translate preclinical and epidemiologic data into clinical benefit? Discov. Med. 20, 413–427.
Chae, Y.K., Arya, A., Malecek, M.-K., Shin, D.S., Carneiro, B., Chandra, S., Kaplan, J., Kalyan, A., Altman, J.K., Platanias, L., et al. (2016). Repurposing metformin for cancer treatment: current clinical studies. Oncotarget 7, 40767–40780.
Chen, D., Sun, Q., Cheng, X., Zhang, L., Song, W., Zhou, D., Lin, J., and Wang, W. (2016). Genome‐wide analysis of long noncoding RNA (lncRNA) expression in colorectal cancer tissues from patients with liver metastasis. Cancer Med. 5, 1629–1639.
Cho, S.-J., Kim, J.S., Kim, J.M., Lee, J.Y., Jung, H.C., and Song, I.S. (2008). Simvastatin induces apoptosis in human colon cancer cells and in tumor xenografts, and attenuates colitis-associated colon cancer in mice. Int. J. Cancer 123, 951–957.
Cho, Y.H., Ko, B.M., Kim, S.H., Myung, Y.S., Choi, J.H., Han, J.P., Hong, S.J., Jeon, S.R., Kim, H.G., Kim, J.O., et al. (2014). Does Metformin Affect The Incidence of Colonic Polyps and Adenomas in Patients with Type 2 Diabetes Mellitus? Intest. Res. 12, 139–145.
Chung, E.-J., Do, E.-J., Kim, S.-Y., Cho, E.A., Kim, D.-H., Pak, S., Hwang, S.W., Lee, H.J., Byeon, J.-S., Ye, B.D., et al. (2017). Combination of metformin and VSL#3 additively suppresses western-style diet induced colon cancer in mice. Eur. J. Pharmacol. 794, 1–7.
De Witt, M., Gamble, A., Hanson, D., Markowitz, D., Powell, C., Al Dimassi, S., Atlas, M., Boockvar, J., Ruggieri, R., and Symons, M. (2017). Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors. Mol. Med. 23, 50–56.
Dobrzycka, M., Spychalski, P., Łachiński, A.J., Kobiela, P., Jędrusik, P., and Kobiela, J. (2018). Statins and Colorectal Cancer – A Systematic Review. Exp. Clin. Endocrinol. Diabetes Off. J. Ger. Soc. Endocrinol. Ger. Diabetes Assoc.
Godara, A., Siddiqui, N.S., Hachem, H., Martell, R.E., and Saif, W.M. (2018). First prospective study evaluating effect of metformin (M) on disease control (DC) and activation of AMP-activated protein kinase (AMPKα) in patients (pts) with GI malignancies. J. Clin. Oncol. 36, 264–264.
Gray, R.T., Loughrey, M.B., Bankhead, P., Cardwell, C.R., McQuaid, S., O’Neill, R.F., Arthur, K., Bingham, V., McGready, C., Gavin, A.T., et al. (2017). Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study. Br. J. Cancer 116, 1652–1659.
Higurashi, T., Hosono, K., Takahashi, H., Komiya, Y., Umezawa, S., Sakai, E., Uchiyama, T., Taniguchi, L., Hata, Y., Uchiyama, S., et al. (2016). Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 17, 475–483.
Hosono, K., Endo, H., Takahashi, H., Sugiyama, M., Sakai, E., Uchiyama, T., Suzuki, K., Iida, H., Sakamoto, Y., Yoneda, K., et al. (2010). Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial. Cancer Prev. Res. (Phila. Pa.) 3, 1077–1083.
Hou, Z.-J., Luo, X., Zhang, W., Peng, F., Cui, B., Wu, S.-J., Zheng, F.-M., Xu, J., Xu, L.-Z., Long, Z.-J., et al. (2015). Flubendazole, FDA-approved anthelmintic, targets breast cancer stem-like cells. Oncotarget 6, 6326–6340.
Jang, H.J., Hong, E.M., Park, S.W., Byun, H.W., Koh, D.H., Choi, M.H., Kae, S.H., and Lee, J. (2016). Statin induces apoptosis of human colon cancer cells and downregulation of insulin-like growth factor 1 receptor via proapoptotic ERK activation. Oncol. Lett. 12, 250–256.
Juneja, M., Kobelt, D., Walther, W., Voss, C., Smith, J., Specker, E., Neuenschwander, M., Gohlke, B.-O., Dahlmann, M., Radetzki, S., et al. (2017). Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1. PLoS Biol. 15, e2000784.
Karagkounis, G., DeVecchio, J., Ferrandon, S., and Kalady, M.F. (2018). Simvastatin enhances radiation sensitivity of colorectal cancer cells. Surg. Endosc. 32, 1533–1539.
Kodach, L.L., Jacobs, R.J., Voorneveld, P.W., Wildenberg, M.E., Verspaget, H.W., van Wezel, T., Morreau, H., Hommes, D.W., Peppelenbosch, M.P., van den Brink, G.R., et al. (2011). Statins augment the chemosensitivity of colorectal cancer cells inducing epigenetic reprogramming and reducing colorectal cancer cell “stemness” via the bone morphogenetic protein pathway. Gut 60, 1544–1553.
Lakshminarayana Reddy, C.N., Vyjayanti, V.N., Notani, D., Galande, S., and Kotamraju, S. (2010). Down-regulation of the global regulator SATB1 by statins in COLO205 colon cancer cells. Mol. Med. Rep. 3, 857–861.
Lamb, R., Ozsvari, B., Lisanti, C.L., Tanowitz, H.B., Howell, A., Martinez-Outschoorn, U.E., Sotgia, F., and Lisanti, M.P. (2015a). Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease. Oncotarget 6, 4569–4584.
Lamb, R., Fiorillo, M., Chadwick, A., Ozsvari, B., Reeves, K.J., Smith, D.L., Clarke, R.B., Howell, S.J., Cappello, A.R., Martinez-Outschoorn, U.E., et al. (2015b). Doxycycline down-regulates DNA-PK and radiosensitizes tumor initiating cells: Implications for more effective radiation therapy. Oncotarget 6, 14005–14025.
Lee, J., Jung, K.H., Park, Y.S., Ahn, J.B., Shin, S.J., Im, S.-A., Oh, D.Y., Shin, D.B., Kim, T.W., Lee, N., et al. (2009). Simvastatin plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) as first-line chemotherapy in metastatic colorectal patients: a multicenter phase II study. Cancer Chemother. Pharmacol. 64, 657–663.
Lee, J., Lee, I., Han, B., Park, J.O., Jang, J., Park, C., and Kang, W.K. (2011). Effect of simvastatin on cetuximab resistance in human colorectal cancer with KRAS mutations. J. Natl. Cancer Inst. 103, 674–688.
Lee, J., Hong, Y.S., Hong, J.Y., Han, S.W., Kim, T.W., Kang, H.J., Kim, T.Y., Kim, K.-P., Kim, S.H., Do, I.-G., et al. (2014). Effect of simvastatin plus cetuximab/irinotecan for KRAS mutant colorectal cancer and predictive value of the RAS signature for treatment response to cetuximab. Invest. New Drugs 32, 535–541.
Lee, J.Y., Kim, M.-S., Ju, J.E., Lee, M.S., Chung, N., and Jeong, Y.K. (2018). Simvastatin enhances the radiosensitivity of p53‑deficient cells via inhibition of mouse double minute 2 homolog. Int. J. Oncol. 52, 211–218.
Lim, S.H., Kim, T.W., Hong, Y.S., Han, S.-W., Lee, K.-H., Kang, H.J., Hwang, I.G., Lee, J.Y., Kim, H.S., Kim, S.T., et al. (2015). A randomised, double-blind, placebo-controlled multi-centre phase III trial of XELIRI/FOLFIRI plus simvastatin for patients with metastatic colorectal cancer. Br. J. Cancer 113, 1421–1426.
Lin, C.-Y., Lee, C.-H., Huang, C.-C., Lee, S.-T., Guo, H.-R., and Su, S.-B. (2015). Impact of high glucose on metastasis of colon cancer cells. World J. Gastroenterol. WJG 21, 2047–2057.
Mace, A.G., Gantt, G.A., Skacel, M., Pai, R., Hammel, J.P., and Kalady, M.F. (2013). Statin therapy is associated with improved pathologic response to neoadjuvant chemoradiation in rectal cancer. Dis. Colon Rectum 56, 1217–1227.
Markowitz, D., Ha, G., Ruggieri, R., and Symons, M. (2017). Microtubule-targeting agents can sensitize cancer cells to ionizing radiation by an interphase-based mechanism. OncoTargets Ther. 10, 5633–5642.
Mei, Z.-B., Zhang, Z.-J., Liu, C.-Y., Liu, Y., Cui, A., Liang, Z.-L., Wang, G.-H., and Cui, L. (2014). Survival Benefits of Metformin for Colorectal Cancer Patients with Diabetes: A Systematic Review and Meta-Analysis. PLOS ONE 9, e91818.
de Mey, S., Jiang, H., Corbet, C., Wang, H., Dufait, I., Law, K., Bastien, E., Verovski, V., Gevaert, T., Feron, O., et al. (2018). Antidiabetic Biguanides Radiosensitize Hypoxic Colorectal Cancer Cells Through a Decrease in Oxygen Consumption. Front. Pharmacol. 9.
Meyerhardt, J.A., Irwin, M.L., Jones, L., Zhang, S., Campbell, N., Brown, J.C., Pollak, M.N., Sorrentino, A., Cartmel, B., Harrigan, M., et al. (2017). Multicenter, randomized phase II trial of physical activity (PA), metformin (Met), or the combination on metabolic biomarkers in stage I-III colorectal (CRC) and breast cancer (BC) survivors. J. Clin. Oncol. 35, 10059–10059.
Miranda, V.C., Braghiroli, M.I., Faria, L.D., Bariani, G., Alex, A., Bezerra Neto, J.E., Capareli, F.C., Sabbaga, J., Lobo Dos Santos, J.F., Hoff, P.M., et al. (2016). Phase 2 Trial of Metformin Combined With 5-Fluorouracil in Patients With Refractory Metastatic Colorectal Cancer. Clin. Colorectal Cancer 15, 321-328.e1.
Mogavero, A., Maiorana, M.V., Zanutto, S., Varinelli, L., Bozzi, F., Belfiore, A., Volpi, C.C., Gloghini, A., Pierotti, M.A., and Gariboldi, M. (2017). Metformin transiently inhibits colorectal cancer cell proliferation as a result of either AMPK activation or increased ROS production. Sci. Rep. 7, 15992.
Mussin, N., Oh, S.C., Lee, K.W., Park, M.Y., Seo, S., Yi, N.J., Kim, H., Yoon, K.C., Ahn, S.W., Kim, H.S., et al. (2017). Sirolimus and Metformin Synergistically Inhibits Colon Cancer In Vitro and In Vivo. J. Korean Med. Sci. 32, 1385–1395.
Nanda, N., Dhawan, D.K., Bhatia, A., Mahmood, A., and Mahmood, S. (2016). Doxycycline Promotes Carcinogenesis & Metastasis via Chronic Inflammatory Pathway: An In Vivo Approach. PloS One 11, e0151539.
Nygren, P., and Larsson, R. (2014). Drug repositioning from bench to bedside: tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer. Acta Oncol. Stockh. Swed. 53, 427–428.
Nygren, P., Fryknäs, M., Ågerup, B., and Larsson, R. (2013). Repositioning of the anthelmintic drug mebendazole for the treatment for colon cancer. J. Cancer Res. Clin. Oncol. 139, 2133–2140.
Onoda, T., Ono, T., Dhar, D.K., Yamanoi, A., Fujii, T., and Nagasue, N. (2004). Doxycycline inhibits cell proliferation and invasive potential: combination therapy with cyclooxygenase-2 inhibitor in human colorectal cancer cells. J. Lab. Clin. Med. 143, 207–216.
Onoda, T., Ono, T., Dhar, D.K., Yamanoi, A., and Nagasue, N. (2006). Tetracycline analogues (doxycycline and COL-3) induce caspase-dependent and -independent apoptosis in human colon cancer cells. Int. J. Cancer 118, 1309–1315.
Palko-Łabuz, A., Środa-Pomianek, K., Wesołowska, O., Kostrzewa-Susłow, E., Uryga, A., and Michalak, K. (2019). MDR reversal and pro-apoptotic effects of statins and statins combined with flavonoids in colon cancer cells. Biomed. Pharmacother. Biomedecine Pharmacother. 109, 1511–1522.
Pantziarka, P., Bouche, G., Meheus, L., Sukhatme, V., and Sukhatme, V.P. (2014). Repurposing Drugs in Oncology (ReDO)—mebendazole as an anti-cancer agent. Ecancermedicalscience 8.
Pantziarka, P., Sukhatme, V., Meheus, L., Sukhatme, V.P., and Bouche, G. (2017). Repurposing non-cancer Drugs in Oncology — How many drugs are out there?
Peiris-Pagès, M., Sotgia, F., and Lisanti, M.P. (2015). Doxycycline and therapeutic targeting of the DNA damage response in cancer cells: old drug, new purpose. Oncoscience 2, 696–699.
Petrera, M., Paleari, L., Clavarezza, M., Puntoni, M., Caviglia, S., Briata, I.M., Oppezzi, M., Mislej, E.M., Stabuc, B., Gnant, M., et al. (2018). The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 × 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients. BMC Cancer 18, 1210.
Rokkas, T., and Portincasa, P. (2016). Colon neoplasia in patients with type 2 diabetes on metformin: A meta-analysis. Eur. J. Intern. Med. 33, 60–66.
Sena, P., Mancini, S., Benincasa, M., Mariani, F., Palumbo, C., and Roncucci, L. (2018). Metformin Induces Apoptosis and Alters Cellular Responses to Oxidative Stress in Ht29 Colon Cancer Cells: Preliminary Findings. Int. J. Mol. Sci. 19.
Singh, P.P., Srinivasa, S., Bambarawana, S., Lemanu, D.P., Kahokehr, A.A., Zargar-Shoshtari, K., and Hill, A.G. (2012). Perioperative use of statins in elective colectomy. Dis. Colon Rectum 55, 205–210.
Singh, P.P., Shi, Q., Foster, N.R., Grothey, A., Nair, S.G., Chan, E., Shields, A.F., Goldberg, R.M., Gill, S., Kahlenberg, M.S., et al. (2016). Relationship Between Metformin Use and Recurrence and Survival in Patients With Resected Stage III Colon Cancer Receiving Adjuvant Chemotherapy: Results From North Central Cancer Treatment Group N0147 (Alliance). The Oncologist 21, 1509–1521.
Tang, H., Sampath, P., Yan, X., and Thorne, S.H. (2013). Potential for enhanced therapeutic activity of biological cancer therapies with doxycycline combination. Gene Ther. 20, 770–778.
Tian, S., Lei, H.-B., Liu, Y.-L., Chen, Y., and Dong, W.-G. (2017). The association between metformin use and colorectal cancer survival among patients with diabetes mellitus: An updated meta-analysis. Chronic Dis. Transl. Med. 3, 169–175.
Vasconcelos-dos-Santos, A., Loponte, H.F.B.R., Mantuano, N.R., Oliveira, I.A., de Paula, I.F., Teixeira, L.K., de-Freitas-Junior, J.C.M., Gondim, K.C., Heise, N., Mohana-Borges, R., et al. (2017). Hyperglycemia exacerbates colon cancer malignancy through hexosamine biosynthetic pathway. Oncogenesis 6, e306.
Vernieri, C., Galli, F., Ferrari, L., Marchetti, P., Lonardi, S., Maiello, E., Iaffaioli, R.V., Zampino, M.G., Zaniboni, A., De Placido, S., et al. (2019). Impact of Metformin Use and Diabetic Status During Adjuvant Fluoropyrimidine-Oxaliplatin Chemotherapy on the Outcome of Patients with Resected Colon Cancer: A TOSCA Study Subanalysis. The Oncologist.
Voorneveld, P.W., Reimers, M.S., Bastiaannet, E., Jacobs, R.J., van Eijk, R., Zanders, M.M.J., Herings, R.M.C., van Herk-Sukel, M.P.P., Kodach, L.L., van Wezel, T., et al. (2017). Statin Use After Diagnosis of Colon Cancer and Patient Survival. Gastroenterology 153, 470-479.e4.
Wang, A., Aragaki, A.K., Tang, J.Y., Kurian, A.W., Manson, J.E., Chlebowski, R.T., Simon, M., Desai, P., Wassertheil-Smoller, S., Liu, S., et al. (2016). Statin use and all-cancer survival: prospective results from the Women’s Health Initiative. Br. J. Cancer 115, 129–135.
Williamson, T., Bai, R.-Y., Staedtke, V., Huso, D., and Riggins, G.J. (2016). Mebendazole and a non-steroidal anti-inflammatory combine to reduce tumor initiation in a colon cancer preclinical model. Oncotarget 7, 68571–68584.
YE, L.-C., ZHU, D.-X., QIU, J.-J., XU, J., and WEI, Y. (2015). Involvement of long non-coding RNA in colorectal cancer: From benchtop to bedside (Review). Oncol. Lett. 9, 1039–1045.
Yokomichi, H., Nagai, A., Hirata, M., Tamakoshi, A., Kiyohara, Y., Kamatani, Y., Muto, K., Ninomiya, T., Matsuda, K., Kubo, M., et al. (2017). Statin use and all-cause and cancer mortality: BioBank Japan cohort. J. Epidemiol. 27, S84–S91.
Zhang, P., Li, H., Tan, X., Chen, L., and Wang, S. (2013a). Association of metformin use with cancer incidence and mortality: A meta-analysis. Cancer Epidemiol. 37, 207–218.
Zhang, Y., Guan, M., Zheng, Z., Zhang, Q., Gao, F., and Xue, Y. (2013b). Effects of metformin on CD133+ colorectal cancer cells in diabetic patients. PloS One 8, e81264.
Zhang, Z.-Y., Zheng, S.-H., Yang, W.-G., Yang, C., and Yuan, W.-T. (2017). Targeting colon cancer stem cells with novel blood cholesterol drug pitavastatin. Eur. Rev. Med. Pharmacol. Sci. 21, 1226–1233.
Zinovieva, O.L., Grineva, E.N., Prokofjeva, M.M., Karpov, D.S., Krasnov, G.S., Prassolov, V.S., Mashkova, T.D., and Lisitsyn, N.A. (2017). Treatment with anti-cancer agents results in profound changes in lncRNA expression in colon cancer cells. Mol. Biol. 51, 733–739.
 Note: during research for this article, we have assumed the terms colon, colorectal, and bowel are generally used interchangeably in the research literature, unless otherwise specified.