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The Care Oncology Protocol and Esophageal Cancer

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

  • The COC Protocol is a combination of four commonly prescribed medications (atorvastatin, metformin, mebendazole, and doxycycline) with the potential to target esophageal cancers and help improve the effectiveness of standard anticancer therapies.
  • Lab studies in cells and animals provide evidence that targeting the metabolic pathways of esophageal cancer cells can slow their division, growth, spread, and reduce their viability.
  • Lab studies also provide evidence that statins and metformin may help to enhance standard cancer therapies and reduce resistance developing. In one study which used a mouse model of esophageal cancer, metformin plus the chemotherapy drug 5-flurouracil appeared to reduce tumor volume to a greater extent (i.e. approximately twice as much) than either drug given alone (Honjo et al., 2014). Patient studies are needed to confirm this.
  • An observational study which followed patients with esophageal cancer undergoing standard treatment found that the group of patients who were diabetic and on metformin had a higher rate of complete response to chemoradiation treatment (34.5%) compared to those who were diabetic and not taking metformin (4.8%), or were not diabetic, and therefore not taking metformin (19.6%). (Skinner et al., 2013)
  • A large recent systematic review and metanalysis which grouped together and analyzed data from a huge number of published observational patient studies reports evidence suggesting that for patients with the condition Barrett’s esophagus, those who take statins may be less likely to develop esophageal adenocarcinoma (Thomas et al., 2018).
  • Both mebendazole and doxycycline are known to target cancer cells through mechanisms which may also be relevant to esophageal cancer cells. Preliminary data are beginning to support this.
  • Safety is our top priority. Care Oncology doctors supervise your treatment to minimize risk of polypharmacy.

The COC Protocol and esophageal 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.

Some of the studies which support the use of the COC Protocol as an adjunctive therapy alongside current standard treatments for esophageal cancer are presented below. This evidence mainly comes from cell and animal laboratory studies, large epidemiological studies (a type of patient study which can investigate links between taking medications and cancer outcomes in groups of individuals), and early-stage patient trials.

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

Diagram of cell breaking down each part's capabilities

Metformin and esophageal cancer

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

Some researchers think that using metabolically targeted treatments to block tumor energy pathways could help to improve therapies for esophageal cancer (Shafaee et al., 2015).

Metformin is active against different types of esophageal cancer cells

Lab studies in cells and animals back up the idea that metabolically targeting esophageal cancer cells or tumors can slow their division, growth, and spread, and reduce their viability.

Studies have shown this effect of metformin in both esophageal squamous cell carcinoma (SCC) (Cai et al., 2015; Feng et al., 2014; Kobayashi et al., 2013; Liang et al., 2018) and also the more rare adenocarcinoma cell type (Fujihara et al., 2015).

In small animal models of esophageal cancer, metformin treatment inhibited tumor growth (Cai et al., 2015), and decreased the numbers of precancerous lesions (i.e. areas of cell and tissue changes which occur prior to tumor formation) (Fan et al., 2019). Both of these studies attributed metformin anticancer activity to modulation of a molecular pathway involving mTOR and AMPK proteins. This pathway is well known to be activated by metformin in non-cancer and cancer studies, and is vital for many different cellular activities, including energy generation and use. 

Lab studies suggest metformin might enhance standard cancer therapies

Metformin may also either help to enhance the activity of standard cancer therapies used to treat esophageal cancer, or reduce the chance of treatment resistance developing. Studies using esophageal cells grown in the lab have so far published supportive data suggesting metformin may benefit the activity of the chemotherapy drugs cisplatin (Wang et al., 2017a; Yu et al., 2016), 5-fluorouracil (Honjo et al., 2014), and gemcitabine (Mynhardt et al., 2018). A small amount of published evidence also suggests that metformin may help to reduce invasive characteristics associated with treatment resistance in esophageal cells following radiation therapy (Nakayama et al., 2016).

In one study which used a mouse model of esophageal cancer, metformin plus 5-flurouracil appeared to reduce tumor volume to a greater extent (i.e. approximately twice as much) than either drug given alone (Honjo et al., 2014). Data from further experiments in the same study also provide useful evidence that metformin may work in part by targeting cancer stem cells. These cells are generally regarded to be harder to treat, and are thought to be involved in the development of treatment resistance. 

Patient studies for metformin in esophageal cancer are encouraging

Patient data for metformin and esophageal cancer come mainly from observational studies. A compelling observational study from 2013 followed a group of patients with esophageal adenocarcinoma who were treated with chemoradiation and esophagectomy (i.e. surgery). The researchers studied biopsy samples taken at the time of surgery to determine how well patients had responded to chemotherapy and radiotherapy. They found that the group of patients who were diabetic and on metformin had a higher rate of complete response to chemoradiation treatment (34.5% of 29 patients in this group) compared to those who were diabetic and not taking metformin (4.8% of 21 patients in this group), or were not diabetic, and therefore not taking metformin (19.6% of 235 patients in this group) (Skinner et al., 2013). A later similar type of study also reported better rates of overall survival for patients in the metformin group (Van De Voorde et al., 2015). A different similar study found no association between metformin and better outcomes for patients with esophageal cancer.

We believe that the supportive evidence from cell and animal studies, combined with the two positive population studies mentioned above are very encouraging. More clinical trials in this area are desperately needed (Spierings et al., 2015).

Statins and esophageal cancer

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

Statins can block important esophageal cancer cell pathways

Statins can block an important molecular pathway used by cells called the mevalonate pathway. This pathway is important for generating essential building blocks needed by the cell to grow and survive. Studies in the lab have shown that the mevalonate pathway can be upregulated in esophageal SCC cells, and that blockade of this pathway with statins can slow cancer cells’ growth and survival, and induce cell death (Chen et al., 2018; Shi et al., 2013; Zhong et al., 2014). Statins also appear to reduce tumor growth in mouse models of the disease (Shi et al., 2013; Yuan et al., 2019). In addition, a cell study from 2018 presents interesting evidence that statins can increase the sensitivity of esophageal cancer cells to radiotherapy, and prevent them from developing resistance. These findings need to be repeated in humans, but they hint at the possibility that statins could potentially help to increase the effectiveness of radiotherapy for esophageal cancer (Jin et al., 2018).

Statins and Barrett’s esophagus

Statins can also impact the growth and survival of esophageal adenocarcinoma cells (Chen et al., 2018; Ogunwobi and Beales, 2008; Sadaria et al., 2011). Barrett’s esophagus is a condition where the cell lining of the esophagus becomes damaged due to acid reflux. Very occasionally Barrett’s can progress to esophageal adenocarcinoma. Some scientists think that taking statins may help to prevent the cell changes seen in Barrett’s esophagus from becoming cancerous (i.e. chemoprevention) (Ogunwobi and Beales, 2008; Sadaria et al., 2011). A large recent systematic review and metanalysis which grouped together and analyzed data from a huge number of published observational patient studies supports this idea. The study reports that for patients with Barrett’s esophagus, those who took statins do seem less likely to develop esophageal adenocarcinoma (Thomas et al., 2018). Patients in the study who were taking statins had almost half the odds (i.e. 54%) of developing esophageal adenocarcinoma compared to patients who did not take statins.

Statins may be linked to better esophageal cancer outcomes

Esophageal cancer is relatively rare, and there are not yet many clinical trials in this area. However, a number of observational patient studies suggest that patients who happen to be taking statins around the time they are diagnosed with esophageal cancer are more likely to have better survival than those who are not (Alexandre et al., 2016; Lacroix et al., 2019; Nguyen et al., 2018). One or two published studies have contradicted this finding (Cardwell et al., 2017). However, an overall analysis of all available studies recently found evidence that statin use following diagnosis was linked to a small but significant reduced chance of all-cause death (i.e. a 19% decrease) and also reduced chance of cancer-related death (i.e. 16% decrease) following diagnosis with esophageal cancer, compared to non-statin use (Deng et al., 2019).

Mebendazole and Esophageal cancer

Mebendazole, a member of the benzimidazole drug family, is widely used to treat parasitic infections in both children and adults. Interest in mebendazole as a potential anticancer treatment is relatively new, and mostly based on promising mechanistic studies and compelling reports from case studies in cancer patients (Bai et al., 2011; Nygren and Larsson, 2014; Pantziarka et al., 2014). Based on this preliminary evidence, a number of clinical trials are now currently investigating mebendazole as an adjunctive treatment for cancer.

Preliminary data from lab studies also provide some early-stage evidence that mebendazole use alongside standard therapies may be of use for patients with esophageal cancers. For example, a cell screen of a huge number of compounds has presented supportive data showing that mebendazole was effectively able to reduce cell viability of esophageal cancer cells grown in the lab (Fig 6B. (Nagashima et al., 2018). And a separate study, published in abstract form online (not yet fully published and peer-reviewed) presents tantalizing data from tests in a range of rare cancer cell lines, including esophageal adenocarcinoma, which suggest that mebendazole could be effective as an anticancer agent in combination with standard cancer therapies for these cancers (Samizadeh et al., 2019). We await more studies in this area with interest.

Doxycycline and esophageal cancer

Apart from being an effective antibiotic, doxycycline, a type of tetracycline, may also have real therapeutic potential in targeting cancer (Bahrami et al., 2012).

Recent research has illuminated doxycycline’s potential to target cancer stem cells. Two lab studies show that doxycycline could effectively target cancer stem cells of multiple cancer types by restricting the assembly and activity of important cell components called mitochondria (Lamb et al., 2015a; Scatena et al., 2018; Sotgia et al., 2018). Mitochondria work like ‘batteries’ in cancer cells, generating the energy they need to survive. Restricting mitochondrial activity in cancer cells can severely deplete the cell’s ability to thrive, and particularly to withstand attack by other standard anticancer therapies.

We could find no direct studies investigating doxycycline in esophageal cancer, however data reported from oral cell SCC cell studies hint at the potential for doxycycline activity against other head and neck cancer types. A lab study from 2010 investigated doxycycline’s ability to block oral SCC cell production of enzymes called matrix metalloproteinases (MMPs). Increased MMPs have been linked to oral SCC ability to spread (metastasize). Studies on oral SCC cells grown in the lab showed that doxycycline was able to reduce production of MMP2 and MMP9 by different mechanisms, and that this reduced production was linked with decreased invasion-potential of the cells. Further studies from the same group also showed that doxycycline had a ‘suppressive effect’ on tumor growth in mice with oral SCC tumors (Shen et al., 2010).

Our own evidence: The METRICS Study

What is METRICS?

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

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

METRICS first results

In a first success for METRICS, results from our initial pilot study were recently published in the peer-reviewed scientific journal Frontiers in Pharmacology. The paper can be accessed freely online here.

The METRICS pilot study was an observational retrospective study, which means that our researchers looked back and analyzed patient clinical records to find out what happened. They collected data and recorded the outcomes from 95 patients with an advanced type of brain cancer called glioblastoma who attended the Care Oncology Clinic and who took the full COC Protocol alongside their usual standard treatments. This study did not have a control group, so our researchers compared the results from METRICS with previously published results from earlier studies in patients with the same type of cancer, and who also took standard-of-care treatments.

Initial results suggest that patients who attended our clinic and took the COC Protocol as part of their usual care were much more likely to survive at least 2 years (64.0% of patients in our study survived at least 2 years, compared to 27-29% for patients included in previously published studies), and tended to have longer survival times overall than would usually be expected for patients with this type of cancer (patients survived an average of 27 months in our study, compared to 15-16 months in earlier studies)(Agrawal et al., 2019).

These results are extremely promising, but they are also still preliminary. We don’t yet know exactly how the COC Protocol may have impacted survival times for example, or how other factors such as certain patient characteristics may have also influenced these results. But this first, initial evidence is certainly encouraging, and it suggests to us that we are heading in the right direction. Our next planned stage is to conduct a larger, well-designed study. You can find out more about future METRICS plans by looking online or contacting the clinic.

More FAQs

Why do we only prescribe the COC Protocol?

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

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

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

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

How does the COC Protocol work?

The COC Protocol is designed to work primarily by restricting the overall ability of cancer cells to take up and use (i.e. ‘metabolize’) energy.

Cancer cells need huge amounts of energy to survive, and the vast majority of cancers use an adaptive process called aerobic glycolysis to generate the excessive energy they need (Kroemer and Pouyssegur, 2008). Each of the medications in the protocol can target the various molecular metabolic processes involved in and surrounding aerobic glycolysis, and this can help lower the overall metabolic rate of the cancer cell (Jang et al., 2013).

We believe the COC Protocol medications can work in combination to consistently restrict energy supply and use, while simultaneously preventing cancer cells from adapting and using other pathways to take up energy (Jagust et al., 2019). As a result, cancer cells become increasingly weaker and less able to take in and use the nutrients (e.g. such as glucose and essential amino acids glutamine and arginine) they need from their surroundings (Andrzejewski et al., 2018; Liu et al., 2016). This makes it more difficult overall for cancer cells to survive, grow, and spread in the body. Gradually, the weakened cells (including more resilient and previously treatment-resistant cells) become more vulnerable to attack from other cell‑killing cancer therapies such as radiotherapy, chemotherapy, hormonal therapy, and targeted therapies (Bradford and Khan, 2013; Chen et al., 2012; Lacerda et al., 2014; Lamb et al., 2015b; Pantziarka et al., 2014).

By targeting the adapted metabolic mechanisms which are common to most cancers (but not usually healthy cells), we believe that the COC Protocol can be effective and selective for virtually any cancer regardless of specific type, stage, or location of cancer. Published epidemiological and lab studies increasingly support the potentially broad range of this therapy (Chae et al., 2015, 2016; Iliopoulos et al., 2011; Lamb et al., 2015a; Pantziarka et al., 2014).

Why these four medications together?

The true power of the COC Protocol lies in the specific combination of medications we use. We developed the protocol not just as a regimen of four individual treatments each with anticancer activity, but also to work as a single combined treatment (Mokhtari et al., 2017).

Evidence suggests that each medication in the COC Protocol can target cancer cell metabolism in a distinct and complementary way, and we have termed this action ‘mechanistic coherence’. Put simply, mechanistic coherence describes how each medication can attack the cancer cell from a different angle.

For example, cancer stem cells are a particularly resilient type of cancer cell, and each medication targets these cells in a different way: metformin targets the cell’s ‘batteries’ (called mitochondria) by making it very difficult for mitochondria to run the molecular reactions they need to produce energy, doxycycline blocks the cell-DNA machinery that mitochondria need to replicate and repair (Skoda et al., 2019), statins can alter cancer stem cell gene expression, making the cells more sensitive to other cancer therapies (Kodach et al., 2011), and mebendazole can interrupt numerous molecular processes involved in cell division to help block cancer stem cell growth (Hothi et al., 2012; Hou et al., 2015).

By combining all four agents together, the COC Protocol can hit cancer stem cells (and other cancer cells) across multiple ‘weak spots’, and like a one-two punch, this leaves the cells less able to dodge and recover from standard treatments.

Lab studies are beginning to highlight the effectiveness of this approach using COC Protocol medication combinations. In mechanistic studies, combining statin and metformin greatly decreases the growth of prostate and endometrial cancer cells more than either agent alone (Kim et al., 2019; Wang et al., 2017b).

Observational studies have also reported potentially ‘synergistic’ effects of these medications against various cancers (Babcook et al., 2014; Danzig et al., 2015; Lehman et al., 2012; Nimako et al., 2017). A clinical trial investigating metformin and doxycycline in breast cancer is now underway (NCT02874430), and our own research program, METRICS, is now also beginning to produce promising data. 

Can I take the COC Protocol long-term?

The COC Protocol is primarily designed to be a long-term ‘adjunctive’ therapy, to help optimize standard treatments. However, as metabolic treatment with the COC Protocol is intended to run long-term, patients may also take the protocol as a maintenance regime after standard treatment has been completed or during breaks from standard treatment and as part of a long-term strategy to mitigate the risk of recurrence or metastases. For this reason, it is also worth noting that each of the COC Protocol medications also has reported beneficial mechanisms of action in cancer which are not dependent on the co-administration of standard therapies, and which may independently help to reduce the risk of relapse and metastatic spread.

The Care Oncology model

Active medical supervision of each patient

Although the COC Protocol medications have been used safely in the general population for many years, they are not without side-effects. In addition, every patient’s situation is both complex and unique, and requires careful personalized assessment. This is why every patient who attends the Care Oncology Clinic is placed under the direct care of clinicians with specialist knowledge of prescribing the COC Protocol medications in the context of cancer. Our clinicians individually assess the potential benefits and risks involved in taking the COC Protocol with each patient. We will only recommend the COC Protocol to patients when we believe it will be safe and beneficial to do so. Each COC Protocol prescription is tailored to the needs of the patient, and doses and regimens are carefully reviewed and adjusted based on how the patient progresses.

It is therefore essential that patients are carefully monitored at our clinic throughout the course of their treatment.

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Important Notice

Purpose of this article

This article is an overview of some of the scientific and medical published literature concerning the medications which comprise the patented Care Oncology protocol. Care has been taken to select relevant articles supporting the off-label use of these medicines in a clinical setting for the adjunct treatment of cancer. This article does not purport to be a comprehensive review of all the evidence, nor does it capture all of the potential side-effects of such treatment.

This article is for information purposes only and it does NOT constitute medical advice. The medicines discussed herein are available on prescription-only and should not be taken without consultation with your doctor or other professional healthcare provider. Care Oncology doctors will discuss the suitability of these medicines with you and will liaise with your doctor or oncologist to discuss their suitability for you.

You must NOT rely on the information in this article as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter you should consult your doctor or other professional healthcare provider. If you think you may be suffering from any medical condition you should seek immediate medical attention. You should never delay seeking medical advice, disregard medical advice, or discontinue medical treatment because of information contained in this article.

Copyright

The copyright in this article is owned by Health Clinics USA Corp and its licensors.

Patent

The Care Oncology (“COC”) Protocol is protected by United States patent US9622982B2 and by various additional international patents.

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References

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.

Alexandre, L., Clark, A.B., Bhutta, H.Y., Chan, S.S.M., Lewis, M.P.N., and Hart, A.R. (2016). Association Between Statin Use After Diagnosis of Esophageal Cancer and Survival: A Population-Based Cohort Study. Gastroenterology 150, 854-865.e1; quiz e16-17.

Andrzejewski, S., Siegel, P.M., and St-Pierre, J. (2018). Metabolic Profiles Associated With Metformin Efficacy in Cancer. Front. Endocrinol. 9.

Babcook, M.A., Shukla, S., Fu, P., Vazquez, E.J., Puchowicz, M.A., Molter, J.P., Oak, C.Z., MacLennan, G.T., Flask, C.A., Lindner, D.J., et al. (2014). Synergistic Simvastatin and Metformin Combination Chemotherapy for Osseous Metastatic Castration-Resistant Prostate Cancer. Mol. Cancer Ther. 13, 2288–2302.

Bahrami, F., Morris, D.L., and Pourgholami, M.H. (2012). Tetracyclines: drugs with huge therapeutic potential. Mini Rev. Med. Chem. 12, 44–52.

Bai, R.-Y., Staedtke, V., Aprhys, C.M., Gallia, G.L., and Riggins, G.J. (2011). Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro-Oncol. 13, 974–982.

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.

Cai, X., Hu, X., Tan, X., Cheng, W., Wang, Q., Chen, X., Guan, Y., Chen, C., and Jing, X. (2015). Metformin Induced AMPK Activation, G0/G1 Phase Cell Cycle Arrest and the Inhibition of Growth of Esophageal Squamous Cell Carcinomas In Vitro and In Vivo. PloS One 10, e0133349.

Cardwell, C.R., Spence, A.D., Hughes, C.M., and Murray, L.J. (2017). Statin use after esophageal cancer diagnosis and survival: A population based cohort study. Cancer Epidemiol. 48, 124–130.

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, J., Lan, T., Hou, J., Zhang, J., An, Y., Tie, L., Pan, Y., Liu, J., and Li, X. (2012). Atorvastatin sensitizes human non-small cell lung carcinomas to carboplatin via suppression of AKT activation and upregulation of TIMP-1. Int. J. Biochem. Cell Biol. 44, 759–769.

Chen, Y., Li, L.-B., Zhang, J., Tang, D.-P., Wei, J.-J., and Zhuang, Z.-H. (2018). Simvastatin, but not pravastatin, inhibits the proliferation of esophageal adenocarcinoma and squamous cell carcinoma cells: a cell-molecular study. Lipids Health Dis. 17, 290.

Danzig, M.R., Kotamarti, S., Ghandour, R.A., Rothberg, M.B., Dubow, B.P., Benson, M.C., Badani, K.K., and McKiernan, J.M. (2015). Synergism between metformin and statins in modifying the risk of biochemical recurrence following radical prostatectomy in men with diabetes. Prostate Cancer Prostatic Dis. 18, 63–68.

Deng, H.-Y., Lan, X., Zheng, X., Zha, P., Zhou, J., Wang, R.-L., Jiang, R., and Qiu, X.-M. (2019). The association between statin use and survival of esophageal cancer patients: A systematic review and meta-analysis. Medicine (Baltimore) 98, e16480.

Fan, H., Yu, X., Zou, Z., Zheng, W., Deng, X., Guo, L., Jiang, W., Zhan, Q., and Lu, S.-H. (2019). Metformin suppresses the esophageal carcinogenesis in rats treated with NMBzA through inhibiting AMPK/mTOR signaling pathway. Carcinogenesis 40, 669–679.

Feng, Y., Ke, C., Tang, Q., Dong, H., Zheng, X., Lin, W., Ke, J., Huang, J., Yeung, S.-C.J., and Zhang, H. (2014). Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell Death Dis. 5, e1088.

Fujihara, S., Kato, K., Morishita, A., Iwama, H., Nishioka, T., Chiyo, T., Nishiyama, N., Miyoshi, H., Kobayashi, M., Kobara, H., et al. (2015). Antidiabetic drug metformin inhibits esophageal adenocarcinoma cell proliferation in vitro and in vivo. Int. J. Oncol. 46, 2172–2180.

Honjo, S., Ajani, J.A., Scott, A.W., Chen, Q., Skinner, H.D., Stroehlein, J., Johnson, R.L., and Song, S. (2014). Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer. Int. J. Oncol. 45, 567–574.

Hothi, P., Martins, T.J., Chen, L., Deleyrolle, L., Yoon, J.-G., Reynolds, B., and Foltz, G. (2012). High-Throughput Chemical Screens Identify Disulfiram as an Inhibitor of Human Glioblastoma Stem Cells. Oncotarget 3, 1124–1136.

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.

Iliopoulos, D., Hirsch, H.A., and Struhl, K. (2011). Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res. 71, 3196–3201.

Jagust, P., de Luxán-Delgado, B., Parejo-Alonso, B., and Sancho, P. (2019). Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells. Front. Pharmacol. 10.

Jang, M., Kim, S.S., and Lee, J. (2013). Cancer cell metabolism: implications for therapeutic targets. Exp. Mol. Med. 45, e45.

Jin, Y., Xu, K., Chen, Q., Wang, B., Pan, J., Huang, S., Wei, Y., and Ma, H. (2018). Simvastatin inhibits the development of radioresistant esophageal cancer cells by increasing the radiosensitivity and reversing EMT process via the PTEN-PI3K/AKT pathway. Exp. Cell Res. 362, 362–369.

Kato, S., Smalley, S., Sadarangani, A., Chen-Lin, K., Oliva, B., Brañes, J., Carvajal, J., Gejman, R., Owen, G.I., and Cuello, M. (2010). Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase. J. Cell. Mol. Med. 14, 1180–1193.

Kim, J.S., Turbov, J., Rosales, R., Thaete, L.G., and Rodriguez, G.C. (2019). Combination simvastatin and metformin synergistically inhibits endometrial cancer cell growth. Gynecol. Oncol. 0.

Kobayashi, M., Kato, K., Iwama, H., Fujihara, S., Nishiyama, N., Mimura, S., Toyota, Y., Nomura, T., Nomura, K., Tani, J., et al. (2013). Antitumor effect of metformin in esophageal cancer: in vitro study. Int. J. Oncol. 42, 517–524.

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.

Kroemer, G., and Pouyssegur, J. (2008). Tumor Cell Metabolism: Cancer’s Achilles’ Heel. Cancer Cell 13, 472–482.

Lacerda, L., Reddy, J.P., Liu, D., Larson, R., Li, L., Masuda, H., Brewer, T., Debeb, B.G., Xu, W., Hortobágyi, G.N., et al. (2014). Simvastatin radiosensitizes differentiated and stem-like breast cancer cell lines and is associated with improved local control in inflammatory breast cancer patients treated with postmastectomy radiation. Stem Cells Transl. Med. 3, 849–856.

Lacroix, O., Couttenier, A., Vaes, E., Cardwell, C.R., De Schutter, H., and Robert, A. (2019). Statin use after diagnosis is associated with an increased survival in esophageal cancer patients: a Belgian population-based study. Cancer Causes Control CCC 30, 385–393.

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.

Lehman, D.M., Lorenzo, C., Hernandez, J., and Wang, C. (2012). Statin Use as a Moderator of Metformin Effect on Risk for Prostate Cancer Among Type 2 Diabetic Patients. Diabetes Care 35, 1002–1007.

Liang, F., Wang, Y.-G., and Wang, C. (2018). Metformin Inhibited Growth, Invasion and Metastasis of Esophageal Squamous Cell Carcinoma in Vitro and in Vivo. Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol. 51, 1276–1286.

Liu, X., Romero, I.L., Litchfield, L.M., Lengyel, E., and Locasale, J.W. (2016). Metformin targets central carbon metabolism and reveals mitochondrial requirements in human cancers. Cell Metab. 24, 728–739.

Mokhtari, R.B., Homayouni, T.S., Baluch, N., Morgatskaya, E., Kumar, S., Das, B., and Yeger, H. (2017). Combination therapy in combating cancer. Oncotarget 8, 38022–38043.

Mynhardt, C., Damelin, L.H., Jivan, R., Peres, J., Prince, S., Veale, R.B., and Mavri-Damelin, D. (2018). Metformin-induced alterations in nucleotide metabolism cause 5-fluorouracil resistance but gemcitabine susceptibility in oesophageal squamous cell carcinoma. J. Cell. Biochem. 119, 1193–1203.

Nagashima, F., Nishiyama, R., Iwao, B., Kawai, Y., Ishii, C., Yamanaka, T., Uchino, H., and Inazu, M. (2018). Molecular and Functional Characterization of Choline Transporter-Like Proteins in Esophageal Cancer Cells and Potential Therapeutic Targets. Biomol. Ther. 26, 399–408.

Nakayama, A., Ninomiya, I., Harada, S., Tsukada, T., Okamoto, K., Nakanuma, S., Sakai, S., Makino, I., Kinoshita, J., Hayashi, H., et al. (2016). Metformin inhibits the radiation-induced invasive phenotype of esophageal squamous cell carcinoma. Int. J. Oncol. 49, 1890–1898.

Nguyen, T., Khan, A., Liu, Y., El-Serag, H.B., and Thrift, A.P. (2018). The Association Between Statin Use After Diagnosis and Mortality Risk in Patients With Esophageal Cancer: A Retrospective Cohort Study of United States Veterans. Am. J. Gastroenterol. 113, 1310.

Nimako, G.K., Wintrob, Z.A.P., Sulik, D.A., Donato, J.L., and Ceacareanu, A.C. (2017). Synergistic Benefit of Statin and Metformin in Gastrointestinal Malignancies. J. Pharm. Pract. 30, 185–194.

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. 53, 427–428.

Ogunwobi, O.O., and Beales, I.L.P. (2008). Statins inhibit proliferation and induce apoptosis in Barrett’s esophageal adenocarcinoma cells. Am. J. Gastroenterol. 103, 825–837.

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.

Sadaria, M.R., Reppert, A.E., Yu, J.A., Meng, X., Fullerton, D.A., Reece, T.B., and Weyant, M.J. (2011). Statin therapy attenuates growth and malignant potential of human esophageal adenocarcinoma cells. J. Thorac. Cardiovasc. Surg. 142, 1152–1160.

Samizadeh, M., Chakrabarti, D., Zhu, Y., Treuting, R.L., Kaplan, J., Siders, W., and Barber, J.D. (2019). Abstract 299: Synergistic activity of mebendazole and chemotherapeutic agents for rare cancers. Cancer Res. 79, 299–299.

Scatena, C., Roncella, M., Di Paolo, A., Aretini, P., Menicagli, M., Fanelli, G., Marini, C., Mazzanti, C.M., Ghilli, M., Sotgia, F., et al. (2018). Doxycycline, an Inhibitor of Mitochondrial Biogenesis, Effectively Reduces Cancer Stem Cells (CSCs) in Early Breast Cancer Patients: A Clinical Pilot Study. Front. Oncol. 8.

Shafaee, A., Dastyar, D.Z., Islamian, J.P., and Hatamian, M. (2015). Inhibition of tumor energy pathways for targeted esophagus cancer therapy. Metabolism. 64, 1193–1198.

Shen, L.-C., Chen, Y.-K., Lin, L.-M., and Shaw, S.-Y. (2010). Anti-invasion and anti-tumor growth effect of doxycycline treatment for human oral squamous-cell carcinoma–in vitro and in vivo studies. Oral Oncol. 46, 178–184.

Shi, J., Zhu, J., Zhao, H., Zhong, C., Xu, Z., and Yao, F. (2013). Mevalonate pathway is a therapeutic target in esophageal squamous cell carcinoma. Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med. 34, 429–435.

Skinner, H.D., McCurdy, M.R., Echeverria, A.E., Lin, S.H., Welsh, J.W., O’Reilly, M.S., Hofstetter, W.L., Ajani, J.A., Komaki, R., Cox, J.D., et al. (2013). Metformin use and improved response to therapy in esophageal adenocarcinoma. Acta Oncol. Stockh. Swed. 52, 1002–1009.

Skoda, J., Borankova, K., Jansson, P.J., Huang, M.L.-H., Veselska, R., and Richardson, D.R. (2019). Pharmacological targeting of mitochondria in cancer stem cells: An ancient organelle at the crossroad of novel anti-cancer therapies. Pharmacol. Res. 139, 298–313.

Sotgia, F., Ozsvari, B., Fiorillo, M., De Francesco, E.M., Bonuccelli, G., and Lisanti, M.P. (2018). A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX. Cell Cycle Georget. Tex 17, 2091–2100.

Spierings, L.E. a. M.M., Lagarde, S.M., van Oijen, M.G.H., Gisbertz, S.S., Wilmink, J.W., Hulshof, M.C.C.M., Meijer, S.L., Anderegg, M.C., van Berge Henegouwen, M.I., and van Laarhoven, H.W.M. (2015). Metformin Use During Treatment of Potentially Curable Esophageal Cancer Patients is not Associated with Better Outcomes. Ann. Surg. Oncol. 22 Suppl 3, S766-771.

Thomas, T., Loke, Y., and Beales, I.L.P. (2018). Systematic Review and Meta-analysis: Use of Statins Is Associated with a Reduced Incidence of Oesophageal Adenocarcinoma. J. Gastrointest. Cancer 49, 442–454.

Van De Voorde, L., Janssen, L., Larue, R., Houben, R., Buijsen, J., Sosef, M., Vanneste, B., Schraepen, M.-C., Berbée, M., and Lambin, P. (2015). Can metformin improve “the tomorrow” of patients treated for oesophageal cancer? Eur. J. Surg. Oncol. J. Eur. Soc. Surg. Oncol. Br. Assoc. Surg. Oncol. 41, 1333–1339.

Wang, F., Ding, X., Wang, T., Shan, Z., Wang, J., Wu, S., Chi, Y., Zhang, Y., Lv, Z., Wang, L., et al. (2017a). Metformin inhibited esophageal squamous cell carcinoma proliferation in vitro and in vivo and enhanced the anti-cancer effect of cisplatin. PloS One 12, e0174276.

Wang, Z.-S., Huang, H.-R., Zhang, L.-Y., Kim, S., He, Y., Li, D.-L., Farischon, C., Zhang, K., Zheng, X., Du, Z.-Y., et al. (2017b). Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells in Vitro and in Vivo. Biol. Pharm. Bull. 40, 1247–1254.

Yu, H., Bian, X., Gu, D., and He, X. (2016). Metformin Synergistically Enhances Cisplatin-Induced Cytotoxicity in Esophageal Squamous Cancer Cells under Glucose-Deprivation Conditions. BioMed Res. Int. 2016, 8678634.

Yuan, Q., Dong, C.D., Ge, Y., Chen, X., Li, Z., Li, X., Lu, Q., Peng, F., Wu, X., Zhao, J., et al. (2019). Proteome and phosphoproteome reveal mechanisms of action of atorvastatin against esophageal squamous cell carcinoma. Aging 11, 9530–9543.

Zhong, C., Fan, L., Yao, F., Shi, J., Fang, W., and Zhao, H. (2014). HMGCR is necessary for the tumorigenecity of esophageal squamous cell carcinoma and is regulated by Myc. Tumour Biol. J. Int. Soc. Oncodevelopmental Biol. Med. 35, 4123–4129.