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The COC Protocol™ in Glioma
This document provides a brief summary of the current scientific evidence for the adjuvant use of the COC Protocol medications in glioma, including glioblastoma and other high-grade gliomas. A table of all currently ongoing or recently finished clinical trials related to the use of these medications in glioma and other brain tumours is provided in Table 1, which you can find at the end of this article.
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Glioma tumours grow from glial cells in the brain and are the most common type of brain tumour. Low-grade benign gliomas are slower growing and less dangerous than high-grade, aggressive (malignant) gliomas. Glioblastoma multiforme (GBM), a type of malignant astrocytoma, is the most common high-grade brain tumour in adults.
The standard treatment for high-grade glioma is usually surgery, followed by courses of chemotherapy (i.e. temozolomide) and radiation. Much current glioma research is focussed on adding extra (adjuvant) treatments alongside this standard regime in the hope of improving results for patients.
Scientific interest is growing in the use of treatments which target the metabolic pathways of cancer cells (i.e. the processes used by cells to generate energy) to slow or stop the growth of cancers. Care Oncology specialises in using already-licensed (off-label) medications with known anti-metabolic activity to help treat and control cancer. We have developed an adjuvant treatment called the COC Protocol, which combines what we believe to be the most effective metabolically-targeted offlabel medications available.
The COC Protocol as an adjuvant treatment for glioma
This section summarises briefly the existing evidence for effective use of COC Protocol medications in glioma, and of the current clinical trials in this area.
High-grade gliomas like GBM are thought to be very dependent on the cell processes primarily targeted by statins for survival, and fat-soluble ‘lipophilic’ statins like atorvastatin can cross the human BBB relatively easily (1). These qualities, along with the demonstrated ability of statins to slow and suppress glioma cancer cell growth in the lab and in preclinical mouse models makes atorvastatin a good candidate as a repurposed glioma treatment (2).
Several studies show that statins can target and damage glioma cells in a number of different ways, including by increasing programmed and unprogrammed cell death (eg apoptosis and necrosis) (3–5), and reducing cancer cell growth, division, and movement (proliferation and migration)(5–8).
Other lab studies have also shown that statins can help to reduce tumour resistance to other glioma treatments (9–11). One lab study using pitavastatin, a statin similar in profile to atorvastatin, showed that MDR-1, a molecule which is excessively produced in glioma cells in response to treatment and which helps these cells become resistant, is blocked by statins. In this study, statins helped to improve the effectiveness of chemotherapy (12). In a separate lab study, combining statins with an additional metabolically-targeted drug also appeared to increase potency on glioblastoma cells (13).
Most clinical studies for statin use in glioma patients are still ongoing or awaiting results (see Table 1). But completed clinical studies show promise. Early-phase studies from the 1990s, where adult and child patients with solid central nervous system (i.e. brain) tumours and high-grade gliomas took lovastatin or fluvastatin in 3 or 4 weekly cycles, showed that statins were well tolerated. Promising tumour responses were noted in patients with GBM and anaplastic astrocytoma, and study investigators suggested a less cyclical and more constant treatment regime could be more effective (14,15). Patient population studies monitoring survival in large numbers of people who took statins before and during glioblastoma diagnosis and treatment have had inconclusive results, possible due to different study designs (16–18).
Scientific interest in mebendazole as a potential anticancer treatment is relatively new and is mostly based on promising mechanistic studies and compelling reports from case studies in cancer patients (19, 20).
Emerging evidence also suggests that mebendazole may have particularly high levels of activity against cancers of the brain. This is partly because mebendazole is a small, fat-soluble molecule which can easily cross the BBB. It is also thought to work in a similar way to vincristine, a chemotherapy drug currently used for treatment of some types of cancer, including some gliomas (18). Mebendazole is thought to kill cancer cells partly by disrupting special structures inside the cell, called microtubules (21). It can inhibit glioma tumour cell growth in the lab and has been shown to improve survival in preclinical mouse models of glioblastoma (22). In addition, some forms of mebendazole (including the form which is prescribed as part of the COC Protocol) are thought to cross the BBB more readily than vincristine (23), which has led to suggestions that mebendazole should replace vincristine in the treatment of brain tumours (24). In a computer modelling study which looked at 51 different drugs including all chemotherapies used or previously used for treatment of a childhood glioma called DIPG, mebendazole was one of just 8 drugs which was predicted to reach effective concentrations in the brain following systemic (i.e. by mouth or injection) administration (25). Evidence from lab studies also suggests that simultaneous use of microtubule disruptors like mebendazole can help to improve the effectiveness of radiotherapy and temozolomide, two standard glioma treatments (26,27). Numerous clinical trials are now underway to investigate this possibility (see Table 1).
Metformin is not fat soluble but is predicted to cross the BBB using special transporter molecules (28–30). An impressive number of lab studies show metformin can block glioma and glioblastoma cell and tumour growth via a number of different mechanisms, including supressing growth, division and movement of glioma cells (31–33), increasing programmed glioma cell death (34, 35), and blocking growth of new blood vessels (angiogenesis) to glioma tumours (36).
Within the last 5 years scientists have also discovered that metformin can target and disrupt glioblastoma stem cells (37–39). This is important, because these cells are believed to be the initiating cells of a tumour. They can be less responsive to radio- and chemotherapies and are thought to be responsible for tumour regrowth following treatment. Scientists believe control of these cells is key for ensuring long-term survival for patients with glioblastoma (39,40).
Metformin’s real potential in glioma is revealed when metformin is tested in combination with standard therapies or newly-developed anticancer medications. These studies repeatedly show that metformin’s multi-targeted activity against cancer cells and cancer stem cells can potentially improve potency of a combinatorial anticancer treatment regimen. In lab studies, improved anticancer activity (33,41–43) and/or resistance of glioma cells and glioma stem cells to standard therapies such as temozolomide has been overcome using metformin in combination with other drugs (33, 44, 45).
Numerous clinical trials are now underway investigating metformin in combination with other therapies in the treatment of advanced glioblastoma in both adults and children.
Doxycycline is an antibiotic with other extremely valuable properties, including anti-inflammatory and anticancer activity. This gives doxycycline real therapeutic potential in treating a range of other diseases, including cancer (46).
In glioma, a 2007 lab study has shown that doxycycline helps to block tumour cell growth and division and reduces glioma cells’ potential to move and invade other areas of the body (47). Importantly, doxycycline appears to be particularly good at targeting tumour stem cells. Doxycycline can block a process called ‘mitochondrial biogenesis’, which stem cells need to use to make energy for survival and growth. Lab studies show that doxycycline treatment could make glioma stem cells more susceptible to other treatments like radiotherapy (48), and less able to regrow after temozolomide treatment (49). The results of these lab studies are now starting to be replicated in patients- a very recent study has just reported that doxycycline was able to effectively reduce cancer stem cells in patients with early-stage breast cancer (50).
Doxycycline is also well absorbed by the body and is known to cross the BBB effectively (51). These qualities combine to make doxycycline a potentially very powerful anticancer treatment for brain tumours such as glioma (48).
Ongoing clinical research
Table 1 summarises current ongoing or recently completed clinical trials investigating individual metabolically targeted off-label COC Protocol medications in the treatment of brain tumours, including gliomas of all types, glioblastoma, and childhood brain tumours such as medulloblastoma.