Brain Tumor - Glioblastoma
Novel and Emerging Strategies
There are several intriguing glioblastoma therapies supported by emerging evidence. One way to gain access to some of these therapies may be through participation in a clinical trial. Ask your medical team about available clinical trial options. Alternatively, innovative physicians familiar with the latest research may be willing to incorporate some of the more widely available off-label drugs described here into a conventional treatment plan.
Immunotherapy is a major research focus in the field of oncology. Under healthy conditions, the immune system is able to keep cancer in check (Finn 2018). However, some cancer cells develop the ability to escape the immune system (Beatty 2015). Once cancer cells that are not vulnerable to immune destruction have established themselves in a person’s body, a tumor can start to form (Marcus 2014).
Immunotherapy aims to manipulate the patient’s immune system to enable it to once again attack and eliminate cancer cells (Marin-Acevedo 2018). Recent advances in using immunotherapy for various cancers opened interest towards applying this strategy for glioblastoma, and a better understanding of the tumor microenvironment is critical for these developments (Boussiotis 2018). Researchers are investigating many different types of immunotherapies for glioblastoma (Felthun 2018).
For example, a very novel form of immunotherapy was presented in a recent phase I study on a 50-year-old man with recurrent glioblastoma (Brown 2016). In this study, the investigators created a chimeric antigen receptor–engineered (CAR) T cell, which had been designed to target a marker expressed by many glioblastoma cells, called interleukin-13 receptor alpha 2 (Brown, Badie 2015). The patient received treatment with these cells, which were injected into his brain over a period of 220 days (Brown 2016). The patient had a dramatic clinical response without any serious negative effects. His original tumors disappeared and the response continued for 7.5 months. However, his cancer recurred at new sites after treatment was stopped. Given these intriguing findings, the researchers are expanding an ongoing study to administer the CAR T cells to more patients and are optimizing the treatment (Brown 2018; Brown 2016). CAR T cells have been designed to target other glioblastoma markers, including HER2 and a form of the epidermal growth factor receptor (Migliorini 2017; Ahmed 2017).
In 2013, research conducted at Duke University Medical Center reported complete clinical responses in patients with recurrent glioblastoma that were treated with a modified poliovirus that had been altered using genetic material from a rhinovirus (a type of virus that causes common colds). This poliovirus-rhinovirus hybrid, called PVSRIPO, is engineered to not infect non-cancerous cells (Brown 2014; Brown, Gromeier 2015; Desjardins 2013). However, because glioblastoma cells commonly have high levels of a receptor that binds to poliovirus, the poliovirus hybrid can infect them and trigger cell death (Goetz 2011). In addition, molecules released from the dying cells activate immune and inflammatory responses that help destroy the cancer cells (Brown, Gromeier 2015; Holl 2016; Brown 2017; Denniston 2016). Due to positive reports from early research and lack of effective therapies for glioblastoma, PVSRIPO received “breakthrough therapy” designation from the FDA in May 2016, allowing further investigations to proceed rapidly (Fong 2016; Holl 2016).
A phase I clinical trial designed to identify optimal doses for future clinical trials enrolled 61 patients with recurrent high-grade glioblastoma. Varying doses of PVSRIPO were applied directly to their tumors using catheters. A survival rate of 21% was noted at both 24 and 36 months among those treated with PVSRIPO versus 14% at 24 months and 4% at 36 months in a comparison group of 104 similar patients not treated with this therapy. The non-infectiousness of PVSRIPO was confirmed, and while adverse effects occurred frequently, only one treatment-limiting side effect was observed in a participant receiving the maximum tested dose (Desjardins 2018). Information about current and future clinical trials using this promising therapy can be found at www.ClinicalTrials.gov.
Cancer vaccines, a type of immunotherapy earning much attention in recent years, may be effective against brain tumors (Paolillo 2018; Steiner 2004; Huang 2017). One anticancer vaccine in clinical trials, called SurVaxM, targets a protein called survivin (Fenstermaker 2016). Survivin is commonly expressed in glioblastoma cells and normally protects cancer cells from death (Saito 2017; Tang 2015; Mellai 2008). The vaccine is designed to cause the body's immune system to develop an immune response against survivin, just like a flu vaccine makes the body recognize the virus that causes flu. Early studies showed that the vaccine produced an anti-tumor immune response against gliomas in mice (Fenstermaker 2014). In a phase I trial of patients with recurrent glioblastoma, SurVaxM was safe and improved outcomes for trial participants. The patients on average went 17.6 weeks without worsening of their disease and survived an average of 86.6 weeks (Fenstermaker 2016). This early trial did not have a control group, but a similar patient group would be expected to survive only about 25 weeks (Wong 1999). The FDA has granted SurVaxM orphan drug status, and a larger trial of SurVaxM in combination with standard therapy is underway as of early 2018 in patients with newly diagnosed glioblastoma (Fenstermaker 2018).
Another vaccine under development for treating glioblastoma is called DCVax-L. This strategy involves modulating the patient’s immune cells in the lab so they are primed to attack the patient’s specific cancer (Polyzoidis 2015; Polyzoidis 2014). The cells are then re-introduced into the patient’s body. Promising results were noted in a phase II trial, and a phase III trial is underway as of the time of this writing in early 2018 (Hdeib 2015; Felthun 2018).
Aptamers are small chains of nucleic acids (Lakhin 2013). Like monoclonal antibodies, these small molecules can be designed to recognize and bind specific targets, such as those that occur in glioblastoma cells (Yang 2007). Aptamers have the advantage of being much smaller than antibodies and thus can penetrate into tissue—including the central nervous system—more efficiently (Catuogno 2017). Researchers are exploring ways to use aptamers to improve imaging in the brain (Tang 2017), but they may also be useful for treating brain tumors. For instance, chemotherapy agents can be attached to aptamers designed to target specific markers on a patient’s cancer cells. Numerous aptamers that target different markers on glioblastoma cells are being developed. Laboratory research continues to improve the structure and potential utility of aptamers, with the hope of starting clinical trials soon (Hays 2017).
Metformin, a first-line drug for diabetes, can pass from the bloodstream into the brain (Yarchoan 2014). A number of preclinical studies have shown that metformin may inhibit the division and migration of glioblastoma cells (Seliger 2016; Aldea 2014; Wurth 2014; Ferla 2012; Carmignani 2014; Gritti 2014). In laboratory studies, metformin stopped glioblastoma stem cells from dividing (Gritti 2014), and metformin and arsenic trioxide helped differentiate glioblastoma stem cells into non-tumorigenic cells (Carmignani 2014).
The anticancer effects of metformin may result in part from activation of the enzyme AMP-activated protein kinase (AMPK) and inactivation of the transcription factor STAT3 (Ferla 2012; Elmaci 2016; Leidgens 2017; Sato 2012). AMPK is an important regulator of glucose and fatty acid metabolism that promotes healthy aging and extends lifespan (Burkewitz 2014; Riera 2016), while STAT3 controls cell growth and survival and is activated in many cancer types (Demaria 2014; Carpenter 2014).
Metformin may synergize with some existing cancer treatments. For example, in one study, metformin improved the ability of temozolomide to destroy human brain cancer cells (Soritau 2011). A separate study used a type of glioblastoma cells that were not responding to temozolomide. Treatment with metformin made the cells sensitive to temozolomide (Yang 2016). In mice with experimentally induced glioblastoma, metformin improved the effects of temozolomide, and in cell culture studies, it improved the effects of radiation therapy (Sesen 2015; Yu 2015). In another study, mice with glioblastoma treated with high-dose metformin combined with temozolomide lived significantly longer than those treated with metformin or temozolomide alone (Lee 2018). An angiogenesis inhibitor called sorafenib (Nexavar) was also more effective when combined with metformin in laboratory research (Aldea 2014). In another laboratory study, metformin sensitized glioblastoma cells to radiation or radiation combined with temozolomide (Adeberg 2017). Additional findings from animal research showed that metformin decreased brain swelling and reduced the leakiness of the blood vessels (Zhao 2016).
Initial data in human glioblastoma patients have also been encouraging. One study analyzed data from 276 glioblastoma patients treated with either radiation or radiation plus temozolomide. Forty of the patients had diabetes, and 20 of these were taking metformin. Survival time without evidence of disease worsening was significantly longer in diabetics receiving metformin (10 months) than in other diabetics (less than 5 months) and nondiabetics (7 months) (Adeberg 2015). As of early 2018, there are five clinical trials (two phase II and three phase I) registered with ClinicalTrials.gov that address the potential benefits of metformin in people with glioblastoma (ClinicalTrials.gov 2018). Results of these trials will help establish the value of metformin as an adjuvant therapy for glioblastoma.
Cimetidine is another intriguing off-label drug that may have potential as a brain tumor treatment. This common heartburn drug has several unanticipated effects, including anti-tumor activity against several types of cancer (Pantziarka 2014). In an animal model of human glioblastoma, combining cimetidine with temozolomide prolonged survival compared with temozolomide alone (Berg 2016). A small 2017 study on seven glioblastoma patients found that a cocktail of drugs (cimetidine, lithium, olanzapine, and valproate) led to longer-than-expected survival; the mechanism by which this cocktail improved survival was thought to involve inhibition of the enzyme glycogen synthase kinase 3 beta (GSK3β), a molecule involved in glioblastoma progression (Furuta 2017).
Valganciclovir is an FDA-approved drug used to treat CMV infection (Kalil 2009). In a phase I/II clinical trial of valganciclovir involving 42 patients with glioblastoma, an exploratory analysis of 22 patients receiving at least six months of antiviral therapy found that 50% were still alive after two years compared with 20.6% of the control group not receiving valganciclovir. After four years, about 27% of patients who received valganciclovir for greater than six months and almost 6% of control participants were still alive (Stragliotto 2013). In a similar study, researchers compared data from glioblastoma patients treated with valganciclovir and a control group. Both groups received standard conventional therapy and had similar disease characteristics. After two years, 62% of the valganciclovir group and 18% of the control group were still alive. Among the 40 patients who received valganciclovir for at least six months, 70% were still alive after two years (Soderberg-Naucler 2013).
Based on these results, patients with glioblastoma and evidence of CMV-positive tumor tissue should consider consulting with their oncologist to see if they are eligible to receive the treatment protocol described in the aforementioned studies (Soderberg-Naucler 2013; Stragliotto 2013), which resulted in unprecedented survival improvements. The patients took 900 mg of valganciclovir twice daily for three weeks and then 450 mg twice a day. The dose can be adjusted if any side effects arise such as kidney impairment or bone marrow suppression.
Dichloroacetate is an investigational drug that has shown benefits for certain genetic diseases (Stacpoole 2008). In recent years, dichloroacetate has gained attention for its ability to kill cancer cells and enhance the activity of other cancer therapies (Kankotia 2014).
Early research has been promising: an open-label phase I trial on 15 adults with grade III or IV gliomas or brain metastases from other cancers found that dichloroacetate treatment was feasible and well-tolerated (Dunbar 2014). A similar trial in 24 patients with advanced solid tumors used 28-day cycles of dichloroacetate at different doses and found only mild side effects; this trial was not designed to assess how well the treatment worked (Chu 2015). This research built on an earlier, smaller trial on five glioblastoma patients treated with dichloroacetate for up to 15 months (Michelakis 2010). The authors found evidence of glioblastoma cell death and reduced formation of new blood vessels (angiogenesis) in these patients’ tumors. Studies on cancer cells in the lab have also shown that dichloroacetate increases cancer cell death and decreases angiogenesis, which is necessary for tumors to spread (Dunbar 2014; Michelakis 2010). Dichloroacetate also has been found to make the inside of the glioblastoma cells dramatically more acidic, which may inhibit their growth (Albatany 2018). Ongoing research into the therapeutic potential of dichloroacetate in solid cancers is likely to focus, at least in part, on finding the best dose, as individual responses vary widely (James 2017; James 2016).
Antidepressant drugs are also being examined for possible effects on glioblastoma cells. For example, fluoxetine (Prozac), a common antidepressant drug, has been shown to selectively kill glioblastoma cells in laboratory experiments (Liu, Yang 2015). Additionally, fluoxetine may reduce the amount of MGMT in glioblastoma cells and make them more sensitive to temozolomide (Song 2015). Other antidepressant drugs, such as imipramine (Tofranil) and amitriptyline (Elavil), have been shown to stop glioblastoma stem cells from producing more stem cells (Bielecka-Wajdman 2017).
Rapamycin and mTOR Inhibition
Rapamycin is an immunomodulating drug first identified in soil samples from Easter Island in the 1970s. Since its discovery, much has been learned about how rapamycin functions in the body. The drug inhibits signaling through a pathway called the mammalian target of rapamycin (mTOR). The mTOR signaling pathway integrates growth signals with cellular metabolism and is involved in many cellular processes, including growth, cell division, protein synthesis, and cell death (Li 2014; Laplante 2012; Jhanwar-Uniyal 2017). To perform its cellular activities, mTOR functions as part of two distinct multi-protein complexes, mTORC1 and mTORC2, which have different functions and respond differently to rapamycin (Masui 2015; Neil 2016; Jhanwar-Uniyal 2017). Studies in recent years have identified many interesting properties of the mTOR pathway, and revealed its potential as a target for cancer therapy.
In glioblastoma, increased mTOR signaling has been linked to stem cell proliferation, relapses, and resistance to treatment. In a study that used glioblastoma cells obtained from patients, rapamycin inhibited cell growth, and in mice that had human-derived glioblastomas, it almost doubled the survival time of the animals (Arcella 2013). In another study, rapamycin reduced the proliferation of glioblastoma cancer stem cells and their tumorigenic potential (Mendiburu-Elicabe 2014).
Results of clinical studies using rapamycin have been modest or uncertain (Chheda 2015; Fan 2018).
Rapamycin showed benefits in a phase I clinical trial in certain patients with glioblastoma (Cloughesy 2008), but results from phase II clinical trials were not promising. At least in part, this is explained by the interaction with other signaling pathways (Li, Wu 2016). Additionally, even though targeting mTOR is a promising strategy for glioblastoma, neither of the two complexes is completely inhibited by rapamycin or rapamycin analogs. However, an experimental compound that inhibited both mTORC1 and mTORC2 together was able to block the growth and migration of glioblastoma cells, underscoring the promise of this approach (Neil 2016). The combined inhibition of the two complexes was also underscored as a promising therapy by other studies on glioblastoma (Gulati 2009; Luchman 2014; Kahn 2014).
As of the time of this writing, researchers are exploring ways to manipulate the mTOR pathway that might improve outcomes for people with glioblastoma. Existing drugs that target mTOR do not appear well suited as glioblastoma therapies for the time being.