Very recently, Senator Ted Kennedy died from Glioblastoma multiforme (GBM), possibly the deadliest known cancer(ref). I lost a dear friend to it just three years ago. This post looks at some of the GBM research over the last five years. It touches on the potential role of GBM stem cells and a potential key therapeutic role for one of the supplements many of us take – curcumin.
GBM is an extremely aggressive brain cancer involving glial cells in the brain and kills just about everyone who gets it. “Median survival with standard-of-care radiation and chemotherapy with temozolomide is 15 months. Median survival without treatment is 4 1/2 months(ref).” Patients rarely last more than two years from time of diagnosis. When it comes to glioblastoma, a treatment that adds just 3-4 months to a patient’s life is thought to be worth considering.
The hopelessness of the disease is summarized in the lead paragraph of the monograph entitled State-of-the-art Therapy for Glioblastoma Multiforme: “The treatment of patients with glioblastoma multiforme (GBM) is conventionally considered to be a palliative venture with no hope of cure. Traditionally, patients are treated with maximal surgical resection based on the premise that, although surgery is not a curative procedure, a major resection provides for a longer survival and better quality of life. Radiotherapy increases the duration of survival, but again is not a curative intervention(ref).”
When your friend or relative learns he has GBM, he may have only six months more to live. GBMs can come on very suddenly without warning and can be of two main types known as Primary and Secondary. “Primary glioblastoma multiforme accounts for the vast majority of cases (60%) in adults older than 50 years. These tumors manifest de novo (i.e., without clinical or histopathologic evidence of a preexisting, less-malignant precursor lesion), presenting after a short clinical history, usually less than 3 months.” – “Secondary glioblastoma multiformes (40%) typically develop in younger patients (<45 y) through malignant progression from a low-grade astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO grade III). The time required for this progression varies considerably, ranging from less than 1 year to more than 10 years, with a mean interval of 4-5 years. Increasing evidence indicates that primary and secondary glioblastomas constitute distinct disease entities that evolve through different genetic pathways, affect patients at different ages, and differ in response to some of the present therapies(ref).”
GBM is thought to arise from a unique combination of genetic mutations such as are described in this publication. As written in 2000: “Because most patients with GBMs die of their disease in less than a year and essentially none has long-term survival, these tumors have drawn significant attention; however, they have evaded increasingly cleaver and intricate attempts at therapy over the last half-century(ref).” There has been a stream of news reports in the science press on research related to new treatments for glioblastoma. Here is a selection of headlines and lead paragraphs of reports appearing in Science Daily.
Vorinostat Shows Anti-cancer Activity In Recurrent Gliomas: ScienceDaily (June 5, 2007) — “North Central Cancer Treatment Group researchers, based at Mayo Clinic in Rochester, Minn., report that a novel application of the drug vorinostat shows activity in patients with recurrent glioblastoma multiforme. These findings were presented today at the American Society of Clinical Oncology Annual Meeting by Eva Galanis, M.D., a Mayo Clinic oncologist and lead investigator of the study.” (ref)
Mayo Clinic Researchers Develop New Treatment For Incurable Recurring Form Of Adult Brain Cancer: ScienceDaily (May 17, 2005) — ROCHESTER, Minn. – “A study led by Mayo Clinic researchers and conducted by the North Central Cancer Treatment Group (NCCTG) reports that a new “smart” drug treatment for an incurable form of recurrent brain cancer slowed tumor growth in more than one-third of the 65 adult patients who tried it. The same research team also developed a screening technique to help predict which patients will respond best to this treatment.” (ref)
New Treatment Suitable For All Patients With Least Treatable Brain Tumors, Study Suggests: ScienceDaily (Jan. 5, 2008) — New research at Wake Forest University Baptist Medical Center suggests that a three-drug cocktail may one day improve outcomes in patients with glioblastoma multiforme (GBM), a type of brain tumor with a dismal prognosis. Two of the drug candidates have been developed, and the team is working on the third — all targeted to kill or impair cancer cells and spare healthy brain. (ref)
Why Don’t Brain Tumors Respond To Medication? ScienceDaily (Sep. 2, 2009) — “Malignant brain tumors often fail to respond to promising new medication. Researchers in Heidelberg have discovered a mechanism and a tumor marker for the development of this resistance. A “death receptor” can possibly provide information as to how great the chances of success are for chemotherapy. At the same time, it offers a new approach for promising brain tumor therapy.” (ref)
Research Suggests Molecular Approaches To Brain Tumor Treatment: ScienceDaily (May 10, 2005) — WINSTON-SALEM, N.C. – “Researchers at Wake Forest University Baptist Medical Center have found promising new molecular targets and treatment approaches for some of the most malignant brain tumors. Results of three separate studies were presented at the World Federation of NeuroOncology meeting and the European Association for NeuroOncology meeting, both in Edinburgh, Scotland, on May 6 and 7. The research involved glioblastoma multiforme, the most common form of brain tumor and the least curable of all human cancers. — The first study identified a protein that seems to control the malignant features of brain tumor cells, suggesting a new treatment target for anti-cancer drugs. Researchers found that a little-known protein called Fra-1 was effective in controlling vascular endothelial growth factor D, a factor that promotes the growth of new blood vessels in most malignant brain tumors. “This protein seems to be important in how tumors grow and how they may spread to healthy tissue,” said Waldemar Debinski, M.D., Ph.D., director of the Brain Tumor Center of Excellence at Wake Forest University Baptist Medical Center. “It is a very powerful biological factor and may be an attractive target for anti-cancer therapy.” — The second study builds in earlier research by Debinski and colleagues that found that glioblastoma cells have a particular type of receptor for interleukin 13 (IL-13), a naturally occurring protein that regulates the immune system in the body. Normal cells do not have these same receptors. IL-13 is a very attractive target for molecular anti-brain tumor therapies and two clinical trials are currently ongoing. The new study examined the role of proteins called cytokines in augmenting the amount of IL-13 receptor expressed by tumor cells. The use of these cytokines may improve treatment of glioblastoma cells by increasing the levels of IL-13 receptor in brain tumors and thus making them more accessible to drugs targeting the receptor. — The third research study focused on the search for novel specific molecular markers or targets in brain tumors. EphA2, a cell membrane-anchored protein-receptor, was shown to be uniformly overexpressed in malignant brain tumors, but not in normal brain tissue. “EphA2 represents a novel target for the development of molecular therapeutics for the imaging and treatment of patients with glioblastoma,” said Debinski.” (ref)
All of the above may indicate research progress against GBM. My impression is that much of the research seems to be concentrated on finding means to slow the progress of GBM down. This link describes a clinical trial of an immunotherapy “that targets the tumor specific molecule called EGFRvIII, a functional variant of the epidermal growth factor receptor (EGFR), a protein that has been well validated as a target for cancer therapy.” – “Previous small-scale trials indicated the approach may succeed with a limited objective. “The results of these studies have demonstrated a significant increase in the time to disease progression and overall survival relative to appropriately matched historical controls(ref).”
Glioblastoma stem cells
Previously in this blog, I have touched on research pointing to the importance of cancer stem cells in brain cancers, such as in the post On Cancer Stem Cells. In more detail, you can check out these Science Daily stories:
Cancer Stem Cells Spur Glioma Angiogenesis, Could Hold Key To Brain Tumor Therapy (ref) “Stem cell-like glioma cancer cells that share many characteristics with normal stem cells propel the lethal growth of brain cancers by promoting tumor blood vessel formation, and may hold the key to treating these deadly cancers—“
Glioma: Origin Of Brain Tumor Discovered (ref) “Glioma is the most common and most serious form of brain tumors that affect adults. It has not yet been determined which specific type of cell in the brain is the source of the tumor, but now a research team at Uppsala University can show that glioma can start from immature support cells. — In recent years it has been discussed more and more often that it is neural stem cells in the brain that are transmuted into cancer cells and can then develop into glioma. “But our results show that immature support cells can function as the source cells for the tumor. We can thus establish that it does not have to be stem cells that cause glioma,”
Curcumin for glioblastoma
Back in the post From four-pound hammer to smart molecules – on cancer treatments, I touched on how an old supplement friend curcumin appears to be very effective in leading GBM cells to commit apoptosis. This has led researchers to suggest investigating whether curcumin could be used as a therapeutic approach. You can check out these publications
Curcumin suppressed anti-apoptotic signals and activated cysteine proteases for apoptosis in human malignant glioblastoma U87MG cells (ref) “Results show that CCM is an effective therapeutic agent for suppression of anti-apoptotic factors and activation of calpain and caspase proteolytic cascades for apoptosis in human malignant glioblastoma cells.”
Curcumin activated both receptor-mediated and mitochondria-mediated proteolytic pathways for apoptosis in human glioblastoma T98G cells (ref) “Our results strongly suggest that CCM induced both receptor-mediated and mitochondria-mediated proteolytic mechanisms for induction of apoptosis in T98G cells.”
p21 Waf1/Cip1 expression by curcumin in U-87MG human glioma cells: role of early growth response-1 expression. (ref) “Curcumin, a natural compound, is a well-known chemopreventive agent with potent anticarcinogenic activity in a wide variety of tumor cells. Curcumin inhibits cancer cell proliferation in part by suppressing cyclin D1 and inducing expression of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1).”
Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFkappaB transcription factors. (ref) “Curcumin reduced cell survival in a p53- and caspase-independent manner, an effect correlated with the inhibition of AP-1 and NFkappaB signaling pathways via prevention of constitutive JNK and Akt activation. Curcumin-sensitized glioma cells to several clinically utilized chemotherapeutic agents (cisplatin, etoposide, camptothecin, and doxorubicin) and radiation, effects correlated with reduced expression of bcl-2 and IAP family members as well as DNA repair enzymes (MGMT, DNA-PK, Ku70, Ku80, and ERCC-1). These findings support a role for curcumin as an adjunct to traditional chemotherapy and radiation in the treatment of brain cancer.”
Differential solubility of curcuminoids in serum and albumin solutions: implications for analytical and therapeutic applications. (ref) “CONCLUSION: These results suggest the possibility of alternative therapeutic approaches by injection or infusion of relatively small amounts of curcuminoid-enriched serum.”
How does curcumin work to lead the glioblastoma cells to commit suicide? Collectively, studying the following reports suggests that curcumin works by multiple channels including 1. regulating the p21 apoptosis-inhibitor gene in the tumors, and 2 inducing JNK signaling which activates MDA-7 resulting in inhibition of AP-1, AKT and NF-kappaB pathways necessary for critical gene expression.
Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins (ref) “Because most cancers are caused by dysregulation of as many as 500 different genes, agents that target multiple gene products are needed for prevention and treatment of cancer. Curcumin, a yellow coloring agent in turmeric, has been shown to interact with a wide variety of proteins and modify their expression and activity. These include inflammatory cytokines and enzymes, transcription factors, and gene products linked with cell survival, proliferation, invasion, and angiogenesis. Curcumin has been found to inhibit the proliferation of various tumor cells in culture, prevents carcinogen-induced cancers in rodents, and inhibits the growth of human tumors in xenotransplant or orthotransplant animal models either alone or in combination with chemotherapeutic agents or radiation. Several phase I and phase II clinical trials indicate that curcumin is quite safe and may exhibit therapeutic efficacy.
p21 Waf1/Cip1 expression by curcumin in U-87MG human glioma cells: role of early growth response-1 expression (ref) “Curcumin inhibits cancer cell proliferation in part by suppressing cyclin D1 and inducing expression of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). — Here, we report that transcription of the p21(Waf1/Cip1) gene is activated by early growth response-1 (Egr-1) independently of p53 in response to curcumin treatment in U-87MG human glioblastoma cells.”
Activation of multiple molecular mechanisms for apoptosis in human malignant glioblastoma T98G and U87MG cells treated with sulforaphane (ref)MDA-7 regulates cell growth and radiosensitivity in vitro of primary (non-established) human glioma cells. (ref) “Collectively, our findings demonstrate that MDA-7 reduces proliferation and enhances the radiosensitivity of nonestablished human GBM cells in vitro, and when grown in 3 dimensions, and that sensitization occurs independently of basal EGFR/ERK1/2/AKT activity or the functions of PTEN and p53.”
Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling (ref) “Our data argue that combined inhibition of ERK1/2 and AKT function, regardless of genetic background, promotes MDA-7 lethality in human primary human glioma cells via JNK1-3 signaling and is likely to represent a more ubiquitous approach to enhancing MDA-7 toxicity in this cell type than inhibition of ERBB1 function.”
Expression of the constitutively activated RelA/NF-kappaB in human astrocytic tumors and the in vitro implication in the regulation of urokinase-type plasminogen activator, migration, and invasion. (ref)
mda-7 (IL-24) Inhibits growth and enhances radiosensitivity of glioma cells in vitro via JNK signaling. (ref) “Inhibition of JNK1/2, but not p38, signaling abolished the radiosensitizing properties of MDA-7. Inhibition of neither ERK1/2 nor PI3K signaling enhanced the anti-proliferative effects of Ad.mda-7, whereas combined inhibition of both pathways enhanced cell killing, suggesting that ERK and PI3K signaling can be protective against MDA-7 lethality.”
Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin (ref) “Curcumin, a dietary pigment in curry, suppresses tumor initiation and tumor promotion. Curcumin is also a potent inhibitor for AP-1 and NF-
PERK-dependent regulation of MDA-7/IL-24-induced autophagy in primary human glioma cells. (ref) “Our data demonstrate that GST-MDA-7 induces an ER stress response that, via the induction of autophagy, is causal in the activation of pro-apoptotic pathways that converge on the mitochondrion and ultimately culminate in decreased glioma cell survival.”
Curcumin is found on spice shelves everywhere and is great in Indian curries. It is very homespun stuff. Its bimolecular actions against “incurable” glioblastoma, on the other hand, appear to be very cutting edge. Curcumin might, just might, provide a powerful weapon in the battle against glioblastoma.
Please note the Medical Disclaimer for this blog.