Understanding Glioblastoma

compiled by John G. Connor, M.Ac., L.Ac. edited by Barbara Connor, M.Ac., L.Ac.

Table of Contents 
 

Introduction
Therapeutic Options in Glioblastoma    
Understanding Biomarkers in Glioblastoma
Research on Natural Compounds that May be Suppressive Against Glioblastoma or Glioma    
References

Introduction
Glioblastoma is the most common malignant primary brain tumor in adults and one of the most lethal of all cancers. Glioblastomas invade the surrounding brain, making complete surgical excision highly improbable. They are also among the most radiation therapy- and chemotherapy-resistant cancer types, with a median survival duration of 12–15 months after initial diagnosis. Thus, new therapeutic approaches are needed. (Akhavan et al 2010)

Long-term progression free survival remains low for most glioblastoma multiforme (GBM) patients even after complete surgical excision, combined with the best available treatment. Standard therapy for GBM includes surgery followed by concomitant radiation and/or chemotherapy. These procedures, however, extend median survival by only a few months beyond the no therapy option. (Zuccoli et al 2010)

Individual studies estimate that as many as 69% of US cancer patients employ some type of complementary and alternative medicine, 76% of patients in a study of Midwestern cancer patients and 95% of radiation oncology patients in another study.  (Wargovich et al 2010)

There is an ever growing interest in treatment with natural compounds as an adjuvant cancer therapy along with conventional cancer therapy. (Virk-Baker et al 2010) For example the combination of a natural VEGF inhibitor along with lower doses of a pharmacological agent may prove helpful in reducing the unwanted side effects of chemotherapy. (Wargovich et al 2010)

Recent evidence shows that pharmaconutrients may act against proliferation, angiogenesis and metastasis in different types of human cancer. (Granci et al 2010)

Therapeutic Options in Glioblastoma
1.    Avasimbe – Our findings provide proof of principle that targeting Acyl-CoA: cholesterol acyltransferase -1 with the inhibitor Avasimibe could be an efficient therapy in the treatment of glioblastoma. (Bemlih et al 2010)

2.    Bevacizumab (BV) (Avastin) with radiation therapy (RT) and temozolomide (TMZ) – Newly diagnosed glioblastoma patients treated with BV and TMZ during and after RT showed improved progression-free survival (PFS) without improved overall survival (OS) compared to the University of California, Los Angeles/KPLA control group. (Lai et al 2010)

3.    Carmustine (BCNU) and cis-platinum (cisplatin) have been the primary chemotherapeutic agents used against malignant gliomas. All agents in use have no greater than a 30-40% response rate, and most fall into the range of 10-20%.

4.    Celebrex (Celecoxib) – Recent studies indicate that CD133(+) cells play a key role in radioresistance and recurrence of glioblastoma. Cyclooxygenase-2 (COX-2), which converts arachidonic acid to prostaglandins, is over-expressed in a variety of tumors, including CD133(+) glioblastomas. The COX-2-derived prostaglandins promote neovascularization during tumor development, and conventional radiotherapy increases the proportion of CD133(+) cells rather than eradicating them. Celecoxib combined with radiation plays a critical role in the suppression of growth of CD133(+) glioblastoma stemlike cells. Celecoxib is therefore a radiosensitizing drug for clinical application in glioblastoma. (Ma et al 2011)

5.    Cilengitide – The integrin family of cell adhesion receptors is emerging as a promising target of anticancer therapy. AlphaVbeta3 and alphaVbeta5 integrins are overexpressed on both glioma cells and tumor vasculature. Cilengitide, the most advanced specific integrin inhibitor in oncology, has shown antitumor activity against glioma in early clinical trials. (Tabatabai et al 2010)

* Integrins regulate tumor angiogenesis, invasion and migration by mediating critical cell-to-cell and cell-extracellular matrix interactions. Integrins bind specifically, based on respective alpha and beta domain pairings, to several key microenvironment ligands, including vitronectin, fibronectin, laminin, fibroblast-growth factor, MMP-2, thrombospondin, fibrin and fibrinogen. Integrins are attractive therapeutic targets owing to increased expression by both GBM cells and tumor vasculature. (Reardon et al 2008)

6.    Cimetidine (Tagamet) – added to temozolomide was superior in vivo when compared to temozolomide alone in extending survival of nude mice with human glioblastoma cells orthotopically xenografted into their brain. (Lefranc et al 2006)

7.    COX-2 inhibitors – These results suggest that a selective COX-2 inhibitor appears to be as effective as dexamethasone in prolonging survival in a rat brain tumor model. (Portnow et al 2002)

8.    Dichloroacetate (DCA) – In a separate experiment with five patients who had glioblastoma DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. (Michelakis et al 2010)

9.    Gefitinib or erlotinib – A small proportion of glioblastomas responds to gefitinib or erlotinib (tyrosine kinase inhibitors). The simultaneous presence in glioblastoma cells of mutant EGFR (EGFRviii) and PTEN was associated with responsiveness to tyrosine kinase inhibitors, whereas increased p-akt predicts a decreased effect. (Rich et al 2004; Mellinghoff et al 2005)

10.   Imatinib (Gleevac) and chlorimipramine – The present findings support our hypothesis and demonstrate the potentiation of cytotoxicity by the combination of imatinib and chlorimipramine in C6 glioma. Further, the findings suggest the potential clinical application of the combination in the treatment of drug-resistant glioma. (Bilir et al 2008)

11.   Noscapine – In this study, we show that noscapine inhibits the proliferation of rat C6 glioma cells in vitro and effectively crosses the blood-brain barrier at rates similar to the ones found for agents such as morphine and [Met]enkephalin. These unique properties of noscapine, including its ability to cross the blood-brain barrier, interfere with microtubule dynamics, arrest tumor cell division, reduce tumor growth, and minimally affect other dividing tissues and peripheral nerves, warrant additional investigation of its therapeutic potential. (Landen et al 2004)

12.   Rapamycin – has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. (Cloughesy et al 2008)

13.   Temozolomide – In sum, our results tentatively suggest that patients with PTEN-null glioblastoma multiformes (about 36%) may especially benefit from treatment with DNA alkylating agents such as temozolomide. Significantly, our results also provide a rational basis for treating the subgroup of patients who are PTEN deficient with PARP inhibitors in addition to the current treatment regimen of radiation and temozolomide. (McEllin 2010)

14.   Temozolomide (TMZ) in combination with irinotecan (CPT-11) – Although TMZ plus CPT-11 treatment in newly diagnosed glioblastoma patients is at least comparable in efficacy to TMZ alone, this combination appears more toxic and poorly tolerated. The lack of correlation of activity with MGMT expression is intriguing, but needs further evaluation in subsequent trials. (Quinn et al 2009)

15.   Temozolomide with Radiotherapy – Survival of patients who received adjuvant temozolomide with radiotherapy for glioblastoma is superior to radiotherapy alone across all clinical prognostic subgroups. (Stupp et al 2009)

16.   Valproic acid (Depakote) – Etoposide, a topoisomerase-II inhibitor, promotes DNA damage and apoptosis of cancer cells. In this study, we have examined the ability of the histone deacetylase inhibitor, valproic acid (VPA) to modulate gene expression and sensitize glioblastoma cell lines to the cytotoxic effects of etoposide in vitro. Our study demonstrates that VPA sensitizes U87, U251, and LN18 cells to the cytotoxic effects of etoposide in vitro by inducing differentiation and up-regulating the expression of p21/WAF1 and both isoforms of topoisomerase-II. (Das et al 2007) Valproic acid depletes carnitine, folate and vitamin B6 and raises ammonia and homocysteine levels.

17.   Meta-analyses have suggested that adjuvant chemotherapy results in a 6-10% increase in 1-year survival rate. (Fine et al 1993; Stewart 2002)

18.   Surgery – Median time to recurrence after standard therapy is 6.9 months. For recurrent glioblastoma multiforme, surgery is appropriate in selected patients, and various radiotherapeutic, chemotherapeutic, biologic, or experimental therapies are also employed. (Stupp et al 2005)

19.   An analysis of 28 studies found a mean duration of survival advantage of total over subtotal resection for glioblastoma multiforme (14 vs 11 mo). (Sanai et al 2008; Fadul et al 1988)

20.   The addition of radiotherapy to surgery has been shown to increase survival from 3-4 months to 7-12 months (Stupp et al 2005; Walker et al 1978)
Understanding Biomarkers in Glioblastoma

1.    5-LOX (5-lipoxygenase) – is a key enzyme in the synthesis of leukotrienes (LTs), that might promote carcinogenesis. We confirmed the expression of 5-LOX in various human brain tumors and demonstrated the partial suppression of tumor growth by inhibitors of the 5-LOX-LTA4 hydrolase pathway in human glioma cell lines. The 5-LOX-LTA4 pathway might play roles in the proliferation of human glioma cells. (Ishii et al 2009)

2.    Bcl-2 – Recent studies have identified and validated Bcl2-Like 12 (Bcl2L12) as a potent glioma oncoprotein with multiple strategic points in apoptosis regulatory networks, i.e. effector caspases and the p53 tumor suppressor. Bcl2L12 resides in both the cytoplasm and nucleus. These multi-leveled studies establish Bcl2L12 as an important oncoprotein acting at the intersection of nuclear p53 and cytoplasmic caspase signaling and point to pharmacological disruption of the Bcl2L12:p53 complex as a promising novel therapeutic strategy for the enhanced treatment of glioblastoma multiforme GBM. (Stegh & Pinho 2011)

3.    EGFR (Epidermal growth factor receptor) gene: The EGFR gene is involved in the control of cell proliferation. Multiple genetic mutations are apparent, including both overexpression of the receptor as well as rearrangements that result in truncated isoforms. Overexpression or activation mutations in this gene are more common in primary glioblastoma, with mutations appearing in 40-50% of these tumors. (Sathornsumetee et al 2007; Ekstrand et al 1992)

4.    HIF-1α – (hypoxia inducible factor-1α) – Hypoxic microenvironments are a frequent characteristic of GBM that are the consequences of morphologically and functionally inappropriate neovascularization, irregular blood flow, anemia, and the high oxygen consumption of rapidly proliferating malignant cells. These hypoxic microenvironments are a powerful stimulus for the expression of genes involved in tumor cell proliferation and angiogenesis. Tumor hypoxia can activate the pSTAT3 immunosuppressive pathway thereby triggering the downstream synthesis of hypoxia inducible factor (HIF)-1α that can then induce regulatory T cells and vascular endothelial growth factor (VEGF), which in addition to promoting angiogenesis is also immunosuppressive. In addition, other glioma-elaborated immune suppressive cytokines such as transforming growth factor (TGF)-β, soluble colony stimulating factor (sCSF)-1, C-C chemokine ligand (CCL)-2 and galectin-3 have also been shown to be associated with or induced by HIF-1α and hypoxia.  (Wei et al 2011)

5.    MDM2 – Overexpression of MDM2 is the second most common gene mutation in glioblastoma multiformes and is observed in 10-15% of patients. (Korkolopoulou et al 1997)

6.    MGMT is a DNA repair enzyme that contributes to temozolomide resistance. Methylation of the MGMT promoter, found in approximately 45% of glioblastoma multiformes, results in an epigenetic silencing of the gene, decreasing the tumor cell’s capacity for DNA repair and increasing susceptibility to temozolomide. (Hegi et al 2005)

7.    MMP-1 – Glioblastoma multiforme (GBM) is an aggressive cancer with a poor survival rate. A key component that contributes to the poor prognosis is the capacity of glioma cells to invade local brain tissue in a diffuse manner. Among various proteases that aid in the process of invasion, matrix metalloproteinase-1 (MMP-1) has been identified as an important contributory factor in various cancers. These data suggest that EGFR mediated MMP-1 regulation is mainly via the MAPK pathway in T98G cells and inhibition of EGFR and MMP-1 results in a decrease in T98G cell invasion. (Anand et al 2011)

8.    mTOR – Because it is a key mediator of PI3K signaling and an integrator of signal transduction and cellular metabolism, mTOR represents an attractive therapeutic target for glioblastoma. Despite the relative clinical failure of rapamycin and its derivatives, an enormous amount has been learned from studying mTOR signaling in well-controlled experimental glioma models and rapamycin and its analogues in phase I and II clinical trials. (Akhavan et al 2010)

9.    NFκB (nuclear-factor-kappa-B) – In this work, we evaluated the role of nuclear-factor-kappa-B (NFκB) in the growth of glioblastoma multiforme (GBM) cells, and the potential of NFκB inhibitors as antiglioma agents. NFκB pathway was found overstimulated in GBM cell lines and in tumor specimens compared to normal astrocytes and healthy brain tissues, respectively. These findings support NFκB as a potential target to cell death induction in GBMs, and that the NFκB inhibitors may be considered for in vivo testing on animal models and possibly on GBM therapy. (Zanotto-Filho et al 2010)

10.   p53 – tumor suppressor gene – gene appears to be deleted or altered in approximately 25-40% of all glioblastoma multiformes. (Watanabe et al 1997) The prime importance of p53 signaling for gliomapathogenesis is further evidenced by epistatic genetic events targeting additional pathway components including deletion of p14 (Arf) (CDKN2A) and amplification of the p53-degrading ubiquitin ligases MDM2 and MDM4. (Stegh & DePinho 2011)

11.   PDGFRA  (Platelet-derived growth factor receptor-α) – We investigated the PDGFRA locus in PDGFRA-amplified gliomas and identified two rearrangements. The gene products of both rearrangements showed constitutively elevated tyrosine kinase activity and transforming potential that was reversed by PDGFR blockade. These results suggest the possibility that these PDGFRA mutants behave as oncogenes in this subset of gliomas, and that the prevalence of such rearrangements may have been considerably underestimated. (Ozawa et al 2010)

12.   PTEN mutations have been found in as many as 30% of glioblastomas, more commonly in primary glioblastoma multiformes. (Furnari et al 2007; Duerr et al 1998; Ohgaki et al 2005)

13.   STAT-3 – The transcription factor signal transducer and activator of transcription (STAT) 3 is known to be involved in the development and progression of many different tumor types, including malignant gliomas. Because pharmacological inhibition of the JAK-2/STAT3 signaling pathway affects not only tumor cell proliferation but also the characteristic features of malignant gliomas, i.e. migration and invasion pertinent to invariable tumor recurrence and high morbidity, our findings support the idea that STAT3 is a suitable target in the treatment of brain tumors. (Senft et al 2011)

14.   Survivin – an antiapoptotic protein, is elevated in most malignancies and attributes to radiation resistance in tumors including glioblastoma multiforme. The downregulation of survivin could sensitize glioblastoma cells to radiation therapy. Our studies demonstrated that targeting survivin may be an effective approach for radiosensitization of malignant glioblastoma. (Anandharj et al 2011)

15.   VEGF (vascular endothelial growth factor) – Hypoxic microenvironments are a frequent characteristic of GBM that are the consequences of morphologically and functionally inappropriate neovascularization, irregular blood flow, anemia, and the high oxygen consumption of rapidly proliferating malignant cells. These hypoxic microenvironments are a powerful stimulus for the expression of genes involved in tumor cell proliferation and angiogenesis. Tumor hypoxia can activate the pSTAT3 immunosuppressive pathway thereby triggering the downstream synthesis of hypoxia inducible factor (HIF)-1α that can then induce regulatory T cells and vascular endothelial growth factor (VEGF), which in addition to promoting angiogenesis is also immunosuppressive (Wei et al 2011)

Research on Natural Compounds that May be Suppressive Against Glioblastoma or Glioma 

· Boswellia serrata (BS) – Patients irradiated for brain tumors often suffer from cerebral edema and are usually treated with dexamethasone, which has various side effects. Forty-four patients with primary or secondary malignant cerebral tumors were randomly assigned to radiotherapy plus either BS 4200 mg/day or placebo. Compared with baseline and if measured immediately after the end of radiotherapy and BS/placebo treatment, a reduction of cerebral edema of >75% was found in 60% of patients receiving BS and in 26% of patients receiving placebo. There were no severe adverse events in either group. BS significantly reduced cerebral edema measured by MRI in the study population. BS could potentially be steroid-sparing for patients receiving brain irradiation. (Kirste et al 2011)

· Curcumin – Curcumin exhibits superior cytotoxicity on glioblastoma in a dose- and time-dependent manner in the MTT assay.  Curcumin appears to be an effective anti-glioblastoma drug through inhibition of the two core signaling pathways and promotion of the apoptotic pathway. (Su et al 2010)

· GLA – There was some, but not dramatic, improvement in patients’ survival. No significant prolongation of life span was expected considering the advanced nature of the disease. Nevertheless, it was encouraging that GLA produced no significant side effects in any patient. Regression of the cerebral gliomas was visualized on computed tomography and magnetic resonance imaging. Based on results of the present and previous studies, we believe that GLA is a safe antitumor agent and that higher doses of GLA should be investigated in future studies. (Bakshi et al 2003)

· Gossypol – a polyphenolic in cotton seed extract – is well tolerated and has a low, but measurable, response rate in a heavily pretreated, poor-prognosis group of patients with recurrent glioma. The presumed novel mechanism of action, lack of significant myelosuppression, and activity in patients with advance glioma support further study of gossypol as an antineoplastic agent. (Bushunow et al 1999)

· Oridonin (purified from Rabdosia ruvescens) – Oridonin effectively inhibited the proliferation of a wide variety of cancer cells including those from glioblastoma multiforme (U118, U138) Taken together, oridonin inhibited the proliferation of cancer cells via apoptosis and cell cycle arrest with p53 playing a central role in several cancer types which express the wild-type p53 gene. Oridonin may be a novel, adjunctive therapy for a large variety of malignancies. (Ikezoe et al 2003)

· Resveratrol – Resveratrol treatment of human glioblastoma cells induces a delay in cell cycle progression during S phase associated with an increase in histone H2AX phosphorylation. Furthermore, with an in vitro assay of topoisomerase II alpha catalytic activity we show that resveratrol is able to inhibit the ability of recombinant human TOPO IIalpha to decatenate kDNA, so that it could be considered a TOPO II poison. (Leone et al 2010)

· Ursolic acid (UA)- Taken together, we demonstrated that UA could efficiently inhibit the interaction of ZIP/p62 and PKC-zeta. It also further suppressed the activation of NF-kappaB and downregulation of the MMP-9 protein, which in turn contributed to its inhibitory effects on IL-1beta or TNF-alpha-induced C6 glioma cell invasion. These results all showcase the potential UA has in the chemoprevention and treatment of cancer metastasis and invasion. (Huang et al 2009)
References

1.    Bagchi, Debasis & Harry G. Preuss, Phytopharmaceuticals in Cancer Chemoprevention, CRC Press, Boca Raton, 2005
2.    Beckett, Geoffrey, Simon Walker, Peter Rae & Peter Ashby, Lecture Notes – Clinical Biochemistry, 8th edition, Wiley-Blackwell, Oxford,  2010
3.    Boik, John, Natural Compounds in Cancer Therapy, Oregon Medical Press, Princeton, MN, 2001
4.    Boik, John, Cancer & Natural Medicine, A Textbook of Basic Science and Clinical Research, Oregon Medical Press, Princeton, MN, 1996
5.    Chernecky, Cynthia C, and Barbara J. Berger, Laboratory Tests and Diagnostic Procedures, Saunders, St. Louis, 2008
6.    Davis, Cindy D, Nancy Emenaker and John Milner, “Cellular Proliferation, Apoptosis and Angiogenesis: Molecular Targets for Nutritional Preemption of Cancer, Seminars in Oncology, Vol 37, No. 3, June 2010, pp 243-257
7.    Gullet, Norleena P, Ruhul Arnin, Soley Bayraktar, et al, “Cancer Prevention With Natural Compounds”, Seminars in Oncology, Vol 37, No 3, June 2010, pp 258-281
8.    Heber, David, Editor-in –Chief, Nutritional Oncology, Second Edition, Academic Press, London, 2006
9.    McKenna, Dennis J., PhD,  Kenneth Hones & Kerry Hughes, Botanical Medicines, The Desk Reference for Major Herbal Supplements, Second Edition, The Haworth Herbal Press, New York, 2002
10.   Mills, Simon and Kerry Bone, Principles and Practice of Phytotherapy, Churchill Livingstone, Edinburgh, 2000
11.   Neal, Michael J., Medical Pharmacology at a Glance, Sixth edition, Wiley-Blackwell, Oxford, 2009
12.   Stargrove, Mitchell, Jonathan Treasure & Dwight L. McKee, Herb, Nutrient, and Drug Interactions, Mosby Elsevier, St. Louis,  2008
13.   Weiss, Rudolf, MD & Volker Fintelmann, MF, Herbal Medicine, Thieme, New York, 2000
14.   Yance, Donald, “Donald Yance’s Eclectic Triphasic Medical System (ETMS): An Integrative Wholistic Approach to Treating and Preventing Cancer”, (Monograph) 2010
15.   Yance, Donald, Herbal Medicine, Healing & Cancer, Keats Publishing, Lincolnwood (Chicago) IL, 1999

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