Glossary

• Adjuvant: (a-joo-vant) an added treatment used to improve the primary treatment.



• Akt1: or "Akt" in cancer discussions; or protein kinase B (PKB); an enzyme in the serine/threonine-specific protein kinase family which can block apoptosis and thereby promote cell survival. Akt is normally over-expressed in malignant gliomas. Interestingly, recent research at the NIH demonstrates that Akt does not appear to influence radiosensitivity of tumor cells, contrary to its hypothesized role. Activation of the Akt pathway is sufficient to allow conversion of lower grade anaplastic astrocytoma brain tumors into glioblastoma.



• Alkylation: the process of transferring an alkyl group to a molecule. Akylating agents are organic compounds which transfer alkyl groups between molecules.



• Angiogenesis: the process of developing new blood vessels; one of the crucial processes supporting tumor growth, and a successful target for anti-tumor treatments



• Apoptosis: (ap-up-TOE-sis or a-po-TOE-sis) programmed cell death or "cell suicide." This is a normal, controlled sequence of events in which damaged cells self-destruct to protect the body. Cancer cells are resistant to this process, which makes them harder to kill. Note that when this word was first coined from its Greek origins, the second "p" was intended to be silent, however, many people now pronounce the word without the silent p, as in ap-up-TOE-sis.



• Avastin: Avastin (brand name bevacizumab) is a monoclonal antibody against VEGF, thereby inhibiting angiogenesis. Avastin is only available via infusion and is currently not FDA-approved for use against glioblastoma, however its off-label use is now common at most brain tumor centers. Currently, the combination of Avastin and Irinotecan (or CPT-11, brand name Camptosar) is likely the most effective, conventional, proven chemotherapeutic treatment against glioblastoma. A 2007 study from Duke University reports that this combination used against recurrent glioblastoma produced a PFS-6 of 46% and a 6-month overall survival rate of 77%. Some cancer clinics are also now using Avastin with temozolomide. The primary adverse side effects of Avastin are blood clots, which occurred in 12% of patients in the Duke study, and hypertension. See News for October, 2007 for more info.



• CED: Convection-enhanced delivery is a method of getting chemo drugs directly into a brain tumor via a catheter through the skull. This method, which allows doctors to circumvent the blood brain barrier, uses a pressure gradient to get continuous, convective flow of drugs into the brain. Problems with this method include the appropriate placement of the catheter, tissue compression, and infusate reflux back through the catheter. A company called Twin Star Medical has developed hollow fiber catheter technology, which may provide a more effective form of drug delivery to the brain.



• Concomitant: (kon-KOM-i-tuhnt) occurring simultaneously, as when 2 or more treatments are used at the same time. For example, radiation therapy with concomitant temozolomide.



• Edema: or peritumoral edema; Swelling of brain tissue; a common result of having a brain tumor; conventionally controlled via cortisteroids (synthetic hormones) like dexamethasone (Decadron); also treated with a variety of anti-inflammatory supplements and foods, notably boswellic acids from the extract of Boswellia Serrata (Indian frankincense).



• EGF: Epidermal growth factor; a tyrosine protein kinase whose receptor over-expression is one of the hallmarks of glioblastoma, present in 40-50% of tumors. In addition to the normal EGF receptor (EGFR), glioblastoma tumors can also express a mutant gene, called EGFRvIII. Like VEGF, EGF and its mutant version are tumor growth factors which facilitate angiogenesis, and as such, are the targets of many treatment strategies which collectively are known as EGFR inhibitors. Notable prescription drugs which act as EGFR inhibitors include the small molecule chemo drugs Tarceva (erlotinib) from Genentech and Iressa (gefitinib) from AstraZeneca, as well as the monoclonal antibody Erbitux (cetuximab) from ImClone. Natural EGF inhibitors include genistein and quercetin.



• Glioblastoma multiforme: or GBM; Glioblastomas are Grade IV astrocytomas and the most common type of glioma brain tumor. These tumors are noted for their aggressive nature, heterogeneity, and ability to resist treatments. The name refers to the general origin of such tumors in the glial tissue of the brain. In 2007, the U.S. National Cancer Institute estimates that 20,500 new brain tumors will be diagnosed in the U.S. alone. Glioblastomas comprise approximately 23-30% of primary brain tumors in the U.S., and are the most commonly diagnosed brain tumor in adults aged 45-74. Men are more frequently diagnosed with glioblastoma than women. In most western countries, the incidence of glioblastoma is approximately 2-3 new cases per 100,000 people, per year.



• Heterogeneity: variability (within the same tumor type) from person to person



• Karnofsky Performance Status (KPS): The Karnofsky scale measures a patient's ability to perform everyday tasks on a scale of 0 (dead) to 100 (no symptom of disease). Most clinical trials require a KPS of 60 or higher for participation.



• Methylation: the process of replacing a hydrogen atom in a molecule with a methyl chemical group (CH3); the most common type of alkylation; usually to alter or regulate gene expression because the methyl group is critical to DNA transcription. For example, methylating serotonin makes melatonin.



• MGMT: Often called the "DNA repair gene", MGMT plays an important role in brain tumors because patients whose tumors express MGMT do not benefit significantly from chemotherapy with alkylating agents, like temozolomide. Because of the varying levels of MGMT expression in different tumors, standard temozolomide schedules are only significantly effective in about 45% of glioblastoma patients. The MGMT gene encodes a DNA-repair enzyme called AGT. The level of relative MGMT expression in a person's tumor can be tested by measuring the amount of MGMT promoter methylation using an HPLC assay or one of several other methods. For patients whose MGMT expression is high, a study drug called O6-benzylguanine was developed to block AGT in hopes of making methylating agents like temozolomide more effective, however the drug is still in trials, largely because the effective dosage schedule has proven ellusive. Several studies (Tolcher, et al) also indicate that specific temozolomide schedules may be able to deplete MGMT in those patients in which it is expressed.



• Orphan Drug Status: a designation, conveyed by the U.S. Food and Drug Administration (FDA), which identifies a significant, newly developed or recognized treatment for a disease which affects fewer than 200,000 persons in the United States. Glioblastoma is such a disease. Orphan Drug Status can lead to increased research funding and regulatory fast-tracking. The European Union uses this terminology for the same purpose.



• Resection: tumor tissue removal via surgery. In brain tumor patients, this usually means a craniotomy involving temporary removal of skull bone.



• Temozolomide: (brand names Temodar and Temodal): an alkylating agent widely used in the treatment of brain tumors, especially anaplastic astroycytomas. Temozolomide prevents tumor cells from spreading by interfering with the cell's ability to replicate DNA. Relative to other chemo drugs, temozolomide is fairly easy to administer since it is taken orally, and it's side-effects are usually less severe than many other traditional chemo drugs. Because tumor cells grow much faster than normal cells, they are affected to a much greater degree. The main side-effects of temozolomide treatment are fatigue, constipation, and nausea. Constipation and nausea can usually be kept in check with other drugs, and fatigue is often the side-effect most difficult to prevent. Less common, but more serious side-effects include neutropenia (low white blood cell count, usually below 1,000), thrombocytopenia (low platelet counts, usually below 100,000), and the increased risk of infection associated with a compromised immune system. Often, this risk of infection is controlled through administration of a weekly sulfa antibiotic. Regular blood labs are important when taking temozolomide to monitor these blood-related side-effects.



• VEGF: (VEDGE-eff) Vascular endothelial growth factor; a tyrosine protein kinase which activates blood vessel growth in tumors. Most researchers believe VEGF is one of the most important growth factor proteins for glioblastoma angiogenesis, which is why so much emphasis has been placed on inhibiting it with drugs like the monoclonal antibody Avastin, as well as newer small molecule VEGF inhibitors like Bayer/Onyx Pharmaceuticals' sorafenib, Pfizer's sutent (sunitinib), Novartis/Schering AG's vatalanib, AstraZeneca's Zactima (ZD-6474) and AstraZeneca's Recentin (cediranib or AZD2171). Genentech sponsors a VEGF education web site at ResearchVEGF.com