Glossary of brain tumor terms
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Glossary of Terms

1p/19q codeletion - the combined deletion of the short arm (p) of chromosome 1 and the long arm (q) of chromosome 19. Also referred to as loss of heterozygosity on 1p/19q, this alteration occurs in a high proportion of IDH1-mutant oligodendroglial tumours and is mutually exclusive with TP53 mutations. 1p/19q codeleted tumours seem to be very responsive to chemotherapy, perhaps contributing the better prognosis of oligodendrogliomas.

A

ABC transporter - ATP binding cassette transporters are active pumps which propel drugs and other potential toxins across cell membranes. Several ABC transporters coexist in the endothelial cells of brain capillaries and function as an active component of the blood-brain barrier, ejecting drugs out of the capillary cells back into the bloodstream.

ABCB1 - the gene encoding the ABC transporter protein MDR1 (multidrug resistance protein 1), more commonly known as P-glycoprotein. One of the chief drug efflux pumps found in brain capillary cells as part of the blood-brain barrier.

ABCC1 - the gene encoding the ABC transporter MRP1, or multidrug resistance-associated protein 1.

ABCG2 - the gene encoding the ABC transporter BCRP, or breast cancer resistance protein. Along with ABCB1/P-glycoprotein, this protein is one of the two most important drug efflux pumps found in brain capillary cells as part of the blood-brain barrier.

Accutane - also known as 13-cis retinoic acid or isotretinoin. A vitamin A derivative prescribed for cystic acne which has also been included in several clinical trials for glioma as a cell differentiating agent.

ACNU - nimustine hydrochloride. A nitrosourea chemotherapy agent which alkylates DNA and causes crosslinks, DNA fragmentation and cell death.

adenine - one of four nucleobases making up the DNA code. Abbreviated as A. The other three nucleobases are cytosine (C), guanine (G), and thymine (T).

Akt - also known as protein kinase B. A key protein in the PI3K/Akt/mTOR signaling pathway, involved in such processes as cell proliferation, cell survival, and glucose metabolism.

ALDH - aldehyde dehydrogenase. A group of enzymes catalyzing the oxidation of aldehydes. Aldehyde dehydrogenase has been identified as a marker of glioma stem cells, and is also one of the molecular targets of disulfiram (Antabuse).

alkylating agent - An alkyl group is an alkane missing one hydrogen. An alkane is a chain of one or more carbon atoms saturated with hydrogen. An alkylating agent in chemotherapy is a substance which transfers an alkyl group onto a location in the cellular DNA, causing DNA damage during cell division. The simplest alkyl group is the single-carbon methyl group (CH3), and DNA methylating agents include temozolomide and procarbazine. Other alkylating agents include the nitrosoureas which attach a chloroethyl group to DNA.

alpha-ketoglutarate - also called oxo-glutarate. An intermediate in the Krebs cycle, produced from either isocitrate or glutamate through the action of the enzymes isocitrate dehydrogenase or glutamate dehydrogenase.

ALT - Alternative Lengthening of Telomeres

alternative lengthening of telomeres - a mechanism which replenishes telomeres independently of the enzyme telomerase. A telomere is a buffer of repetitive DNA at the ends of chromosomes. Telomeres are shortened with each cell division, which allows the cell a finite number of divisions before entering senescence, or cellular old age. Lengthening of telomeres allows the cell to escape this natural limitation.

AMPK - AMP-activated protein kinase. An energy sensing enzyme which is activated in situations of energy stress, inhibiting energy consuming processes and stimulating energy producing processes such as glucose transport and fatty acid oxidation.

amplification - in genetics, the abnormal duplication of a gene or multi-gene regions of DNA. Amplification of oncogenes is a common occurrence in cancer, eg. epidermal growth factor receptor (EGFR) amplification in glioblastoma.

anaplastic - neoplastic cells which bear little resemblance to normal cells. In the case of gliomas, anaplastic refers to WHO Grade III.

angiogenesis - the proliferation of new blood vessels to supply a tumour with nutrients.

antineoplastic - neoplastic refers to cancer. Antineoplastic refers to anti-cancer drugs or therapies.

apoptosis - programmed cell death.

arachidonic acid - a 20-carbon omega-6 fatty acid, found mainly in eggs and grain-fed animal products, which may be converted into inflammatory substances such as prostaglandins and leukotrienes by the action of COX-2 and 5-LOX enzymes.

athymic mice - laboratory mice with a genetic mutation causing absence of a thymus gland and therefore a highly compromised immune system. These mice, also called nude mice, are used in xenograft experiments, in which the transplanting of human cancer cells requires animals which lack an effective immune response.

ATP - adenosine triphosphate. The intracellular energy storage molecule which powers all energy-requiring processes in the cell.

ATRX - alpha-thalassemia/mental retardation syndrome X-linked. A gene often co-mutated in lower grade astrocytomas, along with IDH1 and TP53. Mutations in ATRX are associated with alternative lengthening of telomeres.

autologous - derived from the same individual. Autologous dendritic cell vaccines use dendritic cells drawn from a patient, which are later re-injected into the same patient after preparation of the vaccine.

autophagy - (from the Greek words for "self" and "to eat"). Autophagy involves the degradation of cellular components to provide energy in times of stress. Depending on the context, autophagy may be either a survival mechanism, or may precede cell death.

Avastin - the trade name of bevacizumab, an anti-VEGF monoclonal antibody.

B

BCNU - carmustine, or bis-chloroethyl-nitrosourea. An intravenously administered DNA chloroethylating agent, formerly a standard of care drug for malignant glioma.

BCRP - breast cancer resistance protein. See ABCG2.

bevacizumab - an anti-VEGF monoclonal antibody, FDA approved for use in recurrent glioblastoma in 2009. Trade name Avastin.

bioavailable - refers to the fraction of a drug or substance which is absorbed and enters the general circulation unmetabolized by the liver.

C

calcidiol - 25-hydroxycholecalciferol, or 25-hydroxyvitamin D3. The predominant form of vitamin D in the bloodstream, and the form measured by a standard vitamin D blood test.

calcitriol - 1,25-dihydroxycholecalciferol, or 1,25-dihydroxyvitamin D3. The hormonally active form of vitamin D, typically produced from calcidiol in the kidneys.

cannabidiol - CBD, the second most prevalent cannibinoid obtained from the cannabis plant. In contrast to THC, cannabidiol is non-psychoactive.

cannabinoid - a diverse class of naturally occurring or synthesized substances originally isolated from the cannabis plant, some of which stimulate the human cannabinoid receptors CB1 and CB2.

carmustine - see BCNU

catabolism - the breaking down of molecules into smaller units.

CBD - see cannabidiol

CCNU - Lomustine, a chloroethylating nitrosourea chemotherapeutic agent. This drug is taken orally, and in glioma treatment is most commonly used as part of the three drug combination regime PCV, along with procarbazine (P) and vincristine (V).

CD133 - also called prominin 1. A cell surface glycoprotein commonly used as a marker of glioblastoma stem cells.

cell cycle - the stages of active cell division, consisting of G1 (gap 1), S (synthesis), G2 (gap 2), and M (mitosis).

cell cycle arrest - the arresting of the cell cycle, usually at the G1 or G2 checkpoint.

chemokine - chemoattractant cytokines, chemical messengers which attract cells with appropriate chemokine receptors, such as various immune cells.

chloroethylating agent - chemotherapeutic agents which attach a chloroethyl group to cellular DNA. Nitrosoureas such as BCNU and CCNU are chloroethylating agents.

CMV - see cytomegalovirus.

concomitant - in chemotherapy, concomitant typically means combined with radiation therapy.

copy number alterations - abnormal duplication (amplification) or deletion of genes.

COX-2 - cyclooxygenase 2. An enzyme which catalyzes one of the steps in the conversion of arachidonic acid to inflammatory prostaglandins.

CpG site - within the DNA code, a site where a cytosine nucleotide is followed by a guanine. Cytosine and guanine are two of the four nucleobases which make up the DNA code.

CpG island - a region of DNA containing a high frequency of CpG sites. CpG islands are often found in gene promoter regions. A high degree of methylation of CpG sites in gene promoters may lead to silencing of the gene.

CR - caloric restriction.

CRABP2 - cellular retinoic acid-binding protein 2. A protein which binds with and transports retinoic acid to retinoic acid receptors, leading to cell differentiation.

CRBP1 - cellular retinol binding protein 1, involved in the transport and synthesis of retinoic acid from precursor molecules.

CTL - cytotoxic T lymphocyte. Also called killer T-cells, or CD8+ T cells.

CUSP9 - Coordinated Undermining of Survival Paths with 9 repurposed drugs. A proposed combination regime for recurrent glioblastoma devised by Richard Kast, Marc-Eric Halatsch and others. The repurposed drugs making up CUSP9 are aprepitant, artesunate, auranofin, disulfiram plus copper gluconate, nelfinavir, captopril, sertraline, and ketoconazole. Several patients in Germany have been treated with this regime, though a trial has not yet been initiated.

cytokine - intercellular signaling molecules, typically secreted by immune cells, including interleukins, chemokines, interferons, etc.

cytomegalovirus - A genus within the Herpesvirus family commonly infecting humans. Targeted by the drug valganciclovir (Valcyte).

cytosine - one of four nucleobases making up the DNA code, abbreviated as G. The other three nucleobases are adenine, guanine, and thymine.

D

DCA - dichloroacetate. A small, simple molecule, analogous to acetic acid, with two chlorine atoms replacing two hydrogens. DCA has been used for decades in rare metabolic disorders involving lactic acidosis. It is an inhibitor of pyruvate dehydrogenase kinases, which increases the flux of pyruvate into mitochondria and away from conversion into lactic acid outside the mitochondria.

deletion - in genetics, the abnormal loss of one or both copies of a gene, or multi-gene regions of DNA. Loss of both copies is called homozygous deletion, while loss of a single copy is called hemizygous deletion.

dendritic cell - a type of immune cell whose primary function is the processing and presentation of antigens to immune effector cells such as T-cells.

DHA - docosahexaenoic acid. A long-chain (22-carbon, docosa- is Greek for 22) omega-3 fatty acid with 6 (hexa-) double bonds. The primary source is cold-water fish species.

diffuse astrocytoma - this term typically refers to WHO grade II astrocytomas, which are diffusive in brain tissue, in contrast with grade I pilocytic astrocytomas which are non-diffusive.

DNA methyltransferase - one of several enzymes which transfer methyl groups to DNA, thereby maintaining DNA methylation patterns when cells divide. This is an entirely separate process from the cytotoxic DNA methylation due to chemotherapy agents such as temozolomide.

DNMT - see DNA methyltransferase.

differentiation - in cell biology, a process of increasing cell specialization from immature stem cell towards fully mature cells specialized for a specific function.

dimer - in chemistry, a dimer is a two-part entity formed by the joining together (dimerization) of two smaller sub-units. The two sub-units may be identical, forming a homodimer, or distinct, forming a heterodimer.

E

ECOG Performance Status - Eastern Cooperative Oncology Group performance status, similar to the Karnofsky performance score, rates patients on a scale of 0-4 (0=best) according to capacity for independent functioning, mobility and physical activity.

edema - the accumulation of fluid in tissues, leading to swelling. In brain tumours, vasogenic edema is caused by the breakdown of the blood-brain barrier and the leaking of fluid through capillaries.

EGCG - epigallocatechin gallate. The primary catechin found in green tea, and a powerful antioxidant.

EGFR - epidermal growth factor receptor. Activated by epidermal growth factor, this receptor activates several downstream pathways leading to cell proliferation. This receptor is commonly amplified in cancers such as glioblastoma.

eicosanoid - 20-carbon (eicosa is Greek for 20) derivatives of arachidonic acid, eicosapentaenoic acid (EPA), or dihomo-gamma-linolenic acid (DGLA), which are all 20-carbon fatty acids.

endogenous - occurring from within. For example, in preclinical studies, an endogenous IDH1 mutation refers to one which is naturally occuring, as opposed to one that is artificially induced.

EPA - eicosapentaenoic acid. A long chain (20-carbon) omega-3 fatty acid with 5 (penta-) double bonds. The primary source of EPA and DHA, is cold-water fish species. EPA competes for the same enzymes as the inflammatory omega-6 arachidonic acid, and has anti-inflammatory effects.

epigenetics - heritable changes in gene activity or expression which are not caused by changes in the DNA sequence. Major epigenetic categories include DNA methylation patterns, histone modifications, and microRNA (miRNA) activity.

everolimus - also called RAD-001. A drug related to sirolimus (rapamycin). Drugs in this group are inhibitors of mTOR complex 1 (mTORC1). mTORC1 regulates protein translation, an essential requirement for cell proliferation. A drawback of inhibiting mTORC1 alone, is a possible increase in Akt activity. Dual mTOR/PI3K inhibitors, once approved, may therefore be more effective than mTORC1 inhibitors such as rapamycin and everolimus.

exome - the totality of exons in the genome.

exon - sequences within a gene which remain intact in mature RNA, after removal of introns, and are thereafter translated into protein. Essentially, the protein-coding sequences of a gene.

extracellular matrix - composed of interlocking proteins (such as collagen), proteoglycans and hyaluronic acid (a polysaccharide), the extracellular matrix provides support to the surrounding cells and is also involved in other functions, such as intercellular communication.

F

FABP5 - Fatty acid binding protein 5. FABP5 may bind with retinoic acid and transport it to receptors promoting cell proliferation. This is in contrast with CRABP2, which also binds with retinoic acid, but leads to cell differentiation.

FAK - see Focal Adhesion Kinase.

FAO - fatty acid oxidation. An alternative means of providing cells with energy when glucose is limited.

FDG-PET - a form of positron emission tomography in which the radioactive tracer 18F-FDG is used in visualizing tumours. FDG stands for fludeoxyglucose (or fluorodeoxyglucose) and is a glucose analog in which a radioactive isotope of fluorine (fluorine-18) is inserted into a glucose molecule. FDG-PET scans reveal areas in the body with an abnormally high glucose uptake, such as malignant tumours. In glioma, FDG-PET is mostly used to detect grade III or higher tumours, as lower grade tumours have a glucose uptake comparable to normal brain.

focal adhesion kinase - also called p125FAK, and protein tyrosine kinase 2 (PTK2). FAK is one of the central molecules found at focal adhesions, which link the extracellular matrix to the cell cytoskeleton and are a requirement for cell migration.

fotemustine - an intravenously administered "third-generation" nitrosourea chemotherapy agent. Multiple clinical trials in Italy have tested this drug for recurrent glioblastoma.

G

G-CIMP - Glioma CpG Island Methylator Phenotype. See CpG Island. In gliomas, CIMP is often the result of IDH1 mutation, which causes epigenetic disturbances leading to widespread CpG methylation, especially in gene promoter regions, causing gene silencing.

gene silencing - the inactivation of gene transcription, often resulting from methylation in the gene promoter region.

GFAP - Glial fibrillary acidic protein, a marker of astrocytic differentiation.

GL261 - a mouse-derived glioma cell line, considered the gold standard syngeneic glioblastoma model, often used in immunotherapy studies in immunocompetent mice.

glioblastoma - WHO grade IV astrocytoma, characterized by a high degree of angiogenesis, areas of necrosis, and invasive infiltration into normal brain. It is likely derived from a different cell of origin than lower grade gliomas, which often result from IDH1 mutations. Primary glioblastomas are typically IDH1 wild-type (unmutated), but have other genetic abnormalities such as EGFR amplification, PTEN deletions etc.

glioma - a general term for any cancer of glial cells, including astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas.

glucocorticoid - a class of steroid hormone, also called corticosteroids. The commonly used dexamethasone (Decadron) is a glucocorticoid.

GLUT - glucose transporter, a group of several proteins which transport glucose across membranes into the cell.

glutamine - the most abundant amino acid in human blood. Cells can use glutamine as a fuel source when glucose is limited.

glutathione - an important intracellular antioxidant molecule, composed of the amino acid cysteine and a glutamate side-chain.

glycemic index - a system which measures the degree to which a food affects blood glucose in a specified amount of time. Pure glucose is usually taken to be 100 on the index scale.

glycolysis - the splitting of a glucose molecule, through several enzymatic steps, into two molecules of pyruvate, yielding two molecules of ATP as the energy payoff. The resulting pyruvate is then often further metabolized in the cell mitochondria, or alternatively converted to lactic acid outside the mitochondria, as often occurs in cancer cells.

Gross Total Resection - a complete surgical tumour removal leaving no residual tumour visible by MRI or CT imaging.

GSH - the reduced form of glutathione.

guanine - one of the four nucleobases making up the DNA code, abbreviated as G. The other three nucleobases are adenine, cytosine, and thymine.

H

HDAC inhibitor - histone deacetylase inhibitor. Histones are the "spools" around which DNA winds. Histone deacetylases remove acetyl groups from histone tails, causing increased binding between histones and DNA, which disallows gene transcription. HDAC inhibitors preserve histone acetylation, weakening the binding between histones and DNA, allowing gene transcription. Histone modifications are one of the major categories of epigenetics.

heterodimer - see dimer. A heterodimer is a dimer composed of two non-identical sub-units.

hexokinase - an enzyme which catalyzes the first of many stages of glycolysis, converting glucose to glucose-6-phosphate.

HIF-1 - hypoxia-inducible factor 1. A transcription factor which orchestrates the cellular response to hypoxia, regulating many of the genes involved in glycolysis.

2-hydroxyglutarate - an oncometabolite produced by the mutant IDH1 enzyme from alpha-ketoglutarate, abbreviated as 2-HG. 2-HG is assumed to be the cause of the epigenetic disruption which characterizes IDH1 mutant tumours. Agios Pharmaceuticals is developing drugs which inhibit the ability of mutant IDH1 to produce 2-HG, with clinical trials in the planning stages.

hypoxia - low oxygen levels. The atmospheric oxygen content (normoxia) is 21% oxygen by volume. In glioma experiments, oxygen levels of 1-5% are often used to model the effects of hypoxia in brain tumours.

I

Id1 - Inhibitor of DNA binding 1, one of four Id family members. Id proteins bind to basic helix-loop-helix (bHLH) transcription factors, repressing their function. Id1 is implicated in glioblastoma transformation, tumorigenesis, invasion, and stemness.

IDH1 - isocitrate dehydrogenase 1. An enzyme located in the cytoplasm (cellular fluid) and peroxisomes (organelles involved in the breakdown of very long chain fatty acids), which normally converts isocitrate to alpha-ketoglutarate. In contrast, mutant IDH1 converts alpha-ketoglutarate to 2-hydroxyglutarate.

IGF-1 - insulin-like growth factor 1. A hormone with a high degree of similarity to insulin. IGF-1 stimulates cell proliferation by binding to its receptor IGF1R, thereby activating signaling pathways such as PI3K/Akt/mTOR. One way to minimize IGF-1 levels in the bloodstream is through dietary protein restriction.

integrins - a family of cell adhesion receptors, consisting of 18 known alpha-subunits and 8 known beta-subunits, which can form at least 24 heterodimers. Integrins bind to the extracellular matrix and are crucial for cell migration.

intraperitoneal - drugs are often administered to lab animals intraperitoneally, which means by injection into the peritoneum, or abdominal cavity.

in vitro - Latin for "in glass". In laboratory work, in vitro refers to experiments outside of a living body.

in vivo - Latin for "within the living". In laboratory work, in vivo refers to experiments done in a living body.

J

K

Kaplan-Meier method - a means of estimating time to a given event (such as median survival in a clinical trial) when some of the data is missing, for example due to lack of follow-up. Most progression-free survival or survival curves in the publication of clinical trial results use the Kaplan-Meier method.

ketogenic diet - a dietary regimen first developed to prevent seizures in epileptic patients. The diet is currently in clinical trials for cancer patients. It consists of an extreme limitation of carbohydrate consumption and a liberal intake of fats and oils, in a ratio (by weight) of 3 or 4:1 (fats and oils: protein plus carbs). With such an extreme limit to carbohydrate intake, the body is forced to metabolize ketone bodies for energy.

ketolytic - enzymes which are able to break down ketone bodies for energy are termed "ketolytic".

ketone body - fatty acid derivatives produced in the liver in times of low food intake. Often referred to simply as "ketones".

Ki-67 - an antigen used as a marker of cell proliferation. Ki-67 is present in all stages of cell division but is absent in cells not actively dividing.

kinase - any of various enzymes which catalyze phosphorylation of various substrates. Multiple kinases are involved in growth-promoting signaling pathways active in cancer.

L

lactate - the conjugate base of lactic acid. Lactate is produced from pyruvate by the enzyme lactate dehydrogenase. This characterizes some cancers, such as glioblastoma, and is termed "aerobic glycolysis" or "the Warburg effect".

lactate dehydrogenase - Lactate dehydrogenase A (LDHA) is an enzyme which can convert pyruvate to lactate (prevalent in glioblastoma), while LDHB can convert lactate into pyruvate (prevalent in IDH1-mutant tumours).

LDH - lactate dehydrogenase

leukapheresis - a procedure in which white blood cells (leukocytes) are separated from a sample of whole blood. Leukapheresis is a preliminary step required for each patient undergoing dendritic cell vaccination.

leukotriene - a type of inflammatory eicosanoid, produced from arachidonic acid through the action of the enzyme 5-lipoxygenase (5-LOX).

5-lipoxygenase - an enzyme which converts arachidonic acid or eicosapentaenoic acid into leukotrienes. The herb Boswellia serrata is an inhibitor of 5-LOX, which prevents the conversion of arachidonic acid into inflammatory leukotrienes.

lomustine - see CCNU

LOH - see Loss of heterozygosity

loss of heterozygosity - refers to the loss of a single copy of a gene, or multi-gene region of a chromosome.

5-LOX - see 5-lipoxygenase

lymphocyte - a group of immune cells including natural killer cells, T-cells, and B-cells.

lysate - cellular material obtained by destruction of cell membranes.

M

macrophage - an immune cell derived from monocytes, whose function is to scavenge dead and dying cells and cellular debris. Alternatively activated "M2" macrophages are involved in tissue repair and wound healing.

MCT - monocarboxylate transporter. A group of transporters which carry molecules such as lactate across cell membranes. In highly glycolytic cells, MCT4 exports lactate into the extracellular space.

methyl group - the simplest alkyl group, consisting of one carbon atom with three attached hydrogen atoms.

metronomic chemotherapy - lower doses of chemotherapy taken on a daily basis.

MGMT - O6-methylguanine-DNA methyltransferase. A DNA repair enzyme which removes methyl groups and other alkyl groups from the 06 position of guanine in DNA, preventing mismatch during cell replication. The levels of MGMT in a cell determine response to DNA alkylating chemotherapies such as temozolomide and BCNU.

microglia - the resident macrophage of the central nervous system. Normally functioning in a defensive role, microglia may be induced by glioma cells to adopt a tumour-assisting role.

micromolar - one millionth of a mole per litre of solution.

microvessel - small blood vessels including capillaries, arterioles and venules. Also referred to as microvasculature.

millimolar - one thousandth of a mole per litre of solution.

MMP - matrix metalloproteinase. A group of enzymes capable of degrading extracellular matrix proteins. MMPs such as MMP2 and MMP9 are vital for cell invasion in cancers such as glioblastoma.

mole - the amount of a substance, measured in grams, which contains the same number of particles (atoms or molecules) as is contained in 12 grams of pure carbon-12. The atomic mass of an element, expressed in daltons, is the same number as a mole of that element, expressed in grams. For example, the atomic mass of carbon is 12, and one mole of carbon weighs 12 grams.

monoclonal antibody - abbreviated mAB, antibodies which are made by identical immune cells (clones).

mRNA - messenger RNA. The form of RNA which is the intermediary between DNA and protein, conveying genetic information from DNA in the nucleus to the ribosomes for translation of the information into protein.

mTOR - mammalian target of rapamycin. A protein named after a therapeutic drug which targets it (rapamycin). mTOR is a kinase downstream of Akt in the PI3K/Akt/mTOR signalling pathway, which promotes protein synthesis and cell proliferation.

mutifocal recurrence - recurrence of a tumour in multiple independent locations in the same organ. A small percentage of brain tumours recur multifocally.

myelosuppression - the suppression of blood cell production in the bone marrow. Myelosuppression is often a side-effect of chemotherapy.

N

nanomolar - one billionth of a mole per litre of solution.

necrosis - a form of cell death, often found in fast-growing tumours such as glioblastoma when the rate of growth exceeds the ability to acquire oxygen and nutrients.

neutrophils - a granulocytic white blood cell, "first-responders" at a site of injury.

neo-adjuvant - the administration of a therapy, such as chemotherapy, prior to the main treatment, such as surgery.

NF-KB - nuclear factor kappa beta. A transcription factor implicated in tumour progression, involved in processes such as invasion, angiogenesis, inflammation, proliferation and anti-apoptosis.

nitrosourea - DNA alkylating chemotherapy agents, including BCNU, CCNU and ACNU, which contain a nitroso group and a urea.

O

omega-3 - a group of polyunsaturated fatty acids, named for the location of the first double bond at carbon 3, counting from the methyl (or omega) end. Omega-3 fatty acids include the 18-carbon alpha-linolenic acid, 20-carbon eicosapentaenoic acid (EPA), and the 22-carbon docosahexaenoic acid (DHA).

omega-6 - a group of polyunsaturated fatty acids, named for the location of the first double bond at carbon 6, counting from the methyl (or omega) end. Omega-6 fatty acids include the 18-carbon linoleic acid, and the 20-carbon arachidonic acid.

oxidative stress - cellular stress or damage caused by reactive oxygen species (ROS).

P

p53 - a protein named after its apparent molecular mass (53 kilodalton). The protein is encoded by the TP53 gene, or tumor protein 53. It functions as a transcription factor, regulating the expression of other genes involved in cell-cycle arrest, DNA repair, apoptosis, and the general response to cellular stress and DNA damage. TP53 alterations are common in cancer, including inactivating mutations, and single-copy deletions, or both. Inactive p53 may encourage cancer progression in the absence of treatment, but may also make cancer cells more vulnerable to certain chemotherapies, demonstrated in vitro.

PCV - a triple chemotherapy regime consisting of procarbazine, CCNU, and vincristine. This was formerly a common treatment for glioma prior to the introduction of temozolomide.

PDGFRA - platelet-derived growth factor A. This growth factor receptor is commonly amplified in proneural-type glioblastomas, and lower grade gliomas.

peptide - chains consisting of from two to about 70 amino acids, joined by peptide bonds. Peptides are shorter than true proteins.

peripheral neuropathy - damage to nerves, resulting in symptoms such as numbness, pains, tingling, "pins and needles". Peripheral neuropathy is the primary side-effect of DCA, and in this case is reversible by reducing the dose.

PFS - see progression-free survival

PGE2 - prostaglandin E2. An inflammatory eicosanoid derived from arachidonic acid.

P-glycoprotein - see ABCB1

phase I trial - small, single-location trials conducted to determine the safety, maximum-tolerated dose, and side-effects of a drug or therapy, rather than efficacy.

phase II trial - larger trials (usually from about 50-100 patients), either randomized or single-arm, conducted to determine the efficacy of a drug or therapy in terms of endpoints such as progression-free survival or median survival.

phase III trial - a large, multi-institution trial usually involving several hundred patients, designed to prove conclusively the efficacy of a drug or therapy. In phase III trials patients are typically randomized into one of two arms: a comparator arm receiving the current standard of care, and an experimental arm receiving the standard of care plus the experimental drug or therapy. The two arms are balanced for all known prognostic factors such as age, extent of resection, KPS etc.

phenotype - the observable traits or characteristics of an organism.

phosphorylation - the transfer of a phosphate group onto a protein, usually at a serine, threonine or tyrosine amino acid. Phosphorylation is catalyzed by kinases and typically results in activation of an enzyme, though in some cases phosphorylation results in the phosphorylated protein being degraded by the proteasome.

PI3K - phosphoinositide 3-kinase, also called phosphatidylinositide 3-kinase. PI3K is activated by growth factor signals such as insulin-like growth factor 1. PI3K in turn activates Akt, and through Akt, other downstream molecules such as mTOR, leading to increased cell proliferation and survival. PI3K pathway alterations are commonly observed in cancer, including activating mutations in PI3K itself, and mutation and/or deletion of PTEN, an inhibitor of PI3K signaling.

picomolar - one trillionth of a mole per litre of solution.

PPAR - peroxisome proliferator-activated receptor. A group of nuclear receptors which function as transcription factors. Retinoic acid may activate retinoic acid receptors leading to cell differentiation. Alternatively, retinoic acid may activate PPAR beta or delta, leading to transcription of proliferation and survival genes.

PRAS40 - proline-rich Akt substrate of 40 kiloDalton. A component of mTOR complex 1 (mTORC1).

progression-free survival - abbreviated as PFS, also called time-to-progression. PFS is the duration of a response or disease stabilization following a therapy until further disease progression or recurrence. PFS is often one of the primary endpoints measured in clinical trials.

promoter - in genetics, a gene promoter is a region of DNA close to the transcriptional start site of a gene, which is responsible for initiating transcription of the gene.

prospective trial - a trial in which patients are assigned to a treatment according to a pre-established set of eligibility requirements and a pre-established treatment protocol. Prospective trials are designed to eliminate biases which may distort the findings of a retrospective study. Prospective trials are approved and initiated first, and patients are then recruited to the trial over a period of time. Proper clinical trials are prospective, in contrast with retrospective studies, in which patients are treated on an individual basis outside of any trial, and later their records are reviewed to determine outcome according to the treatment received.

proteasome - a complex responsible for degrading surplus or damaged proteins inside the cell. Proteins are tagged for degradation with another small protein called ubiquitin. These tagged proteins are degraded by the proteasome into small-chain peptides which may then eventually be recycled in the building of new proteins. In short, the proteasome regulates the turnover of proteins inside the cell.

pseudopalisades - areas of dense cell clustering around areas of necrosis. This is a common observation in glioblastoma and likely represents a migration of glioma cells away from necrotic areas of hypoxia or anoxia.

PTEN - phosphatase and tensin homolog. A tumour suppressor protein which opposes the action of PI3K and thereby prevents Akt activation. A deletion of the section of chromosome (10q23) containing the PTEN gene is one of the most frequent genetic alterations in glioblastoma.

pyruvate - a product of glycolysis resulting from the splitting of glucose molecules. The resulting pyruvate may then enter the mitochondria to fuel the citric acid cycle, or be converted to lactate by lactate dehydrogenase.

pyruvate dehydrogenase - an enzyme which converts pyruvate into acetyl coenzyme A (acetyl-CoA) for entry into the citric acid cycle (Krebs cycle) in cell mitochondria.

pyruvate dehydrogenase kinase (PDK) - a group of kinases which phosphorylate and deactivate pyruvate dehydrogenase. By disabling pyruvate dehydrogenase, PDKs contribute to the conversion of pyruvate to lactate. The drug DCA reverses this process by inhibiting PDKs, resulting in more pyruvate entering the citric acid cycle inside mitochondria, and less being converted into lactate.

Q

R

randomized trial - a trial consisting of two or more arms, in which patients are randomly assigned to one of the arms. Randomized trials often consist of a comparator arm receiving the current standard of care, and an experimental arm receiving the standard of care plus an experimental drug or therapy. Phase II trials are sometimes randomized, and phase III trials are always randomized.

RAR - retinoic acid receptor, a group of 3 nuclear receptors that can heterodimerize with retinoid X receptors (RXRs). Activated by retinoic acid, RAR/RXR then is able to initiate transcription of target genes, functioning as a transcription factor.

RB1 - retinoblastoma 1, a tumour suppressor gene and protein which inhibits cell cycle progression. RB1 is frequently altered in glioblastoma, either by deletion (primary glioblastoma) or silencing due to methylation of the gene promoter (secondary glioblastoma).

reactive oxygen species - a type of free radical containing oxygen with unpaired electrons in its outer shell. Reactive oxygen species (ROS), like other free radicals, are very unstable and tend to steal electrons from surrounding molecules. ROS such as the superoxide radical are naturally produced in normal cell respiration, but are neutralized by the cell's intrinsic antioxidant systems. Overproduction of ROS may lead to damage to nucleic acids, proteins and lipids.

redox - reduction-oxidation reactions in which atoms change their oxidation state and electrons are transferred from one molecule or atom to another. Oxidation is an increase in oxidation state usually involving loss of electrons. Reduction is a decrease in oxidation state usually involving gain of electrons.

repurposed drug - the use of a drug for a condition other than that for which it received official approval.

resection - the surgical removal of a tumour, or part of an organ or gland.

retinoic acid - a vitamin A derivative, the most biologically active retinoid which activates nuclear retinoic acid receptors leading to cellular processes such as differentiation.

retinoids - any of group of compounds related to or derived from vitamin A.

retrospective study - a study which reviews the records of patients who have a certain characteristic or have received a given treatment in order to compare outcomes. In contrast with a prospective trial, patients included in a retrospective study are treated on an individual basis outside of any formal trial protocol. Investigators then assemble the records of any patients who display the characteristic or have received the treatment being investigated. Retrospective studies "look back" at patients who have already been treated. Prospective trials "look forward", and are initiated prior to the application of the treatment under study.

rindopepimut - a vaccine developed by Celldex Therapeutics, which targets the mutated form of EGFR known as EGFR variant III (EGFRvIII). Also known as CDX-110, the vaccine is currently being tested in trials for glioblastoma.

ROS - see Reactive oxygen species

S

S6K - S6 kinase, phosphorylates S6 ribosomal protein leading to protein synthesis and cell proliferation. S6K is a downstream target of mTOR complex 1.

secondary glioblastoma - a case of glioblastoma which developed from a lower grade (WHO grade II or III) glioma.

senescence - in cell biology, replicative senescence occurs when cells are no longer capable of dividing.

serum - blood from which all blood cells and fibrinogens (clotting factors) have been removed.

STAT3 - Signal transducer and activator of transcription 3. A transcription factor commonly active in malignant glioma, which has multiple effects, such as increased angiogenesis, invasion, immunosuppression, anti-apoptosis, and cell cycle progression. In healthy tissue, STAT3 is involved in the wound healing response.

statistical significance - an outcome is conventionally said to be statistically significant if the p-value is less than 0.05, meaning the probability of the outcome being due to chance alone is less than 5%.

syngeneic - in animal studies of cancer, a syngeneic model refers to one in which an animal species (usually mice or rats) is implanted with cancer cells derived from the same species and strain. Syngeneic models are therefore immunocompetent, a necessity especially when testing immunotherapies.

T

TAM - tumour-associated macrophages/microlia. Immune cells which are recruited and re-trained by tumour cells to a tumour-assisting function. TAMs aid glioma by secreting cytokines promoting angiogenesis and invasion. Glioblastoma tumours may consist of up to 30% TAM cells, signifying their importance in glioblastoma progression.

Th1 - T-helper 1. Th1 immunity is mediated by T-helper type 1 cells. This type of immune response is capable of destroying bacteria, viruses and malignant cells.

Th2 - T-helper 2. Th2 immunity results in B-cells manufacturing non-cytolytic antibodies. This type of immune response would be less effective in destroying malignant cells.

THC - tetrahydrocannabinol. The most prevalent and famous cannibinoid derived from the cannabis plant. THC is the main psychoactive component in marijuana.

thymine - one of four nucleobases making up the DNA code, abbreviated as T. The other 3 nucleobases are adenine, cytosine, and guanine.

TMZ - temozolomide, trade name Temodar or Temodal. A cytotoxic DNA methylating agent leading to futile attempts at mismatch repair, causing cell cycle arrest and apoptosis. MGMT is an enzyme capable of removing the TMZ-induced methyl groups on DNA, neutralizing the toxic effect of TMZ. In the absence of functional mismatch repair, TMZ may lead to hypermutation, or the accumulation of thousands of novel random mutations in tumour cells.

TP53 - see p53

transcription - in genetics, the copying of the DNA code of a gene into RNA by the enzyme RNA polymerase. Gene transcription is regulated by transcription factors which bind to the promoter region adjacent to the gene, initiating transcription. The copying of genetic material as RNA is the first step towards its eventual translation into a protein.

transcription factor - any of thousands of proteins which bind to enhancer or promoter regions adjacent to genes and either initiate or block transcription of the target gene.

U

V

Valcyte - trade name of valganciclovir.

valganciclovir - a prodrug of ganciclovir, an anti-cytomegalovirus drug. Valganciclovir has been tested in a glioblastoma trial, and in a retrospective study the long-term (over 6 months) use of the drug appeared to prolong survival in newly diagnosed glioblatoma patients. This retrospective study has caused a controversy in the neuro-oncology community, signifying the need for a well-designed clinical trial to prove the efficacy or lack of efficacy of the drug for malignant glioma.

VEGF - vascular endothelial growth factor. In cancer, the most significant growth factor leading to microvascular proliferation and angiogenesis to supply a tumour with blood.

W

WHO - World Health Organization. The definition of glioma grades (Grades I-IV) is determined by WHO criteria.

wild-type - in genetics, wild-type (WT) refers to the unmutated form of a gene.

X

xenograft - in lab experiments, xenografting is the transplantation of cells of one species (usually human) into an animal of a different species (usually mouse or rat).

Y

Z



This page was created on 02/28/2014 and last updated on 03/01/2014



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