Research Terms Glossary

17AAG: A first generation inhibitor of the hsp90 protein. Inhibition of hsp90 causes degradation of activated KIT. 17AAG has poor solubility. Newer compounds in this class include IPI-504, 17DMAG and CNF2024.

Activation loop: The activation loop (exon 17 in KIT and exon 18 in PDGFRA) of the KIT and PDGFRA receptor tyrosine kinases is a structural domain that influences access to, and the conformation of, the ATP binding pockets of KIT and PDGFRA. When these kinases are activated by ligand binding and dimerization, the activation loop ‘swings out’ to expose the ATP pocket and allow ATP binding. Mutations in the activation loop (a common site of secondary KIT mutations) can interfere with the binding of Gleevec and other TK inhibitors.

AMN107: Both AMN107 and Gleevec are manufactured by Novartis. AMN107 is a newer and possibly more potent tyrosine kinase inhibitor. Like Gleevec, it also inhibits KIT, PDGFRA, and BCR/ABL. 

Antibodies: An antibody is a protein used by the immune system which recognizes and binds to specific molecules, such as other proteins; synonym: immunoglobin. Antibodies to specific proteins are often used to help identify cell types.

BA/F3 cells : A cell line derived from mouse blood cells, and very useful in testing the properties of the varied KIT and PDGFRA mutations found in GIST, and in testing new drugs that might inhibit the mutant KIT and PDGFRA proteins.

BMS-354825: An approved drug (for CML) that is manufactured by Bristol-Myers Squibb. It is a tyrosine kinase inhibitor of Src, abl, KIT, and PDGFR.

CHO cells: Chinese Hamster Ovary cells (CHO cells) are a cell line derived from Chinese Hamster ovaries. They are often used in biological and medical research. CHO cells are used in studies of genetics, toxicity screening, nutrition and gene expression, particularly expression of recombinant proteins.

DNA: The biological macromolecule that encodes genetic information; contained in the chromosome. Chemically, DNA is a polynucleotide, a polymer made up of very many subunits (deoxyribonucleotides) linked in a linear sequence. The four sub-units are A, C, G, and T. DNA contains the instructions for making proteins.

DOG1: A protein that has been identified by the van de Rijn lab. It is present in almost all GISTs and could be used to help identify GISTs.

Domain: A structural/ functional region of a protein.

Exon: Portion of a gene which contains sequence information encoding the amino acid sequence of a protein; specific exons usually correspond to specific domains of a protein.

Exon 11: Gene region that encodes the juxtamembrane (inside the cell, right next to the cell membrane) domain of the KIT protein. Most GIST patients have mutations in exon 11.

Exon 9: Gene region that encodes the extracellular portion (exon 9) of the KIT protein. The second most common type of mutation in GIST.

Exon 13: Gene region that encodes the part of the KIT protein that Gleevec and other TK inhibitors bind to. Secondary mutations in exon 13 are a common cause of Gleevec resistance but are sensitive to Sutent.

Exon 17: Gene region that encodes the KIT “activation loop” (see activation loop). Like exon13, this region is a site of frequent secondary mutations, but these mutations are often  resistant to both Gleevec and Sutent.

Gene Expression: Gene expression, or simply expression, is the process by which a gene's DNA sequence is converted into messenger RNA (mRNA). mRNA is translated into the proteins which make up the structures and functions of a cell.

GIST cell lines: GIST cell lines that were developed from tumors from GIST patients. They are used for laboratory experiments (testing new drugs, etc). About a half-dozen or so different types of cell lines exist representing different types of mutations.

HEEBO: Novel oligonucleotide microarrays (Human Exonic Evidence based Oligonucleotide DNA Microarrays “HEEBO”) contain a total of ~42,000 elements. A major advantage of these arrays is that they allow for determination of exon usage within each individual gene.

Heterogeneous (Heterogeneity): Heterogeneous means that something (an object or system) consists of a diverse range of different items. It is the opposite of homogeneous, which means that an object or system consists of many identical items.

Histology: The branch of the science of anatomy which deals with the microscopic structure of tissues.

HMC cells: A cell line created from a non-GIST tumor, but containing KIT mutations similar to those found in many GISTs, and therefore useful in developing methods that will also be applicable to GIST cell lines.

Homogeneous: An object or system that consists of many identical items.

HSP90: HSP90 1) helps proteins to fold into their correct three dimensional shapes; 2) stabilizes a variety of proteins, among which many are involved in the development of cancer, and; 3) protects them from degradation. Very recent preclinical work has shown that some of these mutant proteins, including KIT, can be effectively inhibited by interrupting the HSP90 function.

Immunohistochemistry: A method for staining cells; antibodies to specific proteins are used as probes to analyze specimens and identify specific types of cells, especially for diagnosis of specific types of cancer, e.g., KIT (CD117), CD34, DOG1, etc.

KIT: The name of the gene that contains the instructions for manufacturing the "KIT" protein. When referring to the gene, the name is italicized (KIT). When referring to the protein, the name is shown in regular font (KIT). The alternate name, c-kit, is also used widely by the medical and scientific communities.  When a pathologist tests (using stains) for the KIT protein on tumor cells, the test is often called KIT, c-kit, or CD117.

KIT: A protein, expressed on Interstitial cells of Cajal, which regulates their replication; GIST cells usually express a mutated form of KIT. Inhibition of KIT signaling is the primary therapeutic aim of most GIST drug treatments.

LBH 589: A Novartis drug that is in phase I clinical trials. It is an HDAC inhibitor. HDAC inhibitors have been shown to have multiple effects in tumor cell lines: decreased oncoprotein expression (eg, Bcr-Abl, HER-2), inhibition of angiogenesis, induction of apoptosis, induction of cell cycle arrest, and decreased tumor cell motility. Preclinically, LBH589 has also been seen to overcome resistance to kinase inhibition in tumor cell lines.

Micro-arrays: A DNA microarray (also commonly known as gene chip, DNA chip, or gene array) is a collection of microscopic DNA spots attached to a solid surface, such as glass, plastic or silicon chip forming an array for the purpose of expression profiling, monitoring expression levels for thousands of genes simultaneously.

Mutaganize(d): To deliberately induce mutations. This is sometimes done in the form of a screen that is intended to predict mutations that might develop over time.

Paraffin Block: A sample of tissue that has been fixed in formalin, processed to remove water, then infused with molten paraffin, which is allowed to harden within and around the tissue in a square mold. This is the standard method of preparing tissue for clinical histologic analysis.

PDGFRA: Platelet-derived growth factor receptor alpha: a protein closely related to KIT, which was recently (2003) found to be activated in some cases of GIST.

PDGFRB: Platelet-derived growth factor receptor beta: a protein important in angiogenesis. It is inhibited by many of the TK inhibitors that are being tried in GIST (Gleevec, Sutent, etc).

PI3K: PI3 Kinase is a very important signaling protein that is close to the start (top) of the KIT signaling pathway. A potential therapeutic target in GIST.

Plasma: Blood plasma is the liquid component of blood, in which the blood cells are suspended. Plasma is the largest single component of blood, making up about 55% of total blood volume.

PTK activation profile: Shows whether other KIT-like proteins (KIT is one member of the family of protein tyrosine kinases = PTK) are activated in GIST cells, and might thereby be useful as targets of novel GIST therapies.

RAD001: A Novartis drug, RAD001 is in clinical trials for GIST. It is an inhibitor of the mTOR protein and is given in combination with Gleevec.

T670I: A KIT exon 14 mutation that is extremely resistant to Gleevec but is sensitive to Sutent. The T670I mutation affects the ATP/imatinib pocket of KIT, making it insensitive to the drug. This substitution is a homologue to the T315I mutation already reported in CML, where it is responsible for acquired resistance to imatinib.

V654A: The most commonly reported secondary mutation in GIST. This exon 13 mutation is resistant to Gleevec but sensitive to Sutent.

Wild-type GIST: GISTs with no detectable mutation in any of the commonly mutated exons in KIT (exon 9, 11, 13, 17) or PDGFRA (exon 12, 18).