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News from the 8th NIH Clinic for
Pediatric & Wildtype GIST

by Becky Bensenhaver


The 8th Pediatric and Wildtype GIST Clinic was held January 18th through 20th, 2012 at the National Institutes of Health in Bethesda, Maryland.  The Clinic, which is held every six months, is a collaborative effort between clinicians, research scientists and advocates who share the goal of helping pediatric and adult Wildtype Gastrointestinal Stromal Tumor (WT GIST) patients.  The Consortium for Pediatric and Wildtype GIST Research (CPGR), coordinated through the National Institutes of Health, was formed in 2008 to gather data and investigate what can be done to improve the outcome for WT GIST patients.  The photo shows the participants in the 8th Clinic.

GIST originates from the pacemaker cells that produce the slow mechanical muscle contractions responsible for moving food through the digestive tract. Most GIST tumors have a mutation in either the c-KIT or Platelet-Derived Growth Factor Receptor alpha (PDGFRA) gene.  GIST tumors bearing either KIT or PDGFRA mutations are referred to as being KIT-mutant or PDGFRA-mutant GIST, respectively.  85% of children with GIST, and a small subset of adults with GIST (10-15%) do not have a mutation of either the KIT or PDGFRA genes. These patients are described as having Wildtype (WT) GIST. The term wild type refers to the fact that there are not any known KIT or PDGFRA gene mutations present, likening them more to the phenotype found in the wild or the natural population. KIT-mutant and PDGFRA-mutant GIST patients frequently have a very good response to imatinib (Gleevec) leading to a nice reduction in tumor growth or actual tumor shrinkage.  Imatinib has been shown to be less effective with WT GIST. 

So what have we learned since 2008? 

Most GISTs are caused by KIT/PDGFRA mutations resulting in defects in growth factor receptors located on the cell surface; this makes the cell growth switch stay on all of the time.  These GIST cells have an activating oncogene that can be likened to having a stuck accelerator in a car. In contrast, WT GIST cells do not possess the defective KIT or PDGFRA activating oncogene. Instead, the causal mechanism behind tumor growth appears to a defect of the tumor suppressor gene Succinate Dehydrogenase (SDH). 

In WT GIST tumor cells the Succinate Dehydrogenase (SDH) protein is frequently nonfunctional.  Patients who have KIT/PDGFRA-mutated GIST do not have impaired SDH function.  When a stain for the "subunit B" part of this protein is applied to KIT/PDGFR-mutant tumor samples they turn brown, confirming the presence of Succinate Dehydrogenase B within the cells and normally functioning SDH. This is referred to as being SDH+ (SDH positive).  Conversely, WT GIST tumor samples frequently display a deficiency of the protein Succinate Dehydrogenase subunit B. These SDH- (SDH negative) staining tumors do not turn brown, indicating a nonfunctional SDH protein in the cells.  This biologic difference has led to speculation about treatment implications.  The SDH-negative WT GIST patients appear to be less likely to respond to drugs such as imatinib.  Some patients who are  SDH-negative have mutations of the SDH subunit genes, but others do not.

Unlike KIT or PDGFRA, the SDH protein is located inside the mitochondria of the cell. It is part of the machinery that converts food into ready-to-use energy, known as the "Krebs cycle" or "citric acid cycle" or "cellular respiration."  This is carried out through a sequential process that breaks down nutrients and transports them into the cells in order to extract the energy the cells need to grow and survive.  During the process, an enzyme called Succinate Dehydrogenase (SDH) converts the metabolic by-product Succinate into Fumarate, and Fumarate Hydratase converts Fumarate into Malate. The circle continues to spin around in order to liberate all the energy from the nutrients.  SDH-deficient patients are missing Succinate Dehydrogenase, resulting in an accumulation of Succinate during the energy conversion cycle.


Dr. Fernanda Arnaldez of NIH kindly provided this simplified illustration.

Meanwhile, while the cell is busy trying to get energy out of food, there are other things going on. Hypoxia-inducible factor (HIF) is normally a survival signal unleashed when cells are under low oxygen conditions (hypoxia).  A build-up of Succinate caused by defective SDH enzyme activity will cause an aberrant build-up of HIF, even under normal oxygen levels, a situation referred to as “pseudohypoxia”. Some of the downstream consequences of this include an accumulation of the growth factors VEGF and EGFR, leading to the oncogenic problem.

Dr. Fernanda Arnaldez of NIH kindly provided this simplified illustration.

How do we test this theory? 

Scientists typically use a cell line for the particular type of cancer in question in order to test treatment hypotheses.  Cell lines are cancer cells that are growing in the lab.  Experiments can be conducted with them by exposing the cells to different reagents and conclusions can be drawn.  Unfortunately, we do not have WT GIST cells lines available, although the scientists at NIH are working very hard to try to grow them.  An alternative approach is to use an animal model, but there are none for GIST from which to draw conclusions.  So the next available mechanism of scientific study involves the study of other types of tumors that behave in a similar way. There is a very specific type of kidney cancer where the protein that is absent is the next one down the energy transformation chain, Fumarate Hydratase (FH).  When this is absent, Fumarate accumulates.  As with Succinate, this build-up results in elevated HIF, VEGF, and EGFR, leading to proliferation of the cancerous tumors.  Blocking of VEGF and EGFR appears to result in a striking reduction in tumor growth and survival.  It is speculated that dual inhibition of the VEGF and EGFR proteins could likewise effectively inhibit growth of SDH-deficient GIST tumors. 

How would we test this hypothesis?

Last year the drug Vandetanib received FDA approval for the treatment of medullary thyroid carcinoma.  Vandetanib is an oral, dual inhibitor of VEGF and EGFR (as well as additional proteins that are important in other cancers). Pre-clinical data in the laboratory are encouraging, showing that SDH-deficient and FH-deficient cells stopped growing when exposed to the drug.  A Phase I clinical trial has already been conducted at the NIH administering Vandetanib to children with medullary thyroid carcinoma, helping the process of designing a safe and effective trial dedicated to GIST patients.  The side effects of Vandetanib included diarrhea, rash, nausea, high blood pressure, fatigue, and headache.  The NIH Pediatric Oncology Division is striving to open a Phase II clinical trial of Vandetanib in children and adults with WT GIST and decreased SDH expression.  It is hoped that this trial will be starting soon.   

You can watch a video of the lecture given by Dr. Fernanda Arnaldez to the 8th clinic participants at this NIH link:  The 8th NIH GIST Clinic Invitational Lecture
In this video Dr. Arnaldez discusses the proposed trial.

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