Biology

Pediatric-like GIST has been considered to be a subset of adult GIST. There are however, important differences between adult GIST and pediatric-like GIST. Adult forms of GIST seem to be caused by mutations in the KIT or PDGFRA genes. Pediatric GIST does not have these mutations; instead, they seem to have a defect in a protein called succinate dehydrogenase (SHD). Because of this, they behave much differently than adult GIST.

GISTs without mutations in either the KIT or PDGFRA genes are commonly called "wild-type GIST". Wild-type GIST is however, not a very precise term because there are different types of wild-type GIST. Some wild-type GISTs have mutations in known genes such as BRAF, KRAS and NRAS. These forms of wild-type GIST tend to occur in older adults and are not related to pediatric GIST even though they are often grouped together as wild-type GIST.

Some pediatric patients with pediatric-like GISTs have Carney Triad or Carney-Stratakis syndrome which increases the chance that a second type of tumor will be present. When GISTs found in patients younger than 18 have KIT and PDGFRA mutations, they will behave more similarly to typical adult GISTs, including responsiveness to Gleevec and Sutent, than to pediatric wild-type GISTs. It is still unclear whether some or all wild-type GISTs occurring in adults will behave more similarly to pediatric wild-type GIST or to adult KIT or PDGFRA mutant GIST.

Pediatric GIST is much more common in girls than in boys. It usually occurs between the ages of about 6 and 18, but a few cases of GISTs have occurred in younger patients (see neonatal GIST). Pediatric GIST typically occurs in the stomach (adult GIST can occur throughout the digestive tract). The table below describes the differences typically seen between adult GIST and pediatric GIST.

Typical differences between adult and pediatric GIST

Adult
Pediatric
Affects males slightly more than females
Affects females much more often than males
Can start anywhere in the GI tract (and elsewhere in the abdomen)
Usually starts in the stomach
Starts at a single tumor site

 

May present with multiple stomach tumors (not metasases). This is often described as "multifocal" or "multinodular"
Rarely metastasizes to the lymph nodes
Lymph node metastasis are more common
Faster growing; more aggressive
Slower growing; less aggressive
Tumor cells usually have a spindle shape
Tumor cells usually have an epetheloid shape (more rounded and similar to the shape of other, non-sarcoma cancers)
Has a high response rate to the current first-line drug treatment, Gleevec
Has an undefined; but generally believed to be lower, response rate to Gleevec.
Typically has mutations in either KIT or PDGFRA genes, very rare mutations in BRAF, NRAS or KRAS
Typically does not have KIT or PDGFRA mutations . There are exceptions to this however (especially in boys) and mutational testing is available (Patients diagnosed under age 18 have KIT or PDGFRA mutations 15% of the time).
No defects in SDH Has mutations (~40%*) or other defects in SDH protein.
Stains positive for SDHB

Stains negative for SDHB.

Some cases stain negative for SHDB and SDHA (those with SDHA mutations).

* The percentage of SDH mutations found in pediatric-like GIST has been increasing as technology allows for increased ability to find mutations, so this number may change over time. Mutations have been found in all four subunits of SDH. These include SDHA, SDHB, SDHC and SDHD.

Genes and protein expression DNA

The human genome has approximately 30,000 different genes. Each of these genes is contained within the DNA in each cell in the body. When genes are expressed, they tell the cell to manufacture specific types of proteins. Some of these proteins are used to communicate with other cells/genes. Cells use receptors (and other methods) to listen for the protein messages of other cells. These receptors are manufactured according to instructions provided by their respective gene within their own cell.

Oncogenes and tumor suppressor genes

The most important discovery ever made in basic cancer research is that cancer cells have mutations in specific genes, called "oncogenes" and "tumor suppressor genes". Harold Varmus and Michael Bishop discovered the first oncogene in 1976, and won the Nobel prize for the discovery. Many other oncogenes were discovered later, including "KIT".

Oncogenes are genes that are involved in promoting or regulating cell growth. When mutated, these are the genes that contribute to or cause cancer. A normally functioning (non-mutated) oncogene is called a "proto-oncogene". When mutated and involved in cancer it is called an "oncogene". The normal function of proto-oncogenes is the cell-signaling pathway, they tell cells what to do. It is through this pathway that cells receive the stimulus to either grow or to die.

Tumor suppressor genes are involved in inhibiting cell growth. Mutations that keep tumor suppressor genes from doing their job contribute to cancer. Oncogenes and tumor suppressor genes can be compared to a car. In cancer cells oncogenes act like a stuck gas pedal, and tumor suppressor genes act like broken brakes. A defective tumor suppresor gene(s) SDH appears to be the primary defect (possible cause) of the various forms of pediatric-like GIST. Because of this, it is increasingly being called SDH-deficient GIST.

KIT appears to be the dominant oncogene in GIST in adults. In fact, adult GIST seems to be a simple cancer in terms of its genetics. Activated KIT (or, in a few cases, a closely-related protein called PDGFR-alpha) is the primary cellular event that causes adult GIST. In pediatric GIST however, the KIT and PDGFRA genes appear to play a less important role than in adult GIST. These two genes are rarely mutated in pediatric GIST (and if they are, an argument could be made that they are not "pediatric GIST", but would be more closely related to adult GIST) and thus do not appear to be the primary driving force behind pediatric GIST. KIT has been shown to be activated in pediatric GIST however. This suggests that inhibiting KIT may still have benefit in pediatric GIST. See Activated KIT remains a target in wild-type and pediatric GIST

GISTs without mutations in either of the two genes commonly mutated in GIST typically respond poorly to Gleevec, the primary drug used to treat adult GIST. Andrew Godwin, Ph.D. of Fox Chase Cancer Center and other researchers appear to have found a protein, IGF1R,  that is overexpressed (too much protein) in these tumors. Dr. Godwin presented his findings at the 2008 American Society of Clinical Oncology (ASCO) meeting in Chicago on Saturday, May 31. In addition, Dr. Godwin’s work is scheduled to be published in the Proceedings of the National Academy of Sciences (PNAS) on June 1, 2008. Overexpression of IGF1R may be a consequence of SDH mutations. One way to think of this is that the SDH defect is the primary defect (the "cause") and overexpression of IGF1R may be a result of the SDH defect.

Effective targeted therapies such as Gleevec rely on blocking pathways that are critical to a specific cancer. Gleevec inhibits the aberrant signaling caused by KIT and PDGFRA gene mutations (although some mutations are resistant to Gleevec). KIT mutations are involved in about 75 percent of GISTs and PDGFRA mutations are the driving force in another eight to eleven percent of GISTs. The other ten to 15 percent of GISTs without KIT or PDGFRA mutations are called wild-type GISTs (there are severl different subtypes).

Mutations that alter a proteins shape and function are one cause of abnormal signaling in cancer cells, but they are not the only cause. Sometimes cancer cells have too much (or too little) of a protein (overexpression). Godwin and his colleagues at Fox Chase have found that wild-type GISTs have extra copies of the insulin-like growth factor 1 receptor (IGF1R) gene and they make too much of the IGF1R protein. Two groups; Cristina Antonescu, M.D., and colleagues of Memorial Sloan-Kettering Cancer Center and Godwin and colleagues have shown that IGF1R is also over expressed in pediatric GIST. Other groups, including Andrew Wagner and colleagues at Dana Farber Cancer Center have found that IGF1R overexpression seems to be limited to the pediatric-like version of wild-type GIST.

 

In an interview with Michael Smith of Medpage Today, Dr. Godwin said, "Our real excitement is that we think this might be the 'oncogenic driving force' behind wild-type GIST. We’re talking to companies right now about possible clinical trials."

Godwin's team tested an IGF1R inhibitor, NVP-AEW541 (Novartis) against Gleevec-sensitive and Gleevec-resistant GIST tumor cells and found that it induced a cytotoxic response as a single agent and a strong cytotoxic response in combination with Gleevec.

In an audio interview on the Medpage Today website, Godwin said that Fox Chase currently tests for KIT and PDGFRA mutations and is setting up assays to be used in the clinic to measure the level of IGF1R in GIST.

Although Godwin found that IGF1R was highly over expressed in wild-type GIST versus GISTs with mutations in KIT or PDGFRA, he did note in his ASCO presentation that IGR1R was, in general, activated in GISTs. C. Braconi and colleagues have shown that the IGF1 receptor (IGF1R) and two IGF growth factors (ligands), IGF1 and IGF2 can be over expressed in some GISTs and that higher levels of IGF1 and IGF2 correlated with shorter times to recurrence after resection of primary tumors. This raises the question of whether or not anti-IGF1R therapy might be useful in GISTs with KIT or PDGFRA mutations as well.

In a paper published in Clinical Cancer Research on May 15, 2008, Dr. Cristina Antonescu reaffirmed her earlier finding that IGF1R was over expressed in pediatric GIST providing additional support for anti-IGR1R therapy for wild-type and pediatric GIST. In addition, Dr. Antonescu tested several of the most popular KIT inhibitors against cells that were engineered to be dependent on wild-type KIT. In this screen of the five most popular KIT inhibitors, Gleevec was found to be the least effective at inhibiting wild-type KIT (see Table). Although the KIT gene is not mutated in wild-type GIST, the KIT protein is known to be strongly activated and to date has still been the primary target in wild-type GIST, including pediatric GIST. It remains to be seen whether therapy that targets both KIT and IGF1R will be needed to control wild-type GISTs or whether some other undiscovered protein will be important.

A phase II trial of an IGF1R inhibitor opened in 2012 for patients with pediatric-like GIST and adult wild-type GIST. Details of the trial and trial sites can be found at: http://clinicaltrials.gov/show/NCT01560260

Also see:

The role of IGF-1R in Pediatric Malignancies: full text article by Su Kim, Jeffrey Toretsky, Daniel Scher, Lee Helman

Potency of Approved KIT inhibitors against wild-type KIT

Approved Drug Name
(IND name, used in trials)
Generic Name
IC50
 
Tasigna (AMN107)
Nilotinib
35 nmol/L
Most potent
Sutent (SU11248)
Sunitinib
245 nmol/L
 
 
Sprycel (BMS-354825)
Dasatinib
316 nmol/L
Nexavar (BAY 43-9006)
Sorafenib
910 nmol/L
Gleevec (STI-571)
Imatinib
3,132 nmol/L
Least potent

NOTE: This table is based on in vitro data (lab experiments). This information should be considered to be preliminary. Response of patients to treatment may vary from this table.
IC50 is the concentration of drug required to inhibit cell proliferation by 50%. A higher number indications more drug was required to inhibit cell proliferation.

The new findings and the possibility of new clinical trials provide new hope for both children and adults with wild-type GIST.