Biology

Pediatric GIST has been considered to be a subset of adult GIST. There are however, important differences between adult GIST and pediatric GIST. At a historic meeting at the 2004 Connective Tissue Oncology Society (CTOS), a working definitition was developed. Pediatric GIST is now described as GISTs having a first occurence in patients less than 18 years of age. We recently received a more detailed definition from Dr. Katherine Janeway (Dana-Farber Cancer Center). " Pediatric GIST is generally accepted to be a GIST diagnosed before the age of 18. Pediatric GIST has a number of unique clinical and biological features when compared to GISTs occurring in adult patients. The most prominent difference is the lack of KIT and PDGFRA mutations in most GISTs occurring in young patients-- these GISTs without mutations are often referred to as wildtype GIST.

Also, some pediatric patients with wildtype 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 wildtype GISTs. It is still unclear whether some or all wildtype GISTs occurring in adults will behave more similarly to pediatric wildtype GIST or to adult KIT or PDGFRA mutant GIST"

 Pediatic 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

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 tha 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.

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 thus are probably not 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 major driving force 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.

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 80 percent of GISTs and PDGFRA mutations are the driving force in another five to eight percent of GISTs. The other ten to 15 percent of GISTs without KIT or PDGFRA mutations are called wild-type GISTs.

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 (over expression). 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 both shown that IGF1R is also over expressed in pediatric GIST (another type of wildtype 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 wildtype 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.

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 wildtype GIST.