Wild-type GIST

Wild-type GIST is a diagnosis of exclusion. The typical defition of "wild-type GIST" is that a patient has had their tumor tissue tested (mutational testing) and it does not have a mutation in the KIT or PDGFRA gene.

The special case of Carney-Stratakis Syndrome also needs to be addressed. Although these patients have wild-type KIT and wild-type PDGFRA, they do have mutations in one of the succinate dehydrogenase genes. At the present time, these patients are still frequently grouped with others as wild-type GIST. Some other patients with either Carney's Triad or Pediatric GIST also appear to have mutations in one of the SDH subunits.

What does wild-type mean?

Wild-type is the term used for the typical form of a gene, or characteristic as it was first observed in nature (in the wild). When someone refers to “wild-type KIT”, it means that the KIT gene is “normal”; it has no detectable mutation.  Since it is somewhat clumsy to say that a GIST patient has wild-type KIT and wild-type PDGFRA, we often shorten this to say a person has “wild-type GIST”. It means that they don’t have a mutation in either of the two genes (KIT and PDGFRA) that typically play the dominant role in GIST.

Adult wild-type GIST versus Pediatric wild-type GIST

The large majority of pediatric GIST patients don't have mutations in KIT or PDGFRA or in the succinate dehydrogenase genes; they have "wild-type GIST". But adults, even older adults, also can have wild-type GIST. In a recent educational presentation, Dr. George Demetri commented on the difference noting that adult wild-type GIST seemed to be more aggressive than the pediatric version of wild-type GIST.

Dr. Cristina Antonescu has recently reported that a small subset of adult wild-type GIST may have mutations in another gene, BRAF.  In a series of 61 patients with wild-type GIST, they found that three of them (5%) had mutations in a gene called BRAF. This same mutation, a “V600E” mutation in exon 15 of the BRAF gene, occurs frequently in melanoma. They also found the same mutation in one of 28 GIST patients that were resistant to Gleevec.

Two major drug strategies for wild-type GIST

At this time the drug treatment strategies for adult and pediatric wild-type GIST would seem to be the same. The two basic strategies are to inhibit wild-type KIT signaling or to inhibit IGFR-1R signaling. It is unknown which of these strategies will play the more important role in wild-type GIST. There is clinical evidence that inhibiting KIT is beneficial but the evidence of benefit for IGFR-1R is based on test-tube results.

IGF1R in wild-type and pediatric GIST

GISTs without mutations in either of the two genes commonly mutated in GIST typically respond poorly to Gleevec. Andrew Godwin, Ph.D. of Fox Chase Cancer Center and other researchers may have one of the driving forces in these tumors. Dr. Godwin presented his findings at the 2008 American Society of Clinical Oncology (ASCO) meeting in Chicago on Saturday, May 31.

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 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 (overexpression). Godwin and his colleagues at Fox Chase have found that (some) wild-type GISTs have extra copies of the insulin-like growth factor 1 receptor (IGF1R) gene and they make way 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”). Andrew Wagner and colleagues at Dana Farber Cancer Center and other groups have shown that overexpression of IGF1R seems to be limited to the SDH-deficient GISTs (pediatric-like GISTs).

In 2012, a new clinical trial for an IGF1R inhibitor started. Details can be found at: http://clinicaltrials.gov/show/NCT01560260

Potential new signal pathway in wild-type GIST

Full text article: Insulin-line growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors-Tarn et al., 2008

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

KIT remains an important target

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.

See story about Dr. Katie Janeway's article,"Activated KIT remains a target in wild-type and pediatric GIST"

 

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 indicates more drug was required to inhibit cell proliferation.