SDH-deficient GISTs are rare but sometimes lethal tumors that can affect patients with paraganglioma syndromes. These tumors do not harbor the c-Kit or PDGF mutations typical of other GISTs and are therefore not amenable to typical GIST treatments with tyrosine kinase inhibitors. They can grow unpredictably, metastasize to lymph nodes and exhibit extensive local invasion. As with PGLs, there is currently no cure other than complete surgical excision, and there is a paucity of experimental models. The lifetime risk of developing SDH-deficient GIST in patients with SDHB mutation is still uncertain. However, the tumors accounted for ~3% of all GISTs and 5% of gastric GISTs in an unselected adult population.
We now have in our laboratory the first Patient Derived Xenograft (PDX) and cell culture model for basic and pre-clinical studies of SDH-deficient GIST. The model, which we have named the Ian GIST model, is derived from a gastric GIST that arose in a young man with a hereditary SDHB mutation and family history of multiple paragangliomas. Despite a remarkable multi-institutional translational research effort aimed at developing an effective treatment (“the Ian GIST Project”), the entire clinical course before the patient died was approximately 3 years. In addition to absence of SDHB protein expression and loss of SDH activity, the tumor was found to harbor a somatic KRAS G12D mutation, possibly contributing to its aggressive behavior.
It is generally believed that use of early passage PDX models for preclinical drug testing predicts clinical outcomes better than cell lines or grafts derived from cell lines. However, cell lines are needed for mechanistic research. Further, PDX models, like cell lines, are known to exhibit phenotype drift over multiple consecutive passages. In view of these concerns we have adopted a multi-tiered approach to this model, tracking morphology, transcriptomic and metabolomic profiles in consecutive in vivo passages and in transition to cell cultures. The pathology of the patient-derived xenografts is very similar to that of the patient’s surgically resected tumor except for somewhat increased proliferation in the fifth mouse passage. The tumor expresses GIST markers including c-Kit (also known as CD117, the receptor tyrosine kinase for stem cell growth factor) but is of an unusually high histologic grade compared to most GISTs. An important difference from primary paragangliomas and preliminary PDX models of paraganglioma is an extremely high proliferative fraction in the GIST, as assessed by Ki 67 labeling. This is consistent with the rapid clinical course and fatal outcome of the tumor, in contrast to the relatively slow growth and prolonged clinical course of many paragangliomas. This difference in proliferation between tumor types would likely result in greatly different responses to many types of cytotoxic drugs. At the same time, electron microscopy of the GIST cells shows extensive evidence of autophagy and mitochondrial stress, suggesting possible vulnerabilities to new types of drugs targeting those properties.
This GIST model is important for two reasons. First, it is a unique human-derived model for a specific type of tumor that occurs in patients with hereditary SDHB mutations. Although the basic metabolic defect in all SDH-deficient tumors is similar, different tumor types are likely to be affected by that defect in different ways because of intrinsic differences in their cells of origin. Second, because SDH-deficient GIST does have similarities to other SDH-deficient tumors, information gained from studying this model might also lead to increased understanding of and improved treatments for other tumor types.
This research was supported by the Pheo Para Alliance and the Paradifference Foundation