Are we winning the war on gastrointestinal stromal tumour (GIST)?

Ping Chi, MD, PhD

The "War on Cancer" was established in 1971 at a time when combinations of newly discovered chemotherapies were, for the first time, curing rare types of cancers, such as childhood leukemia and testicular cancer. Despite the fact that most chemotherapeutic agents act nonspecifically through killing rapidly dividing cells, the prevailing optimism reasoned that with time, we can define combinations to cure all types of cancers. Yet, there were tumour types that do not respond to any conventional systemic chemotherapeutic agent, as exemplified by gastrointestinal stromal tumor (GIST), one of the most common subtypes of soft tissue sarcomas. Patients suffering from GISTs used to be subjected to toxic and ineffective systemic chemotherapy. It became clear that the "war" cannot be won without detailed understanding of the biology of each tumour type through collaborative research between basic scientists and clinicians. In this context, GIST became a poster child.

"The clinical success of imatinib in GIST has brought tremendous enthusiasm and promise for future success of targeted therapy in solid tumors, and maybe a glimpse of 'cure' for GIST."

GISTs have long been thought to derive from the interstitial cells of Cajal (ICCs), the pacemaker cells of the gastrointestinal tract. Despite the fact that ICCs were initially described by Santiago Ramon Cajal nearly a century ago, it wasn't until 1995, Huizinga and colleagues discovered that KIT, a receptor tyrosine kinase, was highly expressed in ICCs and was required for their normal development and lineage specification.1 In 1998, Hirota and colleagues discovered that GISTs harbor activating mutations of KIT and confirmed ICCs as the cell of origin for GIST. The work further established KIT as a "lineage-specific oncogene", first of a class of oncogenes which are critical for normal development of specific cell types, and when aberrantly activated, will result in oncogenic transformation.2 These landmark discoveries led to the clinical development of Imatinib (Gleevec®), a multitargeted tyrosine kinase inhibitor (TKI) that targets mutant KIT/PDGFRA/ABL, and changed our clinical practice forever. Imatinib is well tolerated, highly effective and significantly improves progression free survival and overall survival in patients with locally advanced and metastatic GISTs.3-6 Imatinib is truly a "targeted agent" having no activity in tumour types that were not driven by its targets. Based on these results, Gleevec received accelerated FDA approval for patients with KIT-positive unresectable and/or metastatic GIST in February, 2002, and full approval in September, 2008. The clinical success of imatinib in GIST has brought tremendous enthusiasm and promise for future success of targeted therapy in solid tumors, and maybe a glimpse of "cure" for GIST.

However, 12 years later, we have learned that despite the initial clinical success, the majority of advanced GIST patients develop resistance to imatinib within 2-3 years of treatment.4,6 Second and third line FDA approved systemic therapies, e.g. suitinib (Sutent®) and regorafenib (Stivarga®), have limited efficacy and durability of response.7,8 It is clear that once GIST patients develop imatinib resistance, a general disease resistance to this class of inhibitors develops and patients eventually succumb to their disease.

"...Once GIST patients develop imatinib resistance, a general disease resistance to this class of inhibitors develops and patients eventually succumb to their disease."

The mechanisms of imatinib resistance in GIST are complex and heterogeneous. About 10% of patients have primary resistance to imatinib with progression of disease within six months of therapy, e.g. wild-type GISTs that do not harbor KIT or PDGFRA activating mutation.9-12 Most patients develop secondary resistance after an initial benefit from imatinib. About 50-80% of these cases harbor secondary resistance mutations in KIT exons 13 and 14 that evade imatinib binding, or in exons17 and 18 that enhances KIT kinase activation.9-13 Many of the secondary resistant lesions are distinctly different amongst different patients or even different lesions in the same patient,13 making it impossible to effectively target all the lesions with salvage TKI monotherapy. What is more disturbing is the potential presence of pre-existing resistant subclonal populations even prior to the initiation of therapy as suggested by studies in many other cancer types,14-20 and of the Kit-low, intrinsically imatinib-resistant GIST stem/progenitor cells as suggested by studies of murine GIST tumors.21

Needless to say, we desperately need novel therapeutics and novel therapeutic strategies in GIST treatment. The heterogeneous mechanisms of secondary resistance that may exist within each individual patient suggest that no drug that targets a single resistance mechanism will likely have significant and durable benefit when given in the second or third line setting. We should consider intervening early, and it is critical to develop more effective front-line therapy. Nevertheless, a significant effort of developing better KIT/PDGFRA single agent inhibitors than imatinib in the front line clinical setting has not come to fruition.

Recently the transcription factor ETV1 was discovered as a second "lineage-specific oncogene" in GIST. Like KIT, ETV1 is required for ICC development and GIST tumor maintenance.22 If targeting the KIT/PDGFRA oncogene alone is not enough in advanced GIST, we should consider combination therapies that target both lineage dependencies in GIST. One might expect that such combination therapy may have the potential to be more effective than single agent imatinib and prevent the development of secondary imatinib resistance and also target the GIST stem/progenitor pool. However, these benefits may come at a price of more toxicity associated with the combination therapy.

"...the clinical benefits of immunotherapy are completely unknown in GISTs. I encourage primary oncologists and patients to keep these clinical trials in mind when thinking about treating newly diagnosed GIST patients."

Additionally, immunotherapy in other cancer types, such as melanoma, lung cancer, head and neck cancer and bladder cancer, have shown promising clinical benefits that can be durable.23,24 Yet, the clinical benefits of immunotherapy are completely unknown in GISTs. The challenge lies in the philosophy of risk and benefit assessment. In other words, how much potential and theoretical benefits is worth the potential added risks of novel therapeutics in clinical trials, especially when compared to imatinib front line therapy in GIST, a relatively well tolerated and effective regimen within the first 2-3 years? Some of the combination and immunotherapy clinical trials are already open and ongoing at Memorial Sloan-Kettering Cancer Center, Dana-Farber Cancer Institute and MD Anderson Cancer Center. I encourage primary oncologists and patients to keep these clinical trials in mind when thinking about treating newly diagnosed GIST patients. Although the treatment decisions may be easy at the initial diagnosis of GIST, they can become significantly harder as imatinib-resistance develops for the reasons discussed above.

Through bench-to-bedside research, we have won a major battle against GIST with the discovery of KIT-dependence and clinical development of imatinib therapy. Yet the war rages on. Are we winning or losing the war on GIST? In another 12 years, if we have not tried anything new, we are definitely not winning.

I thank Drs. William D. Tap (MSKCC) and Yu Chen (MSKCC) for their feedback and scientific input.

by Ping Chi, MD, PhD
Geoffrey Beene Junior Faculty Chair
Assistant Attending Physician in the Department of Medicine
Assistant Member of the Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center
Assistant Professor of the Department of Medicine at Weill Cornell Medical College


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