The GIST (gastrointestinal stromal tumor) field has done a nice job of determining that each GIST is not alike, said Lori Rink, PhD, thus breaking these tumors down into smaller subtypes.
Knowing the subtypes of GIST and the molecular information about the tumors can not only dictate treatment for patients, but has also acted as a paradigm for other solid tumors, Rink said.
In an interview with ‘Targeted Oncology’, Lori Rink, assistant professor, Molecular Therapeutics Program, Fox Chase Cancer Center, spoke about what oncologists have learned about GIST in the past 3 decades, the important role of imatinib mesylate (Gleevec) in treating the disease, and the personalized treatment approach on the horizon.
TARGETED ONCOLOGY: Since GIST was identified 30 years ago, what have we learned about the disease?
Rink: Over 30 years ago, GIST was distinguished from other sarcomas based on the discovery that these tumors not only comprise smooth muscle but also possess a neural component as well. There are about 5,000 of these diagnosed each year in the United States.
In 1998, several years after that initial discovery, which separated GISTs from other sarcomas, Hirota and colleagues identified gain-of-function mutations in a gene called KIT in GIST. We now know that approximately, ~80-85% of all GIST tumors harbor a mutation in KIT or in another gene named PDGFRA. These mutations have been shown to be the drivers of these tumors. This discovery paved the way for GIST to be the first solid tumor to be treated at the molecular level when the FDA approved imatinib for the treatment of unresectable/metastatic GIST. So GIST has served as a sort of paradigm for precision medicine in solid tumors.
It’s kind of been this step-wise progression of learning more and using that progression to improve on treatment.
TARGETED ONCOLOGY: How has the use of imatinib evolved and where do you see it going in the future?
Rink: Imatinib was originally designed for targeting the BCR-ABL translocation in patients with chronic myeloid leukemia, but fortunately, scientists figured out that not only does imatinib target that translocation, but it also had specificity for the mutations that I just described in KIT and PDGFRA.
In 2000, GIST was the first solid tumor to be targeted with a molecularly targeted agent, imatinib. This was at the very beginning of precision medicine. Imatinib targets the gain-of-function mutation in KIT, and also to some extent, in PDGFRA, so it works by shutting down that constitutive activation and stops the cells from growing.
The interesting thing about GIST is that these tumors are completely refractory to traditional chemotherapies and radiation, so prior to that discovery, unless the tumor could be surgically resected, there were really no other treatment options, so imatinib really revolutionized the therapy for these patients.
TARGETED ONCOLOGY: As other cancers are being broken down into smaller subtypes, what do you think they can learn from the sarcoma field?
Rink: The GIST field has really done a nice job of studying patient by patient and realizing that not all GISTs are the same. Many clinical studies have shown that the clinical benefit afforded by imatinib to patients is correlated with tumor mutation, so a really important clinical piece of information is knowing the mutational status of a patient’s tumor, which can actually dictate the specific treatment plans.
The most common mutation occuring in GIST is found in KIT exon 11, and these patients do really well on imatinib. There are reports of patients staying on imatinib for greater than 15 years with the tumor having disease stabilization. However, there are subtypes of GIST that don’t respond initially at all, whether they have a KIT or a PDGFR mutation that doesn’t allow for the drug to bind as well, or whether they’re lacking mutations in KIT and PDGFRA, and we have often called these wild-type (WT) GIST.
Knowing the subtype of GIST and mutational status of these tumors can not only dictate treatment in these patients but also has acted as a paradigm for other solid tumors, in appreciating the heterogeneity that can exist within tumor types.
TARGETED ONCOLOGY: What do you think are the biggest challenges in the GIST field that you would like to see tackled?
Rink: Imatinib revolutionized treatment for patients, but clinical resistance is an increasing problem, as in other cancer types. There are about 20% of patients with advanced disease who do not respond at all to imatinib, but then for the other 80% who respond really well upfront, many of them, within 2 years’ time, will become resistant to the drug, so this is an increasing problem.
There are 2 drugs approved for second- and third-line therapies in GIST, which are sunitinib (Sutent) and regorafenib (Stivarga). Unfortunately, these agents only provide disease stabilization measured in months, not years, so once patients have failed on imatinib, it is a problem.
TARGETED ONCOLOGY: Are there any recent studies or ongoing studies that you are excited about?
Rink: I am excited about two new approaches. First, I am excited for new studies which will examine more personalized therapies in the patients who never respond to imatinib. For instance, there is a group of PDGFRA tumors that are completely resistant to imatinib. There have been impressive preclinical and early clinical studies looking at crenolanib, a PDGFRA inhibitor. In addition, the new finding that WT GIST have defects in the succinate dehydrogenase (SDH) metabolic pathway has prompted the initiation of studies examining VEGF inhibitors.
This is a more personalized approach, whereas historically, every time someone was diagnosed with a GIST, they were treated with imatinb and we hoped that it would work. Learning about the molecular profile of these tumors, I think can now allow for a more personalized approach to treatment.
Second, I am interested in some of the trials which are looking at combining imatinib with a second inhibitor to delay or abrogate resistance. We have recently published a paper presenting impressive preclinical data showing that an up-front combination of imatinib and an AKT inihibitor can significantly increase time to resistance.
TARGETED ONCOLOGY: What other agents are making an impact in the GIST field?
Rink: More than 15 years after its approval, imatinib is still used quite successfully as the first-line therapy in many GIST patients. Sunitinib and regorafenib are second- and third-line agents. They work, but only in terms of months, so they don’t provide what imatinib does. I am hopeful that ongoing preclinical and clinical studies will provide novel agents or combinations of agents that will be successful in addressing the issue of clinical resistance to imatinib. There is research looking at immunotherapy as well as other targeted agents, most of which are still targeting KIT and PDGFRA. Because of what we know about the molecular pathways in GIST cells that are resistant to imatinib, combinations are being explored trying to trick the pathways that become active in resistance.
Published October 5, 2016