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Beyond Imatinib: Expert Explores Next Frontier in GIST

Shannon Connelly
Published: Thursday, Oct 06, 2016

Lori Rink, PhD

Lori Rink, PhD

Gastrointestinal stromal tumors (GIST) became one of the first solid tumors with an approved targeted therapy when imatinib (Gleevec) was approved in 2002 to treat patients with advanced or metastatic GIST.

Although tremendous strides have been made with imatinib, many patients with GIST develop resistance, and others have subtypes of GIST that do not respond to the drug.

In an interview with OncLive, Lori Rink, PhD, an assistant professor in the Molecular Therapeutics Program at Fox Chase Cancer Center, discussed the groundbreaking impact of imatinib in GIST, the heterogeneity of GIST and its impact on personalizing treatment, and emerging therapies in the field.

OncLive: 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 5000 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% to 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.

How has the use of imatinib evolved and where do you see it going in the future?

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 has 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.

As other cancers are being recategorized into smaller subtypes, what do you think can be learned from the sarcoma field?

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 occurring 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.

What do you think are the biggest challenges in the GIST field that you would like to see tackled?

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.

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