It was just in the last century that Alexander Fleming accidentally discovered antibiotics, changing the world of medicine forever. Today, there are seemingly endless types of antibiotics for different diseases used for different durations. Antibiotics are so widely used across the globe today that scientists are worried about the growing threat of antibiotic resistance.
Antibiotics have meant faster recoveries, fewer complications, and safer surgeries. It is difficult to grasp the world of difference that antibiotics have made to our modern life; anyone living before the 20th century did not have access to antibiotics as we understand them today, meaning that even minor bacterial infections could result in death.
Wouldn’t it be fascinating if we could draw a scale of lives saved after the discovery of antibiotics vs lives lost before? We may never know what that would look like due to insufficient data, but there are newer drugs that allow us to evaluate their impact on prognosis before and after their introduction. In the treatment of gastrointestinal tumors (GISTs), one drug that has become incredibly vital is imatinib. Imatinib has been discovered only fairly recently, around two decades or so ago.
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Cavnar and colleagues analyzed 1000 GIST patients seen at the Memorial Sloan Kettering Cancer Center in New York City from July 1982 to April 2016, and were able to study the impact of imatinib on patients by contrasting them with patients treated in the pre-imatinib era. Their study lifts the veil on the incredible impact that a single treatment can make on a patient group.
Before vs After
In 1998, Hirota discovered the gain-of-function mutation in the KIT oncogene, rapidly increasing our understanding of the disease and fuelling the research that followed. Imatinib was a drug that was already in use for chronic myeloid leukemia. It functions as a small molecule tyrosine kinase inhibitor of KIT and PDGFR. Hirota’s discovery prompted scientists to quickly introduce that drug into clinical trials, and it was soon discovered to yield significant clinical benefits for GIST patients. As Cavnar et al put it, this led to the “modern paradigm for targeted therapy.”
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In their study on the impact of imatinib, the US research team classified patients into when they presented: primary tumor only (PRIM), primary with synchronous metastasis (PRIM+MET), or metachronous recurrence/metastasis (MET). Researchers discovered that regardless of when the patients presented, all showed longer overall survival (OS) in the imatinib era. The median OS was 13.6 years in PRIM, 5.3 years in PRIM+MET, and 4.0 years in MET.
Researchers also looked into which factors were significant in impacting recurrence-free survival (RFS). They discovered that in the pre-imatinib era, factors such as site (small bowel or rectal), high mitotic rate, and large size were independently associated with worse RFS. Fast forward to the imatinib era, only tumor size that was larger than 10cm was independently associated with worse RFS.
There were some limitations with this study. Some patients who were first treated in the pre-imatinib era were later started on imatinib when it became available; however, these patients were still analyzed with the pre-imatinib cohort. In other words, patients were grouped according to “intention to treat.” In addition, the study was purely retrospective in nature.
Despite these limitations, this study paints a vivid picture of the incredible impact of imatinib on prognosis. The researchers concluded “patients treated in the imatinib era had prolonged overall survival across all presentations” and said “imatinib should still be prescribed for patients with high-risk features.”
Overcoming Imatinib Resistance
Now that we have established the positive impact that imatinib has on the prognosis of GIST patients, we will turn our attention to the problem of resistance toward this medication. Boichuk and colleagues published a study detailing an approach to solving this problem.
Imatinib inhibits KIT-signaling in GISTs and induces significant changes in the cellular secretome, causing the release of a number of chemokines, including FGF-2. How does imatinib behave in imatinib-resistant GISTs? The research team wrote, “imatinib increased migration, invasion, and colony formation of imatinib-resistant GISTs in an FGF2-dependent manner.” In other words, imatinib promotes malignant behavior in imatinib-resistant GISTs.
Since FGF-2 is involved, researchers found out that the use of a selective FGFR inhibitor is able to abolish these effects, restoring sensitivity to imatinib both in vitro and in vivo. This means that FGFR inhibition may be useful in improving the long-term efficacy of imatinib in patients with GIST.
Read more about GIST etiology
Boichuk et al concluded that “the continuation of imatinib-based therapy for imatinib-resistant GISTs might have a negative impact and facilitate disease progression via the promotion of GIST malignant behavior in an FGF2-dependent manner”, thus “providing a rationale to evaluate the effectiveness of FGFR-inhibitors to improve the therapeutic strategies for imatinib-resistant GISTs.”
Drug Development: An Ongoing Task
This article shows that when the pathophysiology of a disease has been discovered, it allows for the research and development of new therapies that target specific pathways. New therapies can make a profound impact on prognosis, such as in the case of imatinib in GIST patients.
However, just when a drug becomes in use more prominently, the question of drug resistance immediately arises, meaning that research must continue in order to maintain the efficacy of that drug. This demonstrates that drug development is a task that is simultaneously arduous and ongoing, as well as deeply rewarding.
References
Cavnar MJ, Seier K, Curtin C, et al. Outcome of 1000 patients with gastrointestinal stromal tumor (GIST) treated by surgery in the pre- and post-imatinib eras. Ann Surg. Published online January 1, 2021. doi:10.1097/SLA.0000000000003277
Boichuk S, Galembikova A, Mikheeva E, et al. Inhibition of FGF2-mediated signaling in GIST—promising approach for overcoming resistance to imatinib. Cancers. Published online June 24, 2020. doi:10.3390/cancers12061674
