What Is Gastrointestinal Stromal Tumor?
A gastrointestinal stromal tumor is a type of cancer that originates in the digestive system. GISTs can occur in any part of the gastrointestinal tract but most commonly occur in the stomach and small intestine. GIST is cell growth that is thought to occur from a special type of nerve cell present in the walls of the digestive organs, which plays a key role in the movement of food through the body.
GIST became the first solid tumor used for tyrosine kinase inhibitor therapies when it was found that GIST was caused by a KIT (receptor tyrosine kinase) or PDGFRA (platelet-derived growth factor receptor α) mutation. These mutations lead to the activation of kinase proteins, which play an important role in cell division and growth.
The overactive kinase proteins present in the GISTs drive uncontrolled tumor growth. Recently, other molecular mechanisms for GIST pathogenesis have been found. These are associated with deficiencies in the succinate dehydrogenase complex, mutational activation of the BRAF oncogene, and NF1-gene alterations linked with neurofibromatosis 1 tumor syndrome.
If the GISTs are small, they may cause no symptoms. As a GIST grows, visible signs and symptoms can be noted. These tumors are often challenging to diagnose as their symptoms are not specific, which can include abdominal pain, bleeding, or a mass, and can mimic other gastrointestinal conditions.
Which Targeted Therapy Is Used for Gastrointestinal Stromal Tumors?
Targeted therapy is a kind of cancer treatment that targets specific proteins that control cancer cell’s growth and division. Certain drugs can target specific proteins in gastrointestinal stromal tumor (GIST) cells that help their division and growth. These targeted drugs are often very helpful in treating GISTs. The targeted drugs used in managing GIST are referred to as tyrosine kinase inhibitors (TKIs), as they target proteins that are tyrosine kinases, such as KIT and PDGFRA.
Imatinib Mesylate (Gleevec)
Imatinib was originally developed to treat chronic myeloid leukemia (CML) but it was found to be highly effective for the treatment of GISTs. This drug targets the mutated PDGFRA kinases and KIT in GISTs, inhibiting their activity and restricting tumor growth.
Imatinib is the first-line treatment for metastatic, or high-risk GISTs. It significantly improved overall survival rates for GIST patients. However, some patients do not respond equally to Imatinib, and noted that few patients develop resistance over time, leading to additional therapies. Two mechanisms contribute to resistance:
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Secondary Mutations: Some GISTs develop secondary mutations in PDGFRA or KIT that alter the drug-binding site, making Imatinib less effective.
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Alternative Pathways: In some cases, GISTs activate other signaling pathways to promote cell survival and growth, making the inhibitory effects of Imatinib less effective.
In addition, Imatinib has some side effects that include muscle pain, mild stomach upset, diarrhea, and skin rashes. When the drug is taken with food, stomach upset will be reduced. Imatinib retains fluid, causing some swelling in the face or the ankles. Rarely, fluid builds up in the lungs or the abdomen, causing serious problems. Changes in heart function are also noted in some people.
What Are the Recent Advances in Targeted Therapies for Gastrointestinal Stromal Tumors?
Researchers have made advancements in targeted therapies to address the challenges of Imatinib resistance and provide effective treatment options for GIST patients. Some of the notable developments include:
Sunitinib (Sutent)
Sunitinib was approved for treating Imatinib-resistant or intolerant GIST patients. It is a multi-kinase inhibitor targeting multiple receptors, including PDGFRA, KIT, and vascular endothelial growth factor receptors (VEGFRs). As Sunitinib has a broader target profile, it counteracts some forms of Imatinib resistance, making it a second-line treatment option. It acts by shrinking or slowing the tumor's growth, helping some people live longer.
Some common side effects of sunitinib include fatigue, nausea, mouth irritation, diarrhea, and skin and hair color changes. Serious side effects can include an increased risk of bleeding, swelling, heart problems, high blood pressure, and serious liver problems.
Regorafenib (Stivarga)
Regorafenib is approved as a third-line treatment for GIST patients who are resistant or have progressed on both Imatinib and Sunitinib. It is also a multi-kinase inhibitor that targets KIT, PDGFRA, VEGFRs, and other kinases. Regorafenib has demonstrated a survival benefit in patients with advanced GISTs by slowing tumor growth and even shrinking some tumors.
Side effects of Regorafenib include stomach pain, diarrhea, fatigue, mouth or throat irritation, loss of appetite, fever, and weight loss. Some serious side effects can include infections, high blood pressure, heart problems, delayed wound healing, serious bleeding, severe rashes, and holes forming in the wall of the stomach.
Ripretinib (Qinlock):
Ripretinib was approved for fourth-line treatment for GISTs. It is a selective KIT and PDGFRA kinase inhibitor that helps to address mutations resistant to other therapies and Imatinib. Ripretinib helps to slow down tumor growth and even shrink tumors, although it is unclear if it can help people live longer.
Side effects of Ripretinib include hair loss, loss of appetite, diarrhea or constipation, nausea and vomiting, feeling tired, and muscle or belly pain. Serious side effects can include an increased risk of new skin cancers, high blood pressure, heart problems, problems with redness, delayed wound healing, and even blistering of the palms of the hands and soles.
Avapritinib (Ayvakit): Avapritinib is a selective KIT and PDGFRA kinase inhibitor. This drug is specifically designed to target mutations less responsive to other therapies. Side effects of Avapritinib can include swelling or fluid retention, nausea and vomiting, hair color changes, loss of appetite, fatigue, diarrhea or constipation, increased tears in the eyes, stomach pain, rash, and dizziness. Some serious side effects may include bleeding in the brain, leading to forgetfulness, confusion, hallucinations, changes in mood or behavior, and trouble sleeping.
LOXO-101 (Larotrectinib): It was developed for tumors with NTRK gene fusions, but LOXO-101 has shown promise in some GIST patients with KIT mutations.
Conclusion
In the initial time, treatment for gastrointestinal stromal tumors included only surgery as other therapies were not effective. Targeted therapies have transformed the treatment for GIST. Imatinib was a groundbreaking discovery. However, it was not effective for all GIST patients. Subsequent targeted therapies like Sunitinib, Regorafenib, Ripretinib, and Avapritinib have improved the outlook for GIST patients.
