Gastrointestinal Stromal Tumors (GISTs): From Science to Targeted Therapy

2008 ◽  
Vol 23 (2) ◽  
pp. 96-110 ◽  
Author(s):  
R. Sarmiento ◽  
P. Bonginelli ◽  
F. Cacciamani ◽  
F. Salerno ◽  
G. Gasparini
Keyword(s):  
Targeted Therapy ◽  
Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitor ◽  
Mesenchymal Tumors ◽  
Treatment Scenario ◽  
Stromal Tumors ◽  
Imatinib Resistant ◽  
Review Reports ◽  
Molecular Patterns

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs represent a distinct category of tumors characterized by oncogenic mutations of the KIT receptor tyrosine kinase in a majority of patients. KIT is useful not only for the diagnosis but also for targeted therapy of this disease. Imatinib, a tyrosine kinase inhibitor, is widely used in advanced and metastatic GISTs. This agent revolutionized the treatment strategy of advanced disease and is being tested in the neoadjuvant and adjuvant settings with encouraging results. New therapeutic agents like sunitinib have now been approved, enriching the treatment scenario for imatinib-resistant GISTs. The present review reports on the peculiar characteristics of this disease through its biology and molecular patterns, focusing on the predictive value of KIT mutations and their correlation with clinical outcome as well as on the activity of and resistance to approved targeted drugs.

scholarly journals Gigantic GIST: A Case of the Largest Gastrointestinal Stromal Tumor Found to Date

2018 ◽  
Vol 2018 ◽  
pp. 1-5 ◽  
Author(s):  
Abdalla Mohamed ◽  
Youssef Botros ◽  
Paul Hanna ◽  
Sang Lee ◽  
Walid Baddoura ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumor ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Stromal Tumor ◽  
Definitive Treatment ◽  
Gastrointestinal Neoplasms ◽  
Mesenchymal Tumors ◽  
Stromal Tumors

Gastrointestinal stromal tumors are uncommon when compared to all gastrointestinal neoplasms but are the most common mesenchymal tumors of the gastrointestinal tract. The largest gastrointestinal stromal tumor ever recorded in literature weighed approximately 6.1 kg and measured 39 cm × 27 cm × 14 cm. About two-thirds of GISTs are malignant. The tumor size, mitotic rate, cellularity, and nuclear pleomorphism are the most important parameters when considering prognosis and recurrence. The definitive treatment for these tumors is resection. In the year 2000, the first patient was treated with the tyrosine kinase inhibitor imatinib and since then, gastrointestinal stromal tumors with high-risk features have been treated successfully with tyrosine kinase inhibitors. We present the largest gastrointestinal stromal tumor recorded in medical literature measuring 42.0 cm × 31.0 cm × 23.0 cm in maximum dimensions and weighing in at approximately 18.5 kg in a 65-year-old African-American male who presented with increased abdominal distention. The mass was successfully excised, and the patient was treated with imatinib without local or distant recurrence 1.5 years postoperatively.

scholarly journals Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

2021 ◽  
Vol 22 (2) ◽  
pp. 493
Author(s):  
Christos Vallilas ◽  
Panagiotis Sarantis ◽  
Anastasios Kyriazoglou ◽  
Evangelos Koustas ◽  
Stamatios Theocharis ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Cancer Therapeutics ◽  
Gastrointestinal Neoplasms ◽  
Mesenchymal Tumors ◽  
Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).

PLX9486 shows anti-tumor efficacy in patient-derived, tyrosine kinase inhibitor-resistant KIT-mutant xenograft models of gastrointestinal stromal tumors

2018 ◽  
Vol 19 (2) ◽  
pp. 201-210 ◽  
Author(s):  
Yemarshet K. Gebreyohannes ◽  
Elizabeth A. Burton ◽  
Agnieszka Wozniak ◽  
Bernice Matusow ◽  
Gaston Habets ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitor ◽  
Stromal Tumors ◽  
Xenograft Models

scholarly journals Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST)

Oncotarget ◽  
2014 ◽  
Vol 6 (4) ◽  
pp. 1954-1966 ◽  
Author(s):  
Daruka Mahadevan ◽  
Noah Theiss ◽  
Carla Morales ◽  
Amy E. Stejskal ◽  
Laurence S. Cooke ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumors ◽  
Combination Therapies ◽  
Stromal Tumors ◽  
Imatinib Resistant

scholarly journals The importance of molecular biology in development, prognosis, treatment and resistance to targeted therapy in gastrointestinal stromal tumors

2011 ◽  
pp. 69-79
Author(s):  
Alessandro Comandone ◽  
Elisa Berno ◽  
Simona Chiadò Cutin ◽  
Antonella Boglione
Keyword(s):  
Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Neoplastic Transformation ◽  
Response To Therapy ◽  
Mesenchymal Tumors ◽  
Kit Mutation ◽  
Stromal Tumors ◽  
Receive Treatment

Gastrointestinal stromal tumors (GISTs) are the commonest mesenchymal tumors of the gastroenteric tract, and are generally believed to originate from the neoplastic transformation of the interstitial cells of Cajal, the pacemaker structures of the stomach and intestine. Exon and genetic mutations (point/deletions) are fundamental for the development of GISTs: the constitutional characteristic of this neoplasm is the presence of the cell surface Kit receptor. Kit is the product of the proto-oncogene cKit, situated in chromosome 4. Ninety-eight percent of GISTs express mutated isoforms of Kit or of PDGFRA (Platelet growth factor receptor a). Kit mutation is the basic condition for autophosphorylation of tyrosine kinase residues in proteins. Autophosphorylation initiates pathogenetic processes in Cajal cells, toward a neoplastic transformation. Imatinib mesilate and, more recently, sunitinib are tyrosine kinase inhibitors, specific antagonists for Kit and PDGFRA, with good activity against GISTs. Most molecular and clinical data currently available concern imatinib. Exon mutations are strategic as prognostic and as predictive factors. In recent years, much evidence suggests that survival, response to therapy and resistance to imatinib are related to different mutations. In the near future, GIST patients will receive treatment differentiated by expressed Kit and PDGFRA mutations, thus truly individualized therapy.

scholarly journals Phase I Study of Rapid Alternation of Sunitinib and Regorafenib for the Treatment of Tyrosine Kinase Inhibitor Refractory Gastrointestinal Stromal Tumors

2019 ◽  
Vol 25 (24) ◽  
pp. 7287-7293 ◽  
Author(s):  
César Serrano ◽  
Alessandro Leal ◽  
Yanan Kuang ◽  
Jeffrey A. Morgan ◽  
Constance M. Barysauskas ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Phase I ◽  
Tyrosine Kinase Inhibitor ◽  
Gastrointestinal Stromal Tumors ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Stromal Tumors

The Efficacy of Imatinib in Unresectable/Metastatic Gastrointestinal Stromal Tumors

2009 ◽  
Vol 05 (01) ◽  
pp. 61
Author(s):  
Shreyaskumar R Patel ◽  
Patrick Wong ◽  
◽  
Keyword(s):  
Tyrosine Kinase ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitor ◽  
Initial Therapy ◽  
Stromal Tumors ◽  
Conventional Dose ◽  
Kit Receptor ◽  
Complete Surgical Resection ◽  
Impact On Treatment ◽  
Malignant Gists

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancy in the gastrointestinal tract. Their pathogenesis is largely based on gain-of-function mutations in the c-kitproto-oncogene, resulting in constitutive activation of the KIT receptor tyrosine kinase. Historically, there were limited options for the medical management of GIST, with tumor recurrence frequently observed following complete surgical resection of primary localized GIST and a grim prognosis for patients with unresectable or metastatic disease. However, the introduction of the tyrosine kinase inhibitor (TKI) imatinib mesylate has had a major impact on treatment outcomes for these patients with GIST. Imatinib is currently approved for the treatment of patients with KIT/CD117-positive unresectable and/or metastatic malignant GISTs. Initial therapy with the conventional 400mg/day dose is highly recommended in these patients, while a higher dose (800mg/day) has shown promise in patients who have KIT exon 9-mutant GIST and those who experience disease progression on the conventional dose. Neoadjuvant therapy has also been shown to be safe and beneficial as a palliative treatment.

scholarly journals Recurrent Gastrointestinal Stromal Tumors in the Imatinib Mesylate Era: Treatment Strategies for an Incurable Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Rebecca M. Platoff ◽  
William F. Morano ◽  
Luiz Marconcini ◽  
Nicholas DeLeo ◽  
Beth L. Mapow ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Imatinib Mesylate ◽  
Surgical Resection ◽  
Dose Escalation ◽  
Gastrointestinal Stromal Tumors ◽  
Kinase Inhibitor ◽  
Inhibitor Therapy ◽  
Stromal Tumors ◽  
Tyrosine Kinase Inhibitor Therapy

Introduction. Recurrence of gastrointestinal stromal tumors (GISTs) after surgical resection and imatinib mesylate (IM) adjuvant therapy poses a significant treatment challenge. We present the case of a patient who underwent surgical resection after recurrence and review the current literature regarding treatment. Case Presentation. A 58-year-old man with a large intra-abdominal jejunal GIST was treated with complete surgical resection followed by IM. The patient experienced disease recurrence 3.5 years later and underwent IM dose escalation and reresection. Conclusion. Current strategies to treat recurrent GIST include dose escalation, modifying adjuvant tyrosine kinase inhibitor therapy, and surgery. High-level evidence will be required to better define the combinatory roles of tyrosine kinase inhibitor therapy, guided by molecular profiling, and surgery in the management of recurrent GIST.

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