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Molecular Tailored Therapeutic Options for Advanced Gastrointestinal Stromal Tumors (GISTs): Current Practice and Future Perspectives.

ABSTRACT: Gastrointestinal stromal tumors (GISTs) are one of the most common mesenchymal tumors characterized by different molecular alterations that lead to specific clinical presentations and behaviors. In the last twenty years, thanks to the discovery of these mutations, several new treatment options have emerged. This review provides an extensive overview of GISTs' molecular pathways and their respective tailored therapeutic strategies. Furthermore, current treatment strategies under investigation and future perspectives are analyzed and discussed.

SUBMITTER: Catalano F

PROVIDER: S-EPMC10093725 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Molecular Tailored Therapeutic Options for Advanced Gastrointestinal Stromal Tumors (GISTs): Current Practice and Future Perspectives.

Catalano Fabio F Cremante Malvina M Dalmasso Bruna B Pirrone Chiara C Lagodin D'Amato Agostina A Grassi Massimiliano M Comandini Danila D

Cancers 20230330 7

Gastrointestinal stromal tumors (GISTs) are one of the most common mesenchymal tumors characterized by different molecular alterations that lead to specific clinical presentations and behaviors. In the last twenty years, thanks to the discovery of these mutations, several new treatment options have emerged. This review provides an extensive overview of GISTs' molecular pathways and their respective tailored therapeutic strategies. Furthermore, current treatment strategies under investigation and ...[more]

PMID: 37046734

Similar Datasets

Adjuvant therapy with imatinib in gastrointestinal stromal tumors (GISTs)-review and perspectives.

Project description:Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal (GI) tract. Most of them (>75%) are driven by an oncogenic initiating event involving activating mutations of the genes encoding for tyrosine kinase, KIT or platelet derived growth factor receptor alpha (PDGFRA). Efficacy of the tyrosine kinase Inhibitor imatinib is now well established for advanced disease. For localized GISTs, 3 years treatment is the recommended adjuvant therapy for high risk patients. Whether a longer duration and selection of patients for this adjuvant therapy in localized GISTs remains is not yet established (PERSIST-5 study). Similarly, it will be important to further refine the definition of the population of GIST patients at high risk of relapse including molecular criteria (Annals of Oncology, ESMO guidelines 2018). This review aims to describe current knowledges on the issue of adjuvant therapy of primary GISTs in view of available results.

| S-EPMC6509420 | biostudies-literature

Revolutions in treatment options in gastrointestinal stromal tumours (GISTs): the latest updates

Project description:Opinion statementThe treatment of advanced GIST is rapidly evolving with the development of novel molecular compounds such as avapritinib and ripretinib, but also promising results have been achieved with cabozantinib in a phase II trial. The availability of over five lines of treatment for patients with advanced GIST is likely to completely shift the current second-line and third-line treatment options, and will also potentially enable a personalised approach to treatment. Imatinib will most likely remain as the first-line treatment of choice for the vast majority of GIST patients. However, for GIST patients with tumours harbouring a D842V mutation in PDGFRA exon 18, avapritinib has shown efficacy and will become first-line therapy for this molecular subgroup. For second- and third-line treatment, results are awaited of a number of clinical trials. However, second-line and further treatment could potentially be tailored depending on secondary mutations found in imatinib-resistant GISTs. As secondary resistance to TKIs remains the biggest challenge in the treatment of GIST and despite negative results with alternating regimens in phase II, combination treatments should be further evaluated to tackle this issue. Moreover, the favourable safety profiles observed with avapritinib and ripretinib suggest that combination treatments are feasible, for instance, combining two TKIs or a TKI with drugs targeting downstream signalling pathways, such as PI3K inhibitors or MEK inhibitors. Finally, in line with further personalisation of treatment in GIST, a multidisciplinary approach is essential, and local treatment options, such as RFA, resection in case of unifocal progression, and radiotherapy, should be considered.

| S-EPMC7253383 | biostudies-literature

Targeted Systemic Treatment of Neuroendocrine Tumors: Current Options and Future Perspectives.

Project description:Neuroendocrine tumors (NETs) originate from the neuroendocrine cell system in the bronchial and gastrointestinal tract and can produce hormones leading to distinct clinical syndromes. Systemic treatment of patients with unresectable NETs aims to control symptoms related to hormonal overproduction and tumor growth. In the last decades prognosis has improved as a result of increased detection of early stage disease and the introduction of somatostatin analogs (SSAs) as well as several new therapeutic options. SSAs are the first-line medical treatment of NETs and can control hormonal production and tumor growth. The development of next-generation multireceptor targeted and radiolabelled somatostatin analogs, as well as target-directed therapies (as second-line treatment options) further improve progression-free survival in NET patients. To date, however, a significant prolongation of overall survival with systemic treatment in NET has not been convincingly demonstrated. Several new medical options and treatment combinations will become available in the upcoming years, and although preliminary results of preclinical and clinical trials are encouraging, large, preferrably randomized clinical studies are required to provide definitive evidence of their effect on survival and symptom control.

| S-EPMC6338796 | biostudies-literature

Low frequency of TERT promoter mutations in gastrointestinal stromal tumors (GISTs).

Project description:Somatic mutations in the promoter region of telomerase reverse transcriptase (TERT) gene, mainly at positions c.-124 and c.-146 bp, are frequent in several human cancers; yet its presence in gastrointestinal stromal tumor (GIST) has not been reported to date. Herein, we searched for the presence and clinicopathological association of TERT promoter mutations in genomic DNA from 130 bona fide GISTs. We found TERT promoter mutations in 3.8% (5/130) of GISTs. The c.-124C>T mutation was the most common event, present in 2.3% (3/130), and the c.-146C>T mutation in 1.5% (2/130) of GISTs. No significant association was observed between TERT promoter mutation and patient's clinicopathological features. The present study establishes the low frequency (4%) of TERT promoter mutations in GISTs. Further studies are required to confirm our findings and to elucidate the hypothetical biological and clinical impact of TERT promoter mutation in GIST pathogenesis.

| S-EPMC4795049 | biostudies-literature

SPK1/S1P axis confers gastrointestinal stromal tumors (GISTs) resistance of imatinib.

Project description:BackgroundImatinib mesylate (IM) is highly effective in the treatment of gastrointestinal stromal tumors (GISTs). However, the most of GISTs patients develop secondary drug resistance after 1-3 years of IM treatment. The aim of this study was to explore the IM-resistance mechanism via the multi-scope combined with plasma concentration of IM, genetic polymorphisms and plasma sensitive metabolites.MethodsThis study included a total of 40 GISTs patients who had been regularly treated and not treated with IM. The plasma samples were divided into three experiments, containing therapeutic drug monitoring (TDM), OCT1 genetic polymorphisms and non-targeted metabolomics. According to the data of above three experiments, the IM-resistant cell line, GIST-T1/IMR cells, was constructed for verification the IM-resistance mechanism.ResultsThe results of non-targeted metabolomics analysis suggested that the sphingophospholipid metabolic pathway including the SPK1/S1P axis was inferred in IM-insensitive patients with GISTs. A GIST cell line (GIST-T1) was immediately induced as an IM resistance cell model (GIST-T1/IMR) and we found that blocking the signal pathway of SPK1/S1P in the GIST-T1/IMR could sensitize treatment of IM and reverse the IM-resistance.ConclusionsOur findings suggest that IM secondary resistance is associated with the elevation of S1P, and blockage the signaling pathway of SPK1/S1P warrants evaluation as a potential therapeutic strategy in IM-resistant GISTs. The design of this study from blood management, group information collection, IM plasma concentration with different elements, identification of sphingolipid metabolism and lastly verification the function of SPK1/S1P in the IM-resistance GISTs cells.

| S-EPMC9398498 | biostudies-literature

Gastrointestinal stromal tumors (GISTs): point mutations matter in management, a review.

Project description:The therapeutic implications of the genomic alterations seen within the drivers of gastrointestinal stromal tumors (GIST) are among the best understood in all of solid tumors. Sequencing of cKIT and PDGFRα should be considered standard practice for the treatment of GIST patients. In this article, we will review the common mutations and how they are utilized in clinical management. In addition, we will review the rare D842V PDGFRα mutation and the diverse molecular group that lacks a mutation in either cKIT or PDGFRα (wild-type GIST) which are best treated on clinical trial. Finally, we will look forward at the future therapies that are ever evolving for management of GIST. Taken together, the scientific advances in understanding the molecular basis of GIST validates the importance of knowing and understanding the mutations that are present in any one patient.

| S-EPMC5506287 | biostudies-literature

Treatment of Gastrointestinal Stromal Tumors (GISTs): A Focus on Younger Patients.

Project description:Gastrointestinal stromal tumors (GISTs) originate from Cajal's cells and are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs in young adults, i.e., patients before the age of 40, are rare and differ from those in older patients and GISTs in children in terms of the molecular and clinical features, including the location and type of mutations. They often harbor other molecular abnormalities than KIT and PDGFRA mutations (wild-type GISTs). The general principles of therapeutic management in young patients are the same as in the elderly. Considering some differences in molecular abnormalities, molecular testing should be the standard procedure to allow appropriate systemic therapy if needed. The optimal treatment strategy should be established by a multidisciplinary team experienced in sarcoma treatment. The impact of treatment on the quality of life and daily activities, including the impact on work, pregnancy, and fertility, in this patient population should be especially taken into consideration.

| S-EPMC9221273 | biostudies-literature

Nationwide evaluation of mutation-tailored treatment of gastrointestinal stromal tumors in daily clinical practice.

Project description:BackgroundMolecular analysis of KIT and PDGFRA is critical for tyrosine kinase inhibitor treatment selection of gastrointestinal stromal tumors (GISTs) and hence recommended by international guidelines. We performed a nationwide study into the application of predictive mutation testing in GIST patients and its impact on targeted treatment decisions in clinical practice.MethodsReal-world clinical and pathology information was obtained from GIST patients with initial diagnosis in 2017-2018 through database linkage between the Netherlands Cancer Registry and the nationwide Dutch Pathology Registry.ResultsPredictive mutation analysis was performed in 89% of the patients with high risk or metastatic disease. Molecular testing rates were higher for patients treated in expertise centers (96%) compared to non-expertise centers (75%, P < 0.01). Imatinib therapy was applied in 81% of the patients with high risk or metastatic disease without patient's refusal or adverse characteristics, e.g., comorbidities or resistance mutations. Mutation analysis that was performed in 97% of these imatinib-treated cases, did not guarantee mutation-tailored treatment: 2% of these patients had the PDGFRA p.D842V resistance mutation and 7% initiated imatinib therapy at the normal instead of high dose despite of having a KIT exon 9 mutation.ConclusionIn conclusion, nationwide real-world data show that over 81% of the eligible high risk or metastatic disease patients receive targeted therapy, which was tailored to the mutation status as recommended in guidelines in 88% of cases. Therefore, still 27% of these GIST patients misses out on mutation-tailored treatment. The reasons for suboptimal uptake of testing and treatment require further study.

| S-EPMC8338807 | biostudies-literature

Immunotherapy as a Therapeutic Strategy for Gastrointestinal Cancer-Current Treatment Options and Future Perspectives.

Project description:Gastrointestinal (GI) cancer constitutes a highly lethal entity among malignancies in the last decades and is still a major challenge for cancer therapeutic options. Despite the current combinational treatment strategies, including chemotherapy, surgery, radiotherapy, and targeted therapies, the survival rates remain notably low for patients with advanced disease. A better knowledge of the molecular mechanisms that influence tumor progression and the development of optimal therapeutic strategies for GI malignancies are urgently needed. Currently, the development and the assessment of the efficacy of immunotherapeutic agents in GI cancer are in the spotlight of several clinical trials. Thus, several new modalities and combinational treatments with other anti-neoplastic agents have been identified and evaluated for their efficiency in cancer management, including immune checkpoint inhibitors, adoptive cell transfer, chimeric antigen receptor (CAR)-T cell therapy, cancer vaccines, and/or combinations thereof. Understanding the interrelation among the tumor microenvironment, cancer progression, and immune resistance is pivotal for the optimal therapeutic management of all gastrointestinal solid tumors. This review will shed light on the recent advances and future directions of immunotherapy for malignant tumors of the GI system.

| S-EPMC9224428 | biostudies-literature

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

Project description: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).

| S-EPMC7825300 | biostudies-literature

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