Gastrointestinal Stromal Tumors of the Small Intestine: Progress in Diagnosis and Treatment Research.
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ABSTRACT:
SUBMITTER: Peng F
PROVIDER: S-EPMC7261658 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
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Project description:Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and have gained considerable research and treatment interest, especially in the last two decades. GISTs are driven by mutations commonly found in the KIT gene and less commonly in the platelet-derived growth factor receptor alpha gene, BRAF gene and succinate dehydrogenase gene. GISTs behave in a spectrum of malignant potential, and both the tumor size and mitotic index are the most commonly used prognostic criteria. Whilst surgical resection can offer the best cure, targeted therapy in the form of tyrosine kinase inhibitors (TKIs) has revolutionized the management options. As the first-line TKI, imatinib offers treatment for advanced and metastatic GISTs, adjuvant therapy in high-risk GISTs and as a neoadjuvant agent to downsize large tumors prior to resection. The emergence of drug resistance has altered some treatment options, including prolonging the first-line TKI from 1 to 3 years, increasing the dose of TKI or switching to second-line TKI. Other newer TKIs, such as sunitinib and regorafenib, may offer some treatment options for imatinib-resistant GISTs. New molecular targeted therapies are being evaluated, such as inhibitors of BRAF, heat shock protein 90, glutamine and mitogen-activated protein kinase signaling, as well as inhibitors of apoptosis proteins antagonist and even immunotherapy. This editorial review summarizes the recent research trials and potential treatment targets that may influence our future patient-specific management of GISTs. The current guidelines in GIST management from Europe, North America and Asia are highlighted.
| S-EPMC5526756 | biostudies-literature
Project description:circular RNA (circRNA) is a closed ring structure formed by cyclic covalent bonds connecting the 5'-end and 3'-end of pre-mRNA. circRNA is widely distributed in eukaryotic cells. Recent studies have shown that circRNA is involved in the pathogenesis and development of multiple types of diseases, including tumors. circRNA is specifically expressed in tissues. And the stability of circRNA is higher than that of linear RNA, which can play biological roles through sponge adsorption of miRNA, interaction with RNA binding protein, regulation of gene transcription, the mRNA and protein translation brake, and translation of protein and peptides. These characteristics render circRNAs as biomarkers and therapeutic targets of tumors. Gastrointestinal tumors are common malignancies worldwide, which seriously threaten human health. In this review, we summarize the generation and biological characteristics of circRNA, molecular regulation mechanism and related effects of circRNA in gastrointestinal tumors.
| S-EPMC8082141 | biostudies-literature
Project description:Gastrointestinal stromal tumors (GIST) are rare mesenchymal smooth muscle sarcomas that can arise anywhere within the gastrointestinal tract. Sporadic mutations within the tyrosine kinase receptors of the interstitial cells of Cajal have been identified as the key molecular step in GIST carcinogenesis. Although many patients are asymptomatic, the most common associated symptoms include: abdominal pain, dyspepsia, gastric outlet obstruction, and anorexia. Rarely, GIST can perforate causing life-threatening hemoperitoneum. Most are ultimately diagnosed on cross-sectional imaging studies (i.e., computed tomography and/or magnetic resonance imaging in combination with upper endoscopy. Endoscopic ultrasonographic localization of these tumors within the smooth muscle layer and acquisition of neoplastic spindle cells harboring mutations in the c-KIT gene is pathognomonic. Curative treatment requires a complete gross resection of the tumor. Both open and minimally invasive operations have been shown to reduce recurrence rates and improve long-term survival. While there is considerable debate over whether GIST can be benign neoplasms, we believe that all GIST have malignant potential, but vary in their propensity to recur after resection and metastasize to distant organ sites. Prognostic factors include location, size (i.e., > 5 cm), grade (> 5-10 mitoses per 50 high power fields and specific mutational events that are still being defined. Adjuvant therapy with tyrosine kinase inhibitors, such as imatinib mesylate, has been shown to reduce the risk of recurrence after one year of therapy. Treatment of locally-advanced or borderline resectable gastric GIST with neoadjuvant imatinib has been shown to induce regression in a minority of patients and stabilization in the majority of cases. This treatment strategy potentially reduces the need for more extensive surgical resections and increases the number of patients eligible for curative therapy. The modern surgical treatment of gastric GIST combines the novel use of targeted therapy and aggressive minimally invasive surgical procedures to provide effective treatment for this lethal, but rare gastrointestinal malignancy.
| S-EPMC3520160 | biostudies-literature
Project description:Prior to the early 2000s, patients with advanced gastrointestinal stromal tumors (GIST) had very poor prognoses owing to a lack of effective therapies. The development of tyrosine kinase inhibitors at the turn of the century significantly improved the overall survival for patients with GIST. The resounding success of imatinib in the first clinical trial of a tyrosine kinase inhibitor to treat GIST led to its approval for first-line therapy for advanced GIST; this study was open to all comers and not restricted to any GIST subtype(s). The trials that led to the approvals of second-, third-, and fourth-line therapy for advanced GIST were also open to all patients with advanced/metastatic GIST. Only in retrospect do we realize the role that the molecular subtypes played in the results observed in these studies. In this review, we discuss the studies that led to the US Food and Drug Administration approval of imatinib (first line), sunitinib (second line), regorafenib (third line), and ripretinib (fourth line) for advanced KIT-mutant GIST. In addition, we review how information about GIST molecular subtypes has been used to accelerate the approval of other targeted therapies for non-KIT mutant GIST, leading to the approval of five additional drugs indicated for the treatment of specific GIST molecular subtypes. We also discuss how our understanding of the molecular subtypes will play a role in the next generation of therapeutic approaches for treating advanced GIST.
| S-EPMC10029090 | biostudies-literature
Project description:Constitutively activating mutations in the KIT and platelet-derived growth factor receptor ? (PDGFRA) RTKs play a crucial role in the biology of gastrointestinal stromal tumors (GISTs), and this disease has served as an effective model for targeting gain-of-function kinase mutations in cancer. Imatinib has entered the clinical arena in the last decade and substantially improved the outcome in these formerly untreatable cancers. However, most advanced GISTs responding to imatinib progress within 2-3 years due to heterogeneous subclones harboring a range of imatinib-resistant secondary KIT mutations. Sunitinib, and more recently, regorafenib, have obtained US Food and Drug Administration approval for the treatment of GISTs after imatinib failure, and thus expanded the treatment options in resistant disease. Within this framework, we present an evaluation of current GIST management, emphasizing the most recent advances in the field together with a discussion on future steps to be taken in refractory disease.
| S-EPMC3987653 | biostudies-literature
Project description:Although gastrointestinal stromal tumors (GISTs) are rare disease and rectal GISTs is only 5% of total GISTs, they have the worst prognosis. Due to narrow pelvis, tumor rupture or positive resection margin are common in the management of rectal GISTs. The impact of neoadjuvant treatment on the clinical outcomes of rectal gastrointestinal stromal tumors (GISTs) remains unclear. Thus, we conducted a retrospective study to investigate the impact of neoadjuvant imatinib on rectal GIST. The cohort comprised 33 patients; of them, 10 and 23 belonged to the neoadjuvant (i.e., those who underwent neoadjuvant imatinib treatment) and the control group (i.e., those who underwent surgery without prior imatinib treatment), respectively. Neoadjuvant group was associated with more common levator ani muscle displacement (P = 0.002), and showed significantly larger radiologic tumor size (P = 0.036) than the control group. The mean tumor size was significantly decreased after imatinib treatment (6.8 cm to 4.7cm, P = 0.006). There was no significant difference in resection margin involvement (P >0.999), and sphincter preservation rates (P = 0.627) between the two groups. No difference was observed with respect to morbidities, hospital stay, local recurrence and disease-free survival. Neoadjuvant imatinib treated group had similar propensity with control group after treatment. We thought reduced tumor sized could enhance resectability and provide more chance to preserve sphincter for rectal GIST patients. Considering large tumor size and higher rate of sphincter invasion in the neoadjuvant group, imatinib treatment could be helpful as a conversion strategy to make huge and low-lying rectal GIST operable and achieve better surgical outcomes.
| S-EPMC9462767 | biostudies-literature
Project description:Gastrointestinal stromal tumor (GIST) originates from interstitial cells of Cajal (ICCs) in the myenteric plexus of the gastrointestinal tract. Most GISTs arise due to mutations of KIT and PDGFRA gene activation, encoding the receptor tyrosine kinase (RTK). The clinical use of the RTK inhibitor imatinib has significantly improved the management of GIST patients; however, imatinib resistance remains a challenge. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a critical survival pathway for cell proliferation, apoptosis, autophagy and translation in neoplasms. Constitutive autophosphorylation of RTKs has an impact on the activation of the PI3K/AKT/mTOR pathway. In several preclinical and early-stage clinical trials PI3K/AKT/mTOR signaling inhibition has been considered as a promising targeted therapy strategy for GISTs. Various inhibitory drugs targeting different parts of the PI3K/AKT/mTOR pathway are currently being investigated in phase I and phase II clinical trials. This review highlights the progress for PI3K/AKT/mTOR-dependent mechanisms in GISTs, and explores the relationship between mTOR downstream signals, in particular, eukaryotic initiation factors (eIFs) and the development of GISTs, which may be instrumental for identifying novel therapeutic targets.
| S-EPMC7602170 | biostudies-literature
Project description:Various molecular triggers define heterogeneous subsets of gastrointestinal stromal tumors (GISTs), differing in clinical behavior and drug sensitivity. KIT/PDGFRA-wild-type GISTs, including those succinate dehydrogenase (SDH)-deficient, are overall unresponsive to the tyrosine kinase inhibitors commonly used, fostering the development of specific alternative therapeutic strategies. Epigenetic inactivation of O6-methylguanine-DNA methyltransferase (MGMT) through promoter methylation leads to effectiveness of alkylating agents in several human cancers. SDH-deficient GISTs typically feature widespread DNA methylation. However, the actual occurrence of MGMT methylation in these tumors, potentially predisposing them to respond to alkylating drugs, has not been investigated so far. Here we discuss the recent findings concerning the occurrence of MGMT methylation in different GIST subgroups, including SDH-deficient ones, as a premise for a possible reappraisal of alkylating agents specifically targeting these small, otherwise overall chemorefractory, GIST subgroups.
| S-EPMC6463228 | biostudies-literature
Project description:Gastrointestinal stromal tumors (GISTs) are the most common sarcoma of the gastrointestinal tract, with transformation typically driven by activating mutations of c-KIT and less commonly platelet-derived growth factor receptor alpha (PDGFRA). Successful targeting of c-KIT and PDGFRA with imatinib, a tyrosine kinase inhibitor (TKI), has had a major impact in advanced GIST and as an adjuvant and neoadjuvant treatment. If treatment with imatinib fails, further lines of TKI therapy have a role, but disease response is usually only measured in months, so strategies to maximize the benefit from imatinib are paramount. Here, we provide an overview of the structure and signaling of c-KIT coupled with a review of the clinical trials of imatinib in GIST. In doing so, we make recommendations about the duration of imatinib therapy and suggest how best to utilize imatinib in order to improve patient outcomes in the future.
| S-EPMC3735340 | biostudies-literature
Project description:Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and present predominantly in middle-aged and older individuals. Historically, the outlook for patients with GISTs was very poor because of the general lack of efficacy of conventional chemotherapy and the often limited surgical options. However, the recognition of the role of mutations of the v-kit Hardy/Zuckerman 4 feline sarcoma viral oncogene homolog KIT and the platelet derived growth factor receptor alpha gene PDGFR? in the development of GISTs led to the evaluation of potential antitumor effects of the tyrosine kinase inhibitors imatinib and, more recently, sunitinib. Consequently, these molecularly targeted therapies were introduced into clinical practice, and the outcome for patients with GISTs improved considerably. In the last few years, the European Society of Medical Oncology, the National Comprehensive Cancer Network, and the Canadian Advisory Committee on GIST each published a major set of guidelines or practice recommendations for the management of patients with GIST. In the current review, the latest recommendations from each organization are summarized in terms of diagnosis and risk assessment, tumor staging, surgical and/or drug treatment of primary resectable and recurrent metastatic disease, and patient follow-up and assessment. In addition, areas of consensus and points of divergence among the guidelines are highlighted along with any unresolved issues.
| S-EPMC4167025 | biostudies-other