Concept: Gastrointestinal stromal tumor
- Proceedings of the National Academy of Sciences of the United States of America
- Published over 7 years ago
Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract and arises from the interstitial cells of Cajal. It is characterized by expression of the receptor tyrosine kinase CD117 (KIT). In 70-80% of GIST cases, oncogenic mutations in KIT are present, leading to constitutive activation of the receptor, which drives the proliferation of these tumors. Treatment of GIST with imatinib, a small-molecule tyrosine kinase inhibitor, inhibits KIT-mediated signaling and initially results in disease control in 70-85% of patients with KIT-positive GIST. However, the vast majority of patients eventually develop resistance to imatinib treatment, leading to disease progression and posing a significant challenge in the clinical management of these tumors. Here, we show that an anti-KIT monoclonal antibody (mAb), SR1, is able to slow the growth of three human GIST cell lines in vitro. Importantly, these reductions in cell growth were equivalent between imatinib-resistant and imatinib-sensitive GIST cell lines. Treatment of GIST cell lines with SR1 reduces cell-surface KIT expression, suggesting that mAb-induced KIT down-regulation may be a mechanism by which SR1 inhibits GIST growth. Furthermore, we also show that SR1 treatment enhances phagocytosis of GIST cells by macrophages, indicating that treatment with SR1 may enhance immune cell-mediated tumor clearance. Finally, using two xenotransplantation models of imatinib-sensitive and imatinib-resistant GIST, we demonstrate that SR1 is able to strongly inhibit tumor growth in vivo. These results suggest that treatment with mAbs targeting KIT may represent an alternative, or complementary, approach for treating GIST.
Imatinib mesylate (Gleevec) inhibits Abl1, c-Kit, and related protein tyrosine kinases (PTKs) and serves as a therapeutic for chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib also has efficacy against various pathogens, including pathogenic mycobacteria, where it decreases bacterial load in mice, albeit at doses below those used for treating cancer. We report that imatinib at such low doses unexpectedly induces differentiation of hematopoietic stem cells and progenitors in the bone marrow, augments myelopoiesis but not lymphopoiesis, and increases numbers of myeloid cells in blood and spleen. Whereas progenitor differentiation relies on partial inhibition of c-Kit by imatinib, lineage commitment depends upon inhibition of other PTKs. Thus, imatinib mimics “emergency hematopoiesis,” a physiological innate immune response to infection. Increasing neutrophil numbers by adoptive transfer sufficed to reduce mycobacterial load, and imatinib reduced bacterial load of Franciscella spp., which do not utilize imatinib-sensitive PTKs for pathogenesis. Thus, potentiation of the immune response by imatinib at low doses may facilitate clearance of diverse microbial pathogens.
Gastrointestinal stromal tumors (GIST) arise within the interstitial cell of Cajal (ICC) lineage due to activating KIT/PDGFRA mutations. Both ICC and GIST possess primary cilia (PC), which coordinate PDGFRA and Hedgehog signaling, regulators of gastrointestinal mesenchymal development. Therefore, we hypothesized that Hedgehog signaling may be altered in human GIST and controls KIT expression. Quantitative RT-PCR, microarrays, and next generation sequencing were used to describe Hedgehog/PC-related genes in purified human ICC and GIST. Genetic and pharmacologic approaches were employed to investigate the effects of GLI manipulation on KIT expression and GIST cell viability. We report that Hedgehog pathway and PC components are expressed in ICC and GIST and subject to dysregulation during GIST oncogenesis, irrespective of KIT/PDGFRA mutation status. Using genomic profiling, 10.2% of 186 GIST studied had potentially deleterious genomic alterations in 5 Hedgehog-related genes analyzed, including in the PTCH1 tumor suppressor (1.6%). Expression of the predominantly repressive GLI isoform, GLI3, was inversely correlated with KIT mRNA levels in GIST cells and non-KIT/non-PDGFRA mutant GIST. Overexpression of the 83-kDa repressive form of GLI3 or small interfering RNA-mediated knockdown of the activating isoforms GLI1/2 reduced KIT mRNA. Treatment with GLI1/2 inhibitors, including arsenic trioxide, significantly increased GLI3 binding to the KIT promoter, decreased KIT expression, and reduced viability in imatinib-sensitive and imatinib-resistant GIST cells. These data offer new evidence that genes necessary for Hedgehog signaling and PC function in ICC are dysregulated in GIST. Hedgehog signaling activates KIT expression irrespective of mutation status, offering a novel approach to treat imatinib-resistant GIST.
BACKGROUND: Pigmented villonodular synovitis (PVNS) is a rare locally aggressive tumors. PVNS is characterized in most cases by a specific t(1;2) translocation, which fuses the colony stimulating factor-1 (CSF1) gene to the collagen type VIa3 (COL6A3) promoter thus leading through a paracrine effect to the attraction of non-neoplastic inflammatory cells expressing CSF1-receptor. Imatinib is a tirosin-kinase inhibitors (TKI) active against CSF1-receptor whose activity in naive PVNS was already described. We report on two PVNS patients who responded to imatinib after failure to nilotinib, another CSF1-receptor inhibitor. METHODS: Since August 2012, 2 patients with progressive, locally advanced PVNS resistant to nilotinib (Patient1: man, 34 years; Patient2: woman, 24 years) have been treated with second-line imatinib 400 mg/day. Both patients are evaluable for response. RESULTS: Both pts are still on treatment (7 and 4 months). Patient1 had a dimensional response by MRI after 2 months from starting imatinib, together with symptomatic improvement. In Patient2 a metabolic response was detected by [18F]fluorodeoxyglucose–positron emission tomography (PET) at 6 weeks coupled with tumor shrinkage by MRI, and symptomatic improvement CONCLUSIONS: Imatinib showed antitumor activity in 2 patients with nilotinib-resistant PVNS. This observation strengthen the idea that targeted agent with similar profile can give a different clinical result, as already described for gastrointestinal stromal tumor (GIST) patients treated with the same agents. Molecular studies are needed to clarify the biologic mechanism(s) underlying the response.
Guidelines for time-to-event endpoint definitions in sarcomas and gastro-intestinal stromal tumors (GIST) trials. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)
- Annals of oncology : official journal of the European Society for Medical Oncology / ESMO
- Published about 6 years ago
The use of potential surrogate endpoints for overall survival, such as disease-free-survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCT) in cancer. However, the definition of time-to-event (TTE) endpoints is rarely precise and lacks uniformity across trials. Endpoint definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE endpoints. We report guidelines for RCT in sarcomas and gastro-intestinal-stromal tumors (GIST).
Introduction: Gastrointestinal stromal tumors (GISTs) are abdominal sarcomas which are extremely refractory to chemotherapy treatment. The treatment of GISTs has been revolutionized by use of KIT/platelet-derived growth factor receptor-α (PDGFRA) kinase inhibitors. Unfortunately, most tumors develop resistance to front-line (imatinib) or second-line (sunitinib) therapy. Regorafenib, a KIT/PDGFRA/vascular endothelial growth factor receptor (VEGFR) oral kinase inhibitor, has been shown to improve progression-free survival in the third- or fourth-line setting. Areas covered: This review covers the preclinical and clinical studies of regorafenib for treatment of GIST. A literature search on regorafenib was carried out using the PubMed database up to October 2013. Expert opinion: Currently, imatinib and sunitinib represent the only proven first- and second-line therapies, respectively, for advanced GISTs. Based on the results of a Phase III study, regorafenib is now established as the only proven third-line therapy. Regorafenib activity in this setting is believed to be due to its activity against oncogenic forms of KIT/PDGFRA. Although side effects are common with this agent, they can be effectively managed with a combination of supportive care, dose interruptions/reductions. The toxicity profile is similar to other oral kinase inhibitors with anti-VEGFR activity. Regorafenib is mainly metabolized by CYP3A4, and concomitant use of strong inducers/inhibitors of this enzyme should be avoided.
After identification of activating mutations of the KIT gene in gastrointestinal stromal tumor (GIST)-the most common sarcomaof the gastrointestinal tract-a phase 2 study demonstrated efficacy of imatinib mesylate in patients with metastatic GIST harboring a KIT exon 11 mutation. Initial results of long-term follow-up have found a survival benefit in this subgroup of patients.
In the past decade, the addition of molecular diagnosis of mutations and use of tyrosine kinase inhibitors (TKIs), either as neoadjuvant/adjuvant therapy with surgery or as primary therapy in nonresectable gastrointestinal stromal tumors (GIST), has improved patient outcomes markedly. Additional therapeutics also are on the horizon. The goal of this review is to identify the current incidence, diagnostic modalities, and trends in personalizing the medical and operative management for patients with GIST. Medline, PubMed, and Google scholar were queried for recently published literature regarding new molecular mechanisms, targeted therapies, and clinical trials investigating the treatment of GIST. The objective of this review is to highlight the biomarkers under development, newly discovered mutations, and newer therapies targeting specific mutational phenotypes which are continually improving the outlook for patients with this disease.
About 10-15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies.
One of the most prominent characteristics of gastrointestinal stromal tumors (GISTs) is their unpredictable and variable behavior. GISTs are not classified as “benign” or “malignant” but are rather stratified by their associated clinical risk of malignancy as determined by tumor size, location, and number of mitoses identified during surgical histology. The difficulty in assessing the malignant potential and prognoses of GISTs as well as the increasing incidence of “incidental GISTs” presents challenges to gastroenterologists. Recently, endoscopic enucleation has been actively performed as both a diagnostic and therapeutic intervention for GISTs. Endoscopic enucleation has several advantages, including keeping the stomach intact after the removal of GISTs, a relatively short hospital stay, a conscious sedation procedure, relatively low cost, and fewer human resources required compared with surgery. However, a low complete resection rate and the risk of perforation could reduce the overall advantages of this procedure. Endoscopic full-thickness resection appears to achieve a very high R0 resection rate. However, this technique absolutely requires a very skilled operator. Moreover, there is a risk of peritoneal seeding due to large active perforation. Laparoscopy endoscopy collaborations have been applied for more stable and pathologically acceptable management. These collaborative procedures have produced excellent outcomes. Many procedures have been developed and attempted because they were technically possible. However, we should first consider the theoretical basis for each technique. Until the efficacy and safety of sole endoscopic access are proved, the laparoscopy endoscopy collaborative procedure appears to be an appropriate method for minimally destructive GIST surgery.