Treatment Of Metastatic Gastrointestinal Stromal Tumors Research Articles

Abstract 3925: Inhibition of oncogenic and drug-resistant PDGFRA and KIT alterations by DCC-2618

Abstract Introduction: Activating mutations and other genetic alterations in KIT and PDGFRA receptor tyrosine kinases have been identified in certain cancers and proliferative diseases, including most cases of gastrointestinal stromal tumors (GIST) and systemic mastocytosis, and small percentages of gliomas, lung cancer, and leukemias. The treatment of metastatic GIST has been transformed with KIT inhibitors, but heterogeneous drug-resistant mutations arise during therapy, with individual patients often having multiple KIT mutations in different tumor sites. PDGFRA variants in GIST and other cancers also have a significant unmet medical need. DCC-2618 is a kinase switch control inhibitor that potently inhibits the spectrum of exon 9, 11, 13, 14, 17 and 18 mutations in KIT and exons 12, 14 and 18 mutations in PDGFRA. DCC-2618 has been designed to bind as a type II kinase inhibitor that forces the mutant kinases, including strongly activated mutants such as D816V KIT and D842V PDGFRA, into inactive conformations. DCC-2618 has been observed to be potent in enzyme and cell-based assays, and has demonstrated consistent efficacy in xenograft models driven by PDGFRA and KIT alterations. Methods: DCC-2618, and an active human metabolite, DP-5439, were tested for inhibition of PDGFRA and KIT mutants using standard enzyme and binding assays, and a variety of cell-based assays. Levels of phosphorylated PDGFRA and KIT were determined by Western blot or ELISA. Proliferation was measured using the fluorescent dye resazurin. An x-ray crystal structure of an analog of DCC-2618 was determined at Emerald Biostructures. The H1703 PDGFRA-amplified lung cancer and GIST T1 mutant KIT xenograft models were performed at MI Bioresearch. A GIST PDX exon 17 mutant KIT xenograft model was run at Molecular Response. Results: DCC-2618 and the metabolite DP-5439 inhibited KIT and PDGFRA variants with nanomolar potency. In CHO cells transfected with KIT or PDGFRA variants, DCC-2618 was shown to inhibit the full spectrum of the clinically relevant primary and refractory drug-resistant mutations tested. DCC-2618 also inhibited phosphorylation of KIT or PDGFRA in cell lines with various drug-resistant KIT mutations or PDGFRA alterations. DCC-2618 was compared to the FDA-approved KIT inhibitors imatinib, sunitinib, regorafenib, and midostaurin, as well as other KIT and PDGFRA inhibitors. In vivo, treatment with DCC-2618 led to tumor regressions in KIT- and PDGFRA-driven xenograft models. Conclusions: DCC-2618 has been observed to be a potent inhibitor of KIT and PDGFRA alterations, including mutants, fusions, and amplifications. Based on this profile, DCC-2618 may have utility in the treatment of KIT and PDGFRA-driven cancers including GIST, systemic mastocytosis, and a subset of lung cancers, gliomas, and leukemias. DCC-2618 is currently in a Phase 1 clinical trial in KIT and PDGFRA driven cancers (ClinicalTrials.gov Identifier: NCT02571036). Citation Format: Bryan D. Smith, Michael D. Kaufman, Anu Gupta, Cynthia B. Leary, Wei-ping Lu, Stacie L. Bulfer, Gada Al-Ani, Jarnail Singh, Subha Vogeti, Michael C. Heinrich, Daniel L. Flynn. Inhibition of oncogenic and drug-resistant PDGFRA and KIT alterations by DCC-2618 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3925.

Multidisciplinary approach in diagnosis and treatment of gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GIST) constitute from 0.1% to 3% of all malignant neoplasms of the gastrointestinal tract. Immunohistochemistry plays a key role in the differential diagnosis of GIST and other mesenchymal tumors. The main immunohistochemical marker for GIST is the CD117 (c-Kit), which hyperexpression observed in 95% tumors. When planning treatment of GIST a multidisciplinary approach involving surgeon-oncologist, pathologist, oncologist and radiologist-chemotherapist is required. Surgical treatment remains the main method of treatment in the absence of dissemination of the disease. Tumor size, mitotic index, location of tumor and mutation status of tumor affect on the prognosis of disease progression. Imatinib is a small molecule inhibitor of tyrosine kinase c-Kit, PDGFR, Abl, Bcr-Abl and the main drug in treatment of metastatic GIST. Imatinib is applied in a dose of 400 mg/day, and allows to achieve a clinical improvement (partial response + stabilization) in 90% of patients. Using of imatinib in adjuvant therapy during first year after the operation significantly increases progression-free survival up to 98%. High-risk patients need adjuvant treatment with imatinib for 3 years after the operation according to the ESMO 2012 recommendations. Neoadjuvant therapy with imatinib leads to a reduction of the tumor mass, increase resectability and frequency of performing organ-preserving operations. In case of progression of GIST during therapy with imatinib the last dose may be doubled or a second-line treatment with sunitinib (tyrosine kinase inhibitor of VEGFR, PDGFR, KIT, Flt3) can be used. Sunitinib is applied in a dose of 50 mg/day for 4 weeks daily with an interval of 2 weeks. Treatment with sunitinib allowed to achieve clinical improvement in 24.2% of imatninib-resistant patients. It is necessary to take into account not only the size but also the density and structure of the tumor when performing radiological assessment of response of the tumor to therapy. Currently, the phase II clinical studies are conducted with the aim to investigate the new targeted therapies for the treatment of GIST.

Dystrophin deregulation is associated with tumor progression in KIT/PDGFRA mutant gastrointestinal stromal tumors.

BackgroundIntragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene have been recently described in gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS) and leiomyosarcoma (LMS). We evaluated the copy numbers and gene expression levels of DMD in our series of GIST patients who were already studied with wide genome assays, to investigate more fully a correlation between dystrophin status and disease annotations.FindingsOur study highlighted a recurrent intragenic deletion on chromosome X, involving the DMD gene that codes for human dystrophin in GIST patients. Of 29 KIT/PDGFRA mutant GIST samples, 9 (31%) showed deletions of the DMD gene, which were focal and intragenic in 8 cases, and involved loss of an entire chromosome in one case (GIST_188). DMD loss was seen in only 5 patients with metastasis, whereas 18 out of 20 patients with localized disease had wild-type DMD (P = 0.0004, Fisher exact test). None of the 6 KIT/PDGFRA WT GIST showed DMD alterations.ConclusionsOur study confirms the presence of DMD deletions only in KIT/PDGFRA mutant GIST and this event is almost associated with metastatic disease. These findings are, of course, quite preliminary but support development of potential therapeutic strategies that target and restore DMD function in the treatment of metastatic GIST.

Clinical Relevance of Pharmacogenetics in Gastrointestinal Stromal Tumor Treatment in the Era of Personalized Therapy

Gastrointestinal stromal tumor (GIST) is a well-recognized and now relatively well-understood mesenchymal tumor. Before the imatinib era, the treatment of metastatic GIST was frustrating owing to its refractoriness to conventional chemotherapy and radiotherapy. After a metastatic GIST patient was granted compassionate use of imatinib in 2000, the treatment of this disease has emerged as a model for the development of other molecularly targeted therapies. In this article the authors review how tumor genotypes, in particular KIT and PDGFRA mutational analysis, have been integrated in the optimal clinical management of GIST patients. The authors also discuss the potential practical relevance of pharmacogenetics, which, integrated with therapeutic drug monitoring, should receive greater consideration, with the aim of personalized therapy.

Treatment of recurrent or metastatic gastrointestinal stromal tumor: surgery or not

Currently, the treatment of recurrent or metastatic gastrointestinal stromal tumor(GIST) has become a tremendous challenge. Some international clinical trials revealed that imatinib might significantly improve the survival of patients with recurrent or metastatic GIST. Though the combination of surgery and imatinib has become an ideal treatment of metastatic GIST, there still exist some controversies regarding how to combine the two methods. Imatinib may influence the blood coagulation mechanism, therefore it is suggested that imatinib cessation should be performed a week before operation. Cytoreductive surgery has some clinical effects on recurrent or metastatic GIST, which can be combined with targeted therapy. Furthermore, the clinical trial for recurrent or metastatic GIST needs further evaluation.

Role for the Proapoptotic Factor BIM in Mediating Imatinib-induced Apoptosis in a c-KIT-dependent Gastrointestinal Stromal Tumor Cell Line

The c-KIT receptor tyrosine kinase is constitutively activated and oncogenic in the majority of gastrointestinal stromal tumors. The identification of selective inhibitors of c-KIT, such as imatinib, has provided a novel therapeutic approach in the treatment of this chemotherapy refractory tumor. However, despite the clinical importance of these findings and the potential it provides as a model system for understanding targeted therapy, this approach has not yielded curative outcomes in most patients, and the biochemical pathways connecting c-KIT inhibition to cell death are not completely understood. Here, we show that inhibition of c-KIT with imatinib in gastrointestinal stromal tumors (GISTs) triggered the up-regulation of the proapoptotic protein BIM via both transcriptional and post-translational mechanisms. The inhibition of c-KIT by imatinib increased levels of the dephosphorylated and deubiquitinated form of BIM as well as triggered the accumulation of the transcription factor FOXO3a on the BIM promoter to activate transcription of BIM mRNA. Furthermore, using RNA interference directed against BIM, we demonstrated that BIM knockdown attenuated the effects of imatinib, suggesting that BIM functionally contributes to imatinib-induced apoptosis in GIST. The identification and characterization of the pathways that mediate imatinib-induced cell death in GIST provide for a better understanding of targeted therapy and may facilitate the development of new therapeutic approaches to further exploit these pathways.

Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Despite clinicopathological differences, GISTs share oncogenic KIT or platelet-derived growth factor-alpha (PDGFRA) mutations. Imatinib, KIT and PDGFRA inhibitor, has been successfully used in the treatment of metastatic GISTs. There are primary KIT or PDGFRA mutations diagnosed before imatinib treatment, linked to GIST pathogenesis, and secondary mutations detected during treatment, causing drug resistance. KIT exon 11 mutations are the most common. Gastric GISTs with exon 11 deletions are more aggressive than those with substitutions. KIT exon 11 mutants respond well to imatinib. Less common KIT exon 9 Ala502_Tyr503dup mutants occur predominantly in intestinal GISTs and are less sensitive to imatinib. An Asp842Val substitution in exon 18 is the most common PDGFRA mutation. GISTs with such mutation are resistant to imatinib. PDGFRA mutations are associated with gastric GISTs, epithelioid morphology and a less malignant course of disease. GISTs in neurofibromatosis 1, Carney triad and paediatric tumours generally lack KIT and PDGFRA mutations. Secondary KIT mutations affect exons 13-17. GISTs with secondary mutations in exon 13 and 14 are sensitive to sunitinib, another tyrosine kinase inhibitor. KIT and PDGFRA genotyping is important for GIST diagnosis and assessment of sensitivity to tyrosine kinase inhibitors.

Surgical Interventions during STI 571 Treatment of Metastatic GIST: Experience in Six Patients

Gastrointestinal stromal tumours (GIST), previously classified as smooth muscle tumours, are the most common mesenchymal tumours of the digestive tract. Since the discovery of KIT (CD 117) expression, these tumours can be diagnosed confidently by pathology. Until recently, surgery was the only treatment available because these tumours were not sensitive to chemotherapy nor radiation therapy. In the long run most of these tumours recurred in the abdominal cavity or in the liver. Recently a new drug STI 573 (Glivec) showed very promising results in metastatic disease with response rates of about 65%. In six patients treated at our center, surgery was indicated during STI therapy because of subobstruction, skin necrosis, abdominal distention, bleeding.Surgery proved to be safe and efficient, allowing continuation of STI therapy in much better circumstances.

Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: A review

This paper reviews data on the prognosis of gastrointestinal stromal tumors (GISTs). These tumors are specific KIT-expressing and KIT-signaling–driven mesenchymal tumors, many of which have KIT-activating mutations. GISTs occur in the entire gastrointestinal (GI) tract and may also arise from the omentum, mesenteries, and retroperitoneum. They range from small benign tumors to sarcomas at all sites of occurrence. A KIT tyrosine kinase inhibitor, STI-571 (imatinib [Gleevec]; Novartis, Basel, Switzerland), has recently shown promise in the treatment of metastatic GISTs. Understanding the natural history of GIST before introduction of STI-571 will help assess the impact and position of this new treatment. The frequency of benign versus malignant GISTs varies between sites. Benign GISTs outnumber malignant GISTs in the stomach, whereas malignant GISTs are more common in the intestines. Tumors that have metastasized at presentation have a very poor prognosis. Traditionally, the 3 key prognostic factors have been mitotic rate, tumor size, and site. Tumors that are small (≤2 cm) and show mitotic activity not exceeding 5 mitoses per 50 high-power fields (HPFs) have an excellent prognosis, probably independent of site, although this has not been shown specifically for all sites. In the stomach, most epithelioid GISTs are benign, provided that mitotic counts do not exceed 5/50 HPFs. However, a small proportion of tumors apparently lacking mitotic activity do metastasize. Tumors with a mitotic rate >5/50 HPFs usually have a malignant behavior. The Ki67 index may help identify tumors with malignant potential, but large site-specific series are not yet available. Genetic markers, including DNA-copy number changes, telomerase activity, and KIT mutation status, may be useful in more accurately identifying tumors with malignant potential. HUM PATHOL 33:478-483. Copyright 2002, Elsevier Science (USA). All rights reserved.