Pediatric GIST Research Articles

Latest Advances in the Management of Pediatric Gastrointestinal Stromal Tumors.

Simple SummaryThough gastrointestinal stromal tumor is the most common mesenchymal neoplasm of the gastrointestinal tract, it is a rare entity among pediatric patients. It is usually characterized by a different molecular biology, histology and clinical course. Therefore, different handling of pediatric GIST is needed. Herein, we review the latest updates to the management of pediatric gastrointestinal tumors with a particular focus on the advances in molecular biology of the disease and emerging treatment with kinase inhibitors that could serve as targeted therapy.Gastrointestinal stromal tumor is the most common mesenchymal neoplasm of the gastrointestinal tract, usually found in elderly adults. It is infrequent among pediatric patients and usually differs biologically from adult-type diseases presenting mutations of KIT and PDGFR genes. In this population, more frequent is the wild-type GIST possessing SDH, TRK, RAS, NF1 mutations, among others. Both tumor types require individualized treatment with kinase inhibitors that are still being tested in the pediatric population due to the different neoplasm biology. We review the latest updates to the management of pediatric gastrointestinal tumors with a particular focus on the advances in molecular biology of the disease that enables the definition of possible resistance. Emerging treatment with kinase inhibitors that could serve as targeted therapy is discussed, especially with multikinase inhibitors of higher generation, the effectiveness of which has already been confirmed in the adult population.

Unusual Case of Multiple Synchronous Gastrointestinal Stromal Tumors of the Jejunum Presenting as an Arteriovenous Malformation

Abstract Introduction/Objective Gastrointestinal stromal tumor (GIST) arises from the interstitial cell of Cajal. 30% of GISTs arise in the jejunum. GISTS are generally solitary although multiple GISTs may be synchronous or metachronous. There are a few reports of a GIST of the jejunum mimicking a vascular malformation/arteriovenous malformation (AVM) prior to surgical excision. Methods Herein, we report a case of four synchronous GISTs of jejunum. One GIST, highly vascularized, presented with lower gastrointestinal bleeding. The patient was a 40-year-old female presenting with epigastric pain and melena. Results She was found to have an ulcerated lesion in the distal jejunum by capsule enteroscopy and double balloon enteroscopy, interpreted as an arteriovenous malformation and tattooed. Several other non-ulcerated “polyps” were described. Gross examination of the ensuing segmental resection of jejunum demonstrated four bosselated tumors ranging from 3.1 cm to 6.5 cm. Microscopically, three tumors did not extend to the surface of the jejunum and were predominantly composed of spindle cells. One tumor (identified by tattoo) extended to the surface with ulceration. This tumor was dominated by wide vascular channels with a spindle cell component between the channels. The four tumors were each positive for CD117, DOG1, and Succinate dehydrogenase B (SDH), identifying the four tumors as non-SDH-deficient GISTs. Ki-67 proliferation index was less than 5% in all four masses. Conclusion Multiple GISTs are rare, classified as either sporadic or familial. Familial GEISTs are described in neurofibromatosis type 1, Carney’s triad and Carney-Stratakis syndrome. Pediatric GISTs, with clinical and genetic features often differing from typical adult tumors may also be multiple. Our patient’s four GISTs are considered multiple synchronous sporadic neoplasms. This case serves as an important reminder for pathologists consider GIST in the evaluation of a highly vascular gastrointestinal proliferation and keep in mind the possibility of multiplicity.

Abstract ED01-01: Successes and failures of targeted drug development in adult and pediatric sarcomas

Abstract Development of molecularly targeted anticancer agents has seen major successes in the last 2 decades, also in Soft Tissue Sarcomas. But at the same time, many of those agents never made it beyond the stage of initial excitement. Moreover, the rare incidence of soft tissue sarcomas, and the even more rare incidence of its enormously high number of subtypes, frequently with subtype specific molecular aberrations in the malignancy, has led to different levels of evidence for success, if any. The development of Imatinib in c-KIT expressing GIST, does not only exemplify hallmarks of success, but also identifies some features of development failure. In Pediatric GIST for instance, Imatinib is basically ineffective. This was found to be due to the absence of KIT mutations in pediatric GIST, and the likely presence of different tumor growth drivers that are not sensitive to Imatinib. Taken together these features indicate that similar histologies do not necessarily express similar genetic changes in adult vs pediatric sarcomas, and indicate that it is essential to identify changes that represent true driving factors of tumor growth. And likely crucial to genetically analyse the tumor specimens of individual patients prior to treatment- and/or clinical trial selection. Apart from GIST, most of the other interesting suggestions of clinically successful specific targeting are yet based on fairly limited data. And thus, the level of evidence is much less than for Imatinib in adult GIST. These other subtypes and treatments include for instance Imatinib in PDGFR-beta mutant Dermatofibrosarcoma protruberans (DFSP), PLX3397 in colony-stimulating factor 1 (CSF1) expressing (1;2) translocated Tenosynovial Giant Cell Tumors (TGCT), Larotrectinib in TRK mutated Infantile Fibrosarcoma, Sirolimus in TSC1 or TSC2 mutated Perivascular Epitheloid Cell tumors (PEComa) and Crizotinb for ALK mutated Inflammatory Myofibroblastic Tumor (IMT). While the anti-VEGF monoclonal antibody Bevazicumab as a single agent hardly yielded effect in soft tissue sarcoma subsets such as angiosarcomas and hemangioendothelial sarcomas, the effect of multitargeted agents that a.o included VEGF as a target, has been proven effective in diseases such as non-subtype specific soft tissue Sarcomas (Pazopanib), GIST (Sunitinib, Regorafinib) Desmoid tumors (Sorafenib), and Alveolar Soft Part Sarcoma (Cediranib). Yet, given the inability to differentiate one target from the other, it is difficult to ascribe the successful trials to any of them. While for some drugs and targets (such as MDM2 and CDK4/6) the jury is still out, there is a large number of targets and targeted agents that failed the threshold. Among these are the mTOR inhibitors for other soft tissue sarcoma subtypes than PEComa, pPARgamma inhibitors for liposarcomas, EGFR inhibitors in synovial sarcomas, MET inhibitors in soft tissue sarcomas with specific amplifications and translocations, and again most recently the PDGFR-alpha monoclonal antibody Olaratumab. The failure to achieve clinical effect by inhibition of PDGFR will be discussed in somewhat more detail. In conclusion, to increase success rates and reduce failures, it seems important to closely analyze which preclinical biological factors can better predict clinical success and/or failure. Citation Format: Jaap Verweij. Successes and failures of targeted drug development in adult and pediatric sarcomas [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr ED01-01. doi:10.1158/1535-7163.TARG-19-ED01-01

Pediatric Female with Adult Type Small Intestine Gastrointestinal Stromal Tumor [GIST]: A case report

Background: Gastrointestinal stromal tumor [GIST] is commonest mesenchymal tumor, mainly affects adults. But, 1.5% to 2% GISTs were reported in pediatrics and adolescents. The treatment of GIST is managed as in adult because of lack of information about pediatric GIST. Aim of the work: Here we presented a case report of pediatric GIST. Current literature was reviewed and a summary was formulated to form a base for future optimal treatment of childhood GIST. Case summary: A 14 years Saudi female presented with vague abdominal pain and easy fatigability for 8 months. The pain located in lower abdomen, mild, waning, no aggravation or reliving factor and not radiating. Clinically, there was peri umbilical round, firm and not tender mass extending to right side of the abdomen till right hypochondrium, with no movement with respiratory movements. Investigations demonstrate severe microcytic hypochromic anemia. A computed tomography [CT] abdomen and pelvis showed evidence of soft tissue mass, about 13*11*12cm, of heterogeneous pattern and enhancement with area of hypodensity and cystic degeneration. There was necrosis of mesentery with some calcification seen inside the lesion suggestive of query GIST or Lymphoma. En block resection of the mass done with safety margin, biopsy from lymph node and side-to-side anastomosis done using linear stapler. The histopathological examination revealed ill and well defined fasicles of tumor cells that have spindle, oval and round shape nuclei invading mesentery and small bowel. Mitotic figurer 5-10/50 HPF, reactive lymph node. Immunohistochemistry showed diffused strong positive CD117 and CD34, negative S-100

Liver transplantation for metastatic pediatric GIST: first case of a two-stage surgical approach

Liver transplantation for metastatic pediatric GIST: first case of a two-stage surgical approach

Pediatric gastrointestinal stromal tumors—a review of diagnostic modalities

Gastrointestinal stromal tumors are exceedingly rare tumors in the pediatric population, as a result many clinicians either may never see this diagnosis or will encounter it only a few times throughout their careers. It is imperative in the pediatric population to follow appropriate steps to ensure a swift diagnosis and referral to specialized centers that are equipped with the multidisciplinary teams accustomed to treating rare diseases. This review aims to discuss the most recent data available on the diagnostic modalities utilized in cases of suspected Pediatric GIST.

Surgical Management of Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Pediatric and Wildtype GIST Clinic.

Purpose Wild-type gastrointestinal stromal tumors (WT-GISTs) that lack KIT or PDGFRA mutations represent a unique subtype of GIST that predominantly affects children. We sought to determine the effect on event-free survival (EFS) of staging variables, extent of resection, and repeat resection of tumors. Methods In 2008, a WT-GIST clinic was established at the National Cancer Institute, allowing the development of a large clinical database. We included participants who underwent resection of WT-GIST. Associations with EFS (ie, freedom from disease progression or recurrence) were evaluated using the Kaplan-Meier method and Cox proportional hazards modeling. Results Among 76 participants with WT-GISTs, the median follow-up was 4.1 years. Overall EFS (± SE) was 72.6 ± 5.4% at 1 year, 57.6 ± 6.2% at 2 years, 23.7 ± 6.0% at 5 years, and 16.3 ± 5.5% at 10 years postoperatively. Hazard of disease progression or recurrence was significantly increased for patients with metastatic disease (adjusted hazard ratio [AHR], 2.3; 95% CI, 1.0 to 5.1; P = .04) and > 5 mitoses per 50 high-power fields (AHR, 2.5; 95% CI, 1.1 to 6.0; P = .03), whereas there was no significant effect of negative microscopic resection margins (AHR, 0.9; 95% CI, 0.4 to 2.2; P = 0.86). There was no association between type of gastric resection (ie, anatomic v partial/wedge) and EFS ( P = .67). Repeated resection after the initial resection was significantly associated with decreasing postoperative EFS ( P < .01). Five patients (6%) died after initial enrollment in 2008. Conclusion WT-GIST is an indolent disease, and most patients survive with disease progression. We found no improvement in EFS with more extensive or serial resections. Disease progression or recurrence may be more closely related to tumor biology than surgical management. These data suggest that resections for WT-GISTs be restricted to the initial procedure and that subsequent resections be performed only to address symptoms such as obstruction or bleeding.

The Life Raft Group and establishment of the Virtual GIST Tumor Board in partnership with NIH.

e278 Background: In 2008, the National Institutes of Health (NIH) launched an in-person clinic for the Pediatric and Wild-type GIST community allowing clinicians and researchers from across the world to collaborate with each other and meet patients and their families firsthand. This led to several important breakthroughs, including investigating germline mutations in the succinate dehydrogenase complex (SDH), which helps physicians understand how wild-type GISTs are formed, and that Pediatric GIST can be diagnosed after age 18 and should thus be titled “SDH-deficient GIST.” Yet, decreases in government funding have reduced the number of in-person meetings to one per year. To supplement this loss of an in-person clinic, The Life Raft Group partnered with the NIH to launch the Virtual GIST Tumor Board. Methods: The process is an augmentation of how virtual tumor review boards work. If selected, doctors of GIST patients log on and review their de-identified patient case with a panel of experts using the internet, secure servers, and state-of-the-art video conferencing software. The LRG uses cutting-edge technology to connect the local treating physicians and their team with key opinion leaders in the field of Pediatric (SDH-deficient) GIST. Participants virtually access radiology films such as CT scans and other necessary medical reports to help review particular cases and provide advice. Results: The Virtual GIST Tumor Board has met twice, and reviewed cases from patients as far away as Latin America and the Ukraine. The physicians of these patients have elevated the level of care they provide due to the interaction with experts the Board makes possible. Conclusions: The purpose of the Pediatric GIST Virtual Tumor Board is to bring together leading experts to discuss pediatric/wild-type (SDH-deficient) GIST cases, and be an educational resource for physicians. It is transformative, because it provides valuable access for patients and doctors who would not be able to attend an in-person clinic due to resources or distance; educates doctors on the most up to date treatment options, trials, and studies; serves as a triage to bring patients to the in-person clinic; and encourages collaborative efforts of leading GIST experts around the world.

A Case of Pediatric Gastric GIST: A Study of the Surgical Approach and Therapeutic Strategy Based on Guidelines

A Case of Pediatric Gastric GIST: A Study of the Surgical Approach and Therapeutic Strategy Based on Guidelines

Laparoscopic resection of a rare gastrointestinal stromal tumor in children.

IntroductionGastrointestinal stromal tumors (GIST) are uncommon mesenchymal tumors of the gastrointestinal (GI) tract, accounting for 0.1% to 3% of all GI malignancies. Paediatric GIST have an annual incidence of 0.02 per million children, have a female predisposition, are usually located in the stomach (50–60%) and in up to 85% of cases CD117-cKit or PDGFRA mutation is absent, resulting in a decreased efficacy of the target therapy.Case descriptionWe report the case of an incidentally diagnosed gastric GIST in a 14-year-old boy with multiple malformations. Genetic tests and Kariotype resulted negative.Recently, an abdominal US visualized an hypoechoic heterogeneous abdominal mass. The common tumor markers resulted negative and the abdominal CT-scan confirmed the presence of a solid round lesion (42×36mm) in contact with the stomach and the pancreas. Laparoscopy allowed the recognition and the removal of the nodular mass at the posterior margin of the stomach. The histopathologic and the molecular biology findings were consistent with a kit-wilde type GIST. Surgical margins were microscopically free of tumor cells.These results justify the decision not to add other surgical or medical therapy. However, for high risk of recurrence and metastasis, a close follow-up was started.Discussion and evaluationGIST are asymptomatic in 10% to 30% of patients or present nonspecific symptoms and signs. These tumors present usually irregular, lobulated and ulcerated. CT-scan of the abdomen and pelvis or magnetic resonance imaging (MRI) are mandatory in the diagnostic work-up. The final diagnosis is based on histology and immunohistochemistry. Surgery is the first-line treatment in patients with localized disease.ConclusionGuidelines for the management of pediatric GIST are not presently available for the paucity of reports and data. However it is widely accepted that surgery is the first-line treatment and gross resection with negative microscopic margins can be considered therapeutic and lead to full remission of the pathology. Laparoscopy is a safe surgical approach for the exploration of the abdominal cavity, the evaluation of the disease and the complete removal of the tumor.

SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors

BackgroundA subset of KIT/PDGFRA wild-type gastrointestinal stromal tumors (WT GIST) have been associated with alteration of the succinate dehydrogenase (SDH) complex II function. A recent report identified four non-syndromic, KIT/PDGFRA WT GIST harboring compound heterozygous or homozygous mutations in SDHA encoding the main subunit of the SDH complex II.MethodsNext generation sequencing was applied on five pediatric and one young adult WT GIST, by whole exome capture and SOLiD 3-plus system sequencing. The putative mutations were first confirmed by Sanger sequencing and then screened on a larger panel of 11 pediatric and young adult WT GIST, including 5 in the context of Carney triad.ResultsA germline p.Arg31X nonsense SDHA mutation was identified in one of the six cases tested by SOLiD platform. An additional p.D38V missense mutation in SDHA exon 2 was identified by Sanger sequencing in the extended KIT/PDGFRA WT GIST patients cohort. Western blotting showed loss of SDHA expression in the two cases harboring SDHA mutations, while expression being retained in the other WT GIST tumors. Results were further confirmed by immunohistochemistry for both SDHA and SDHB, which showed a concurrent loss of expression of both proteins in SDHA-mutant lesions, while the remaining WT tumors showed only loss of SDHB expression.ConclusionsGermline and/or somatic aberrations of SDHA occur in a small subset of KIT/PDGFRA WT GISTs, outside the Carney’s triad and are associated with loss of both SDHA and SDHB protein expression. Mutations of the SDH complex II are more particularly associated with KIT/PDGFRA WT GIST occurring in young adults. Although pediatric GIST consistently display alterations of SDHB protein expression, further molecular studies are needed to identify the crucial genes involved in their tumorigenesis.

Pediatric Gastrointestinal Tumors

Gastrointestinal stromal tumors or GISTs belong to a category of gastrointestinal mesenchymal tumors that can have benign or malignant potential. These tumors were formerly identified as gastrointestinal (GI) leiomyomas, leiomyoblastomas, or leiomyosarcomas. GISTs account for approximately 80% of GI mesenchymal tumors and 3% of all childhood tumors. Pediatric GISTs occur in patients younger than 18 years and are extremely rare. In the United States, pediatric GISTs have been reported in the literature less than 100 times. In addition, much research has failed to distinguish between benign and malignant mesenchymal tumors. This makes it extremely difficult for medical professionals to develop any type of expertise because few see more than one or two of these cases in a career, and of those cases, many never differentiate between the two. This case study involves a young patient who had been diagnosed with pediatric GIST. This report details the initial sonographic findings and the follow-up studies that had initially suggested a pediatric GIST of malignant potential but, upon further outside consultation, suggested a benign pediatric GIST.

Special considerations in pediatric gastrointestinal tumors

Pediatric gastrointestinal tumors are rare in children but are being increasingly recognized. These tumors have distinct biologic and clinical feature that are different from those observed in adults. This review highlights the biological and clinical characteristics of pediatric GIST and provides diagnostic and therapeutic guidelines for the management these unique and challenging group of tumors.

Abstract 169: An investigation into the role of miRNAs in the pathogenesis of pediatric gastrointestinal stromal tumor

Abstract The pathogenesis of pediatric gastrointestinal stromal tumors [GISTs] is poorly understood. In adults, GISTs are characterized by activating mutations of tyrosine kinase III receptors KIT or PDGFRα while pediatric GISTs are KIT and PDGFRα wild-type (WT), yet downstream KIT signaling is similar in pediatric and adult tumors. Adult GISTs show genomic losses at 14q, 22q, 1p and 9p with disease progression, findings again absent in the pediatric setting and prompting our miRNA study. 29 adult mutant, 29 pediatric and 16 adult WT gastric GISTs formed the cohort. DNA extracted from tumor micro-dissected from paraffin sections was used for PCR amplification of KIT exons 9,11,13,17 and PDGFRα exons 12, 14 and 18 and the products examined by high resolution melt analysis. Products with aberrant melt curves were subjected to sequencing for definitive mutation status categorization. RNA was similarly extracted from micro-dissected tumor [RecoverAll™ Total Nucleic Acid Isolation Kit for FFPE, Ambion®]. MicroRNA profiling was conducted using Applied Biosystems TaqMan® Low-Density Arrays (TLDAs), investigating 667 targets for each sample and validation was with individual TaqMan® assays. From the heatmap generated from this data a cluster dendrogram is derived, whereby pediatric WT and adult mutant cases are clearly separated. The adult mutant group is further split by differential expression of miRNAs located on chromosome 14q32. This is not explained by simple genomic loss of 14q as analyzed by array comparative genomic hybridization (aCGH). The data were interrogated for miRNAs showing differential expression &amp;gt;5-fold and of statistical significance between the paired groups: 1) adult mutant versus pediatric WT, 2) adult WT versus pediatric WT 3) adult mutant versus adult WT, 4) KIT versus PDGFRα mutant and 5) high- versus low-risk adult mutant GISTs. Included in miRNAs fulfilling these criteria are many which target members of key biological pathways important in GIST. Indeed in comparisons 1) and 2) above, the number of predicted interactions between miRNAs and targets are significantly greater than expected (p-values&amp;lt;0.05), indicating a possible functional role for these miRNAs in the pathogenesis of pediatric GIST. The likely importance of miRNAs in regulating genes important in GIST biology is further substantiated by our finding of expression of miRNA/predicted target pairs in opposite directions, for example between adult mutant and pediatric WT cases, where IGF1R, BAALC and PLAG1 are over-expressed in the pediatric WT cases relative to adult mutant cases and in tandem, miRNA 139-5p and 455-5p, both predicted to target IGF1R, are relatively over-expressed in the adult cases, as are 365 and 455-5p, predicted to target BAALC and 193b predicted to target PLAG1. These findings suggest an important, as yet unrecognised, biological role for miRNAs in the development of pediatric GIST. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 169. doi:10.1158/1538-7445.AM2011-169

Gastrointestinal stromal tumors of the small intestine in pediatric populations: a case report and literature review

An 18-year-old girl presented with abdominal pain and a tumor was subsequently detected in the jejunum. We therefore carried out a wedge resection of the jejunum. The diagnosis of GIST was confirmed histologically, and a mutation in exon 9 of the c-kit gene was observed. GISTs are rare in pediatric populations and pediatric GISTs occur predominantly in females and are characterized by a multifocal gastric location and a wild-type phenotype for the c-kit genes. The features of pediatric GISTs of the small intestine have not yet been categorized, and to date, only 11 cases in patients younger than 18 years have been reported. These cases did not occur primarily in females and tended to present as single tumors with mutations in the c-kit gene. This suggests that these cases do not have the same features as pediatric gastric GISTs, but instead are similar to adult GISTs. In pediatric populations, GISTs of the small intestine were expected to show a better response to imatinib treatment than gastric GISTs because of the alterations in the c-kit gene.

The Gist of literature on pediatric GIST: review of clinical presentation

The Gist of literature on pediatric GIST: review of clinical presentation

Evaluation of the presence of IGF1R overexpression in wild-type and kinase mutant GI stromal tumors

10506 Background: Most adult GI stromal tumors have gain-of-function mutations in KIT (80%) or PDGFRA (5–7%). These pathogenetic mutations are the target for kinase inhibitor therapy. The pathogenesis of the 10–15% of GISTs lacking kinase mutations (WT GIST) is unknown; this includes most pediatric GISTs. Recently, Tarn et al. (PNAS 2008) identified IGF1R over-expression in all WT GIST in their series of cases, including one pediatric case. IGF1R may represent a novel therapeutic target for WT GISTs. Methods: We developed a quantitative RQ-PCR assay for IGF1R and GAPDH transcripts that is linear over 5 logs (R2 values of 0.99 and 0.98, respectively). We prepared cDNA from RNA isolated from 79 archival, formalin-fixed, paraffin-embedded GIST specimens and quantified IGF1R expression as the % ratio of IGF1R/GAPDH transcripts. We had previously genotyped the tumors to identify any kinase mutations. Results: Adult WT GIST had a 10–15 fold higher expression of IGF1R transcript than kinase mutant GISTs (WT GIST 13.7 ±18, n=35; KIT exon 11 mutant GIST 1.0 ± 1.1, n=26; PDGFRA mutant GIST 0.9 ± 1.0, n=8; KIT 9 or 13 mutation 0.8 ± 0.6, n=5). Interestingly, the WT GIST group could be further divided into tumors with low vs. high IGF1R expression. The low IGF1R expression group (mean 0.6, range 0.1–1.9, n=14), had similar IGF1R expression to kinase mutant GISTs. In contrast, the high expression group had more than 30-fold higher levels of IGF1R transcript (mean 22.5, range 7.3–76.5, n=21). We also examined IGF1R expression in 5 WT pediatric GISTs. The mean IGF1R expression in pediatric GISTs resembled that of the adult high expression group, with 4 of 5 cases showing IGF1R over-expression. Conclusions: WT GISTs are heterogeneous with regard to IGF1R expression and can be divided into two subgroups. One third of the WT GISTs overlap with kinase-mutant GISTs, while the remainder express IGF1R at more than 30-fold higher levels. These results have implications for evolving models of GIST pathogenesis and the clinical testing of IGF1R monoclonal antibodies for treatment of metastatic GIST. [Table: see text]

Insulin-like growth factor 1 receptor (IGF-1R): A potential therapeutic target for gastrointestinal stromal tumors (GIST)

10507 Background: Most GISTs possess a gain-of-function mutation in c-KIT or PDGFRα, which are targets of imatinib mesylate. However, wild type (WT) GIST and pediatric GIST lack mutations in either gene. These GISTs tend to be less responsive to imatinib-based therapies and have a poor prognosis. Overexpression of IGF-1R has been identified in many tumor types and inhibitors are currently being studied clinically. We identified amplification of IGF1R in a SNP analysis of GIST tumors and thus studied its potential as a therapeutic target in WT and mutant GIST. Methods: Expression of IGF-1R and downstream effectors in clinical GIST samples were examined using immunoblots and immunohistochemistry. Copy number changes of the IGF1R gene were examined by genomic qPCR and FISH. The role of IGF-1R in GIST signaling and viability were analyzed using NVP-AEW541 (Novartis, Basel, Switzerland), a specific inhibitor of IGF-1R, alone and in combination with imatinib, or via siRNA silencing of IGF1R. Results: IGF-1R was dramatically overexpressed and IGF1R amplification was detected at a significantly higher frequency in majority of WT GISTs and pediatric GIST when compared with mutant GISTs (P=0.000002 and P=0.0163, respectively). Inhibition of IGF-1R activity with NVP- AEW541 or down regulation of expression using siIGF1R led to cytotoxicity and induced apoptosis in both imatinib sensitive and resistant GIST cells via AKT and MAPK signaling. Combination of NVP-AEW541 and imatinib in GIST cell lines induced a strong cytotoxicity response. Conclusions: Our results reveal for the first time that the IGF1R gene is amplified and the protein is overexpressed in WT and pediatric GISTs. Our results demonstrate that the aberrant expression of IGF-1R may be associated with oncogenesis in a subset of GISTs that lack c-KIT or PDGFRα mutations and suggest an alternative or complementary therapeutic regimen in the clinical management of GIST, especially in tumors that respond less favorably to imatinib-based therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis, Pfizer, MedImmune, Human Genome Sciences, Johnson & Johnson, Transgenomic Inc. MolecularMD Novartis, Pfizer Novartis, Pfizer

Sunitinib treatment of pediatric metastatic GIST after failure of imatinib

9519 Background: The genotype of most GIST in pediatric patients (pts) is “wild type” (WT-GIST), with no detectable KIT or PDGFR-α mutations. Adults with metastatic WT-GIST often have suboptimal results and primary resistance to imatinib (IM) therapy. Treatment with sunitinib malate (SU11248), an oral, multitargeted tyrosine kinase inhibitor with antiangiogenic and antitumor activities, results in significant clinical benefit, such as improved survival, for adult pts with IM-resistant GIST, including WT-GIST. We report here the treatment of 3 pediatric pts with IM-resistant, metastatic GIST using sunitinib. Methods and Patients: Pt 1 presented at age 17 with numerous abdominal and hepatic GIST metastases. Following surgical debulking and 6 wks of IM treatment, objective progression was noted due to growth of omental masses and a new hepatic lesion. Pt 2 presented at age 8 with an isolated gastric GIST, fully resected, followed by adjuvant IM that continued until resection of a local recurrence 14 mos later. She had 2 more local recurrences and developed lung metastases. Pt 3 presented at age 13 with a large gastric GIST and a retroperitoneal metastasis, both fully resected and followed by adjuvant IM for 18 mos. Six mos after discontinuing IM, recurrent metastatic GIST was noted in the liver and retroperitoneum; IM therapy was resumed with stable disease for 1 yr when new hepatic lesions appeared with progression of the retroperitoneal mass. Pts 1 and 2 had WT-GIST, while genotyping of Pt 3 is pending. Sunitinib, obtained via an expanded-access protocol, was administered in 6-wk cycles, orally QD for 4 wks followed by 2 wks off dosing. Results: All pts have received 5 cycles of sunitinib. All GIST lesions have stabilized or decreased in size by CT imaging, with complete regression of 2 lung nodules in Pt 2. 18FDG-PET imaging obtained in 2 pts showed significant decreases in tumor-associated activity at all disease sites. Side effects with sunitinib have been manageable, including grade 2 GI and hematologic toxicities in pt 1, grade 3 fatigue in pt 2 and grade 3 hematologic toxicity in pt 3. Conclusions: Sunitinib shows important antitumor activity in pediatric pts with IM-resistant GIST. An expanded phase I/II trial of sunitinib in pediatric GIST is warranted. [Table: see text]