Establishment of Patient-Derived Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor Models for Predicting Therapeutic Response.

Purpose: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase () subunits (A-D) comprising less than 7.5% (i.e.

KIT Cells Mediate Imatinib Resistance in Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumor (GIST) is commonly driven by oncogenic mutations that are effectively targeted by imatinib (IM), a tyrosine kinase inhibitor (TKI). However, IM does not cure GIST, and adjuvant therapy only delays recurrence in high-risk tumors. We hypothesized that GIST contains cells with primary IM resistance that may represent a reservoir for disease persistence.

Location of Gastrointestinal Stromal Tumor (GIST) in the Stomach Predicts Tumor Mutation Profile and Drug Sensitivity.

Purpose: Gastrointestinal stromal tumors (GIST) commonly arise in different regions of the stomach and are driven by various mutations (most often in KIT, PDGFRA, and SDHx). We hypothesized that the anatomic location of gastric GIST is associated with unique genomic profiles and distinct driver mutations.

Experimental Design: We compared KIT versus non-KIT status with tumor location within the National Cancer Database (NCDB) for 2,418 patients with primary gastric GIST.

Cancer-associated fibroblast secretion of PDGFC promotes gastrointestinal stromal tumor growth and metastasis.

Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis.

TGF-β1-mediated transition of resident fibroblasts to cancer-associated fibroblasts promotes cancer metastasis in gastrointestinal stromal tumor.

Cancer-associated fibroblasts (CAFs) are the most abundant cells in the tumor microenvironment. Crosstalk between tumor cells and CAFs contributes to tumor survival in most epithelial cancers. Recently, utilizing gastrointestinal stromal tumor (GIST) as a model for sarcomas, we identified paracrine networks by which CAFs promote tumor progression and metastasis.

Cost-effectiveness Analysis of Genetic Testing and Tailored First-Line Therapy for Patients With Metastatic Gastrointestinal Stromal Tumors.

Importance: Gastrointestinal stromal tumor (GIST) is frequently driven by oncogenic KIT variations. Imatinib targeting of KIT marked a new era in GIST treatment and ushered in precision oncological treatment for all solid malignant neoplasms. However, studies on the molecular biological traits of GIST have found that tumors respond differentially to imatinib dosage based on the KIT exon with variation.

Anti-KIT DNA Aptamer for Targeted Labeling of Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumor (GIST), the most common sarcoma, is characterized by KIT protein overexpression, and tumors are frequently driven by oncogenic mutations. Targeted inhibition of KIT revolutionized GIST therapy and ushered in the era of precision medicine for the treatment of solid malignancies. Here, we present the first use of a KIT-specific DNA aptamer for targeted labeling of GIST.

Loss of the PTCH1 tumor suppressor defines a new subset of plexiform fibromyxoma.

Background: Plexiform fibromyxoma (PF) is a rare gastric tumor often confused with gastrointestinal stromal tumor. These so-called "benign" tumors often present with upper GI bleeding and gastric outlet obstruction. It was recently demonstrated that approximately one-third of PF have activation of the GLI1 oncogene, a transcription factor in the hedgehog (Hh) pathway, via a MALAT1-GLI1 fusion protein or GLI1 up-regulation.

MST1R kinase accelerates pancreatic cancer progression via effects on both epithelial cells and macrophages.

The MST1R (RON) kinase is overexpressed in >80% of human pancreatic cancers, but its role in pancreatic carcinogenesis is unknown. In this study, we examined the relevance of Mst1r kinase to Kras driven pancreatic carcinogenesis using genetically engineered mouse models. In the setting of mutant Kras, Mst1r overexpression increased acinar-ductal metaplasia (ADM), accelerated the progression of pancreatic intraepithelial neoplasia (PanIN), and resulted in the accumulation of (mannose receptor C type 1) MRC1+, (arginase 1) Arg+ macrophages in the tumor microenvironment.

Surgical Management of Adolescents and Young Adults With Gastrointestinal Stromal Tumors: A US Population-Based Analysis.

Importance: There is a dearth of population-based evidence regarding outcomes of the adolescent and young adult (AYA) population with gastrointestinal stromal tumors (GISTs).

Objectives: To describe a large cohort of AYA patients with GISTs and investigate the effect of surgery on GIST-specific survival (GSS) and overall survival (OS).

Design, Setting, And Participants: This retrospective cohort study of 392 AYA patients and 5373 older adult (OA) patients in the Surveillance, Epidemiology, and End Results (SEER) database with GISTs histologically diagnosed from January 1, 2001, through December 31, 2013, with follow-up through December 31, 2015, compared the baseline characteristics of AYA (13-39 years old) and OA (≥40 years old) patients and among AYA patients stratified by operative management.

Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic and Notch Pathway Mutations.

Purpose: GI stromal tumors (GISTs) are commonly associated with somatic mutations in and . However, a subset arises from mutations in , most commonly associated with neurofibromatosis type 1. We define the anatomic distribution of alterations in GIST.

FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors.

Background: 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.

Methods: We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations.

Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression.

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.

Population-Based Epidemiology and Mortality of Small Malignant Gastrointestinal Stromal Tumors in the USA.

Background And Aims: Gastrointestinal stromal tumors (GISTs) have significant variability in size and malignant behavior. Our current understanding is limited to pathological analyses, autopsy studies, and small case series. The aim of the current study is to define the risk factors, incidence, and mortality rates of GIST <2 cm in the National Cancer Institute's Surveillance, Epidemiology, and End Results database.

Increased risk of additional cancers among patients with gastrointestinal stromal tumors: A population-based study.

Background: Most gastrointestinal stromal tumors (GISTs) are considered nonhereditary or sporadic. However, single-institution studies suggest that GIST patients develop additional malignancies at increased frequencies. It was hypothesized that greater insight could be gained into possible associations between GISTs and other malignancies with a national cancer database inquiry.

Platelet-Derived Growth Factor Receptor-α Regulates Proliferation of Gastrointestinal Stromal Tumor Cells With Mutations in KIT by Stabilizing ETV1.

Background & Aims: In gastrointestinal muscles, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) is predominantly expressed by interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor-α (PDGFRA) polypeptide is expressed by so-called fibroblast-like cells. KIT and PDGFRA have been reported to be coexpressed in ICC precursors and gastrointestinal stromal tumors (GISTs), which originate from the ICC lineage. PDGFRA signaling has been proposed to stimulate growth of GISTs that express mutant KIT, but the effects and mechanisms of selective blockade of PDGFRA are unclear.

Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor.

Background: Gastrointestinal stromal tumor (GIST) is the most common sarcoma and its treatment with imatinib has served as the paradigm for developing targeted anti-cancer therapies. Despite this success, imatinib-resistance has emerged as a major problem and therefore, the clinical efficacy of other drugs has been investigated. Unfortunately, most clinical trials have failed to identify efficacious drugs despite promising in vitro data and pathological responses in subcutaneous xenografts.

The glypican 3 hepatocellular carcinoma marker regulates human hepatic stellate cells via Hedgehog signaling.

Background: Hepatocellular carcinoma (HCC) frequently represents two diseases as it often arises in the setting of cirrhosis caused by the proliferation and activation of hepatic stellate cells (HSCs). Previously, we identified that Hedgehog (Hh) signaling regulates HSC viability and fibrinogenesis, as well as HCC tumorigenesis. Although it is increasingly recognized that HSCs and HCCs communicate via paracrine signaling, Hh's role in this process is just emerging.

In vivo fluorescence imaging of gastrointestinal stromal tumors using fluorophore-conjugated anti-KIT antibody.

Background: Gastrointestinal stromal tumors (GISTs) are frequently characterized by KIT overexpression. Tumor-free margins and complete cytoreduction of disease are mainstays of treatment. We hypothesized that fluorescently labeled anti-KIT antibodies can label GIST in vivo.

Genetic variation in phosphodiesterase (PDE) 7B in chronic lymphocytic leukemia: overview of genetic variants of cyclic nucleotide PDEs in human disease.

Expression of cyclic adenosine monophosphate-specific phosphodiesterase 7B (PDE7B) mRNA is increased in patients with chronic lymphocytic leukemia (CLL), thus suggesting that variation may occur in the PDE7B gene in CLL. As genetic variation in other PDE family members has been shown to associate with numerous clinical disorders (reviewed in this manuscript), we sought to identify single-nucleotide polymorphisms (SNPs) in the PDE7B gene promoter and coding region of 93 control subjects and 154 CLL patients. We found that the PDE7B gene has a 5' non-coding region SNP -347C>T that occurs with similar frequency in CLL patients (1.

Endogenous epinephrine protects against obesity induced insulin resistance.

Epinephrine (E) is a hormone released from the adrenal medulla in response to low blood sugar and other stresses. E and related β2-adrenergic agonists are used to treat asthma, but a side effect is high blood sugar. C57BL/6 mice prone to overfeeding induced type II diabetes had the PNMT gene knocked out to prevent E synthesis.

Dopamine D1 receptor (DRD1) genetic polymorphism: pleiotropic effects on heritable renal traits.

Because dopamine D(1) receptors (DRD1) influence renal sodium transport and vascular hemodynamics, we examined whether genetic polymorphisms play a role in renal function. We conducted polymorphism discovery across the DRD1 open reading frame and its 5'-UTR and then performed association studies with estimated glomerular filtration rate (eGFR), plasma creatinine (pCr), and fractional excretion of uric acid (FeUA). We used a twin/family group of 428 subjects from 195 families and a replication cohort of 677 patients from the Kaiser health-care organization sampled from the lower percentiles of diastolic blood pressures.

Impact of GPCRs in clinical medicine: monogenic diseases, genetic variants and drug targets.

By virtue of their large number, widespread distribution and important roles in cell physiology and biochemistry, G-protein-coupled receptors (GPCR) play multiple important roles in clinical medicine. Here, we focus on 3 areas that subsume much of the recent work in this aspect of GPCR biology: (1) monogenic diseases of GPCR; (2) genetic variants of GPCR; and (3) clinically useful pharmacological agonists and antagonists of GPCR. Diseases involving mutations of GPCR are rare, occurring in <1/1000 people, but disorders in which antibodies are directed against GPCR are more common.

Genetic variation in G-protein-coupled receptors--consequences for G-protein-coupled receptors as drug targets.

G-protein-coupled receptors (GPCRs), including 'orphan' GPCRs whose natural ligands are unknown, comprise the largest membrane receptor superfamily and are the most commonly used therapeutic targets. GPCR genetic loci harbour numerous variants, such as DNA insertions or deletions and single nucleotide polymorphisms that alter GPCR expression and function, thereby contributing to inter-individual differences in disease susceptibility/progression and drug responses. In this article, the authors review examples of GPCR genetic variants that influence transcription, translation, receptor folding and expression on cell surface (by affecting receptor trafficking, dimerisation, desensitisation/downregulation), or perturb receptor function (by altering ligand binding, G-protein coupling and receptor constitutive activity).