Gastrointestinal stromal tumors: Pathology and prognosis at different sites

Context.—Gastrointestinal stromal tumors (GISTs) are specific, generally Kit (CD117)-positive, mesenchymal tumors of the gastrointestinal tract encompassing a majority of tumors previously considered gastrointestinal smooth muscle tumors. They are believed to originate from interstitial cells of Cajal or related stem cells. Objective.—To review current clinicopathologically relevant information on GIST. Data Sources.—Literature in Medline and authors' own experience. Conclusions.—GISTs usually occur in older adults (median age 55–60 years) and rarely in children in the second decade (<1%) throughout the gastrointestinal tract: 60% in stomach, 35% in small intestine, and less than 5% in rectum, esophagus, omentum, and mesentery; most GISTs in the latter 2 sites are metastatic. Five percent of GISTs occur in patients with neurofibromatosis type 1 syndrome (multiple small intestinal tumors) and in Carney triad (gastric epithelioid GISTs in young females). Familial GISTs occur in patients with inheri...

Gastrointestinal Stromal Tumors: Review on Morphology, Molecular Pathology, Prognosis, and Differential Diagnosis

The standard of care for managing patients with gastrointestinal stromal tumors (GISTs) rapidly changed after the introduction of effective molecularly targeted therapies involving tyrosine kinase inhibitors (TKIs), such as imatinib mesylate and sunitinib malate. A better understanding of the molecular characteristics of GISTs have improved the diagnostic accuracy and led to the discovery of novel immunomarkers and new mechanisms of resistance to TKI therapy, which in turn have resulted in the development of novel treatment strategies. To address these issues, the NCCN organized a task force consisting of a multidisciplinary panel of experts in the fields of medical oncology, surgical oncology, molecular diagnostics, and pathology to discuss the recent advances, identify areas of future research, and recommend an optimal approach to care for patients with GIST at all stages of disease. The task force met for the first time in October 2003 and again in December 2006 and October 2009. This supplement describes the recent developments in the field of GIST as discussed at the October 2009 meeting.

/pdf/nccn-task-force-report-update-on-the-management-of-patients-3edyqoo5nu.pdf

NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors

The NCCN Soft Tissue Sarcoma Guidelines include a subsection about treatment recommendations for gastrointestinal stromal tumors (GISTs). The standard of practice rapidly changed after the introduction of effective molecularly targeted therapy (such as imatinib and sunitinib) for GIST. Because of these changes, NCCN organized a multidisciplinary panel composed of experts in the fields of medical oncology, molecular diagnostics, pathology, radiation oncology, and surgery to discuss the optimal approach for the care of patients with GIST at all stages of the disease. The GIST Task Force is composed of NCCN faculty and other key experts from the United States, Europe, and Australia. The Task Force met for the first time in October 2003 and again in December 2006 with the purpose of expanding on the existing NCCN guidelines for gastrointestinal sarcomas and identifying areas of future research to optimize our understanding and treatment of GIST.

/pdf/nccn-task-force-report-management-of-patients-with-44w8hvsfg1.pdf

NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines.

Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review.

Understanding local mediterranean diets: a multidisciplinary pharmacological and ethnobotanical approach


 Background CD39 expression is upregulated in the tumor microenvironment (TME), which is characterized by high levels of extracellular ATP (eATP) and low pH. CD39 catalyzes the rate-limiting degradation step of this immunostimulatory ATP, leading to a rise in immunosuppressive adenosine (ADO). CD39 displays broad expression on endothelial cells and macrophages, which represents a significant peripheral sink for CD39 targeting antibodies. Our strategy aims to circumvent this problem through delivery of pH-selective anti-CD39 blocking antibodies that will achieve a high target occupancy in the tumor, maintaining eATP and inhibiting ADO generation to enhance anti-tumor immunity.
 Methods Anti-CD39 antibodies were generated through a yeast-based screening platform and characterized for efficacy of blocking CD39 activity. Cell lines (HEK293 stably overexpressing CD39, parental HEK293, CD39+ SK-MEL28, and CD39high ARH77) or soluble CD39 protein were incubated with candidate antibodies. CD39 enzymatic activity was determined using CellTiter Glo 2.0 assay (Promega) and EnzCheck Phosphate Assay (Thermo Fisher).
 Results Monovalent affinity of 83 candidate antibodies was measured; KDs ranged from 1 × 10−9 - 5 × 10−7M under both physiological (pH 7.4) and acidic (pH 6.0) conditions. All 83 antibodies bound CD39-overexpressing HEK293 cells at pH 6.0; 76 bound CD39-overexpressing HEK293 cells at pH 7.4. We identified 30 antibodies (100 nM) that block CD39 activity on HEK293-CD39 cells (threshold: > 5% inhibition) under either pH 7.4 or pH 6.0 conditions. 26 antibodies inhibit CD39 activity at pH 7.4, whereas 22 antibodies block CD39 at pH 6.0. Among these 30 antibodies, ten (at 200 nM) inhibit CD39 activity on SK-MEL28 cells (moderate CD39 expression) at both pH 7.4 and pH 6.0; 5 of these preferentially inhibit CD39 at pH 6.0 (threshold: > 7.5% inhibition). The 30 antibodies selected above were tested on ARH77 cells (high CD39 expression). Among them, 16 antibodies inhibited CD39 enzymatic activity beyond 10% at pH 6.0 (maximal inhibition: 43%) and > 6.5% at pH 7.4 (maximal inhibition: 35%). All 16 suppressed soluble CD39 activity under both pH conditions. A set of 8 antibodies demonstrating higher efficacy of CD39 inhibition on both cell lines at pH 6.0 versus pH 7.4 were prioritized for lead optimization.
 Summary and conclusions A panel of 83 antibodies were identified and characterized for inhibition of CD39 enzymatic activity at neutral and acidic pH. The 8 most promising antibodies in terms of pH-selective CD39 binding and inhibition are currently undergoing lead optimization. This pH-dependent TME targeting strategy may alleviate undesirable properties of on-target/off-tumor binding such as target-mediated drug disposition (that results in suboptimal pharmacokinetic properties) and effectively bolster the specific blocking of CD39 in the local tumor environs.
 Citation Format: Aiping Bai, Elise Renahan, Kanam Malhotra, Thomas Thisted, F. Donelson Smith, Robert H Pierce, Edward H van der Horst. Identification of conditionally active antibodies that selectively block CD39 activity in the acidic tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4645.

Abstract 4645: Identification of conditionally active antibodies that selectively block CD39 activity in the acidic tumor microenvironment

KIT expression is a key diagnostic feature of gastrointestinal stromal tumors (GISTs), and virtually all of the GISTs express oncogenic forms of the KIT or PDGFRA receptor tyrosine kinase proteins, which serve as therapeutic targets of imatinib mesylate (Gleevec; Novartis, Basel, Switzerland) However, KIT expression can be low in PDGFRA-mutant GISTs, increasing the likelihood of misdiagnosis as other types of sarcoma We report that the signaling intermediate protein kinase C θ (PKCθ) is a diagnostic marker in GISTs, including those that lack KIT expression and/or contain PDGFRA mutations PKCθ is strongly activated in most GISTs and hence may serve, along with KIT/PDGFRA, as a novel therapeutic target

https://cancerres.aacrjournals.org/content/canres/64/15/5127.full.pdf

Protein Kinase C θ (PKCθ) Expression and Constitutive Activation in Gastrointestinal Stromal Tumors (GISTs)

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Understanding local mediterranean diets: a multidisciplinary pharmacological and ethnobotanical approach

Abstract 4645: Identification of conditionally active antibodies that selectively block CD39 activity in the acidic tumor microenvironment

Protein Kinase C θ (PKCθ) Expression and Constitutive Activation in Gastrointestinal Stromal Tumors (GISTs)