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PurposeGastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase (SDH) subunits (A-D) comprising less than 7.5% (i.e., 150-200/year) of new cases annually in the United States. Contrary to GISTs harboring KIT or PDGFRA mutations, SDH-mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKI). Lack of human models for any SDH-mutant tumors, including GIST, has limited molecular characterization and drug discovery.Experimental designWe describe methods for establishing novel patient-derived SDH-mutant (mSDH) GIST models and interrogated the efficacy of temozolomide on these tumor models in vitro and in clinical trials of patients with mSDH GIST.ResultsMolecular and metabolic characterization of our patient-derived mSDH GIST models revealed that these models recapitulate the transcriptional and metabolic hallmarks of parent tumors and SDH deficiency. We further demonstrate that temozolomide elicits DNA damage and apoptosis in our mSDH GIST models. Translating our in vitro discovery to the clinic, a cohort of patients with SDH-mutant GIST treated with temozolomide (n = 5) demonstrated a 40% objective response rate and 100% disease control rate, suggesting that temozolomide represents a promising therapy for this subset of GIST.ConclusionsWe report the first methods to establish patient-derived mSDH tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in patients with mSDH GIST who are refractory to existing chemotherapeutic drugs (namely, TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic.See related commentary by Blakely et al., p. 3.

PurposeGastrointestinal 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 designWe compared KIT versus non-KIT status with tumor location within the National Cancer Database (NCDB) for 2,418 patients with primary gastric GIST. Additionally, we compiled an international cohort (TransAtlantic GIST Collaborative, TAGC) of 236 patients and reviewed sequencing results, cross-sectional imaging, and operative reports. Subgroup analyses were performed for tumors located proximally versus distally. Risk factors for KIT versus non-KIT tumors were identified using multivariate regression analysis. A random forest machine learning model was then developed to determine feature importance.ResultsWithin the NCDB cohort, non-KIT mutants dominated distal tumor locations (P < 0.03). Proximal GIST were almost exclusively KIT mutant (96%) in the TAGC cohort, whereas 100% of PDGFRA and SDH-mutant GIST occurred in the distal stomach. On multivariate regression analysis, tumor location was associated with KIT versus non-KIT mutations. Using random forest machine learning analysis, stomach location was the most important feature for predicting mutation status.ConclusionsWe provide the first evidence that the mutational landscape of gastric GIST is related to tumor location. Proximal gastric GIST are overwhelmingly KIT mutant, irrespective of morphology or age, whereas distal tumors display non-KIT genomic diversity. Anatomic location of gastric GIST may therefore provide immediate guidance for clinical treatment decisions and selective confirmatory genomic testing when resources are limited.

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. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.

Somatic KIT activating mutations drive most gastrointestinal stromal tumors (GISTs). Disease progression eventually develops with first-line imatinib, commonly due to KIT secondary mutations, and different kinase inhibitors have various levels of treatment efficacy dependent on specific acquired resistance mutations. Ripretinib is a broad-spectrum switch-control KIT/PDGFRA tyrosine kinase inhibitor for patients with advanced GIST who received prior treatment with three or more kinase inhibitors, including imatinib. Exploratory baseline circulating tumor DNA analysis from the second-line INTRIGUE trial determined that patients with advanced GIST previously treated with imatinib harboring primary KIT exon 11 mutations and secondary resistance mutations restricted to KIT exons 17/18 had greater clinical benefit with ripretinib versus sunitinib. We describe the rationale and design of INSIGHT (NCT05734105), an ongoing Phase III open-label study of ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib exclusively harboring KIT exon 11 + 17/18 mutations detected by circulating tumor DNA. Clinical Trial Registration:NCT05734105 (ClinicalTrials.gov) Plain Language Summary Gastrointestinal stromal tumor (GIST) is rare, but it is the most common mesenchymal tumor (a type of tumor that develops from cells which give rise to soft tissues) of the gastrointestinal tract. The primary treatment for advanced GIST is medication that targets the abnormal mechanisms in cancer cells in order to block tumor growth and spread. Ripretinib is an inhibitor of a protein known as KIT, which is a member of the tyrosine kinase protein family and is involved in the growth of GIST. In a Phase III clinical trial called INTRIGUE, the effects of ripretinib and another receptor tyrosine kinase inhibitor, sunitinib, were compared in patients with advanced GIST previously treated with the drug imatinib. An exploratory analysis from the INTRIGUE trial that characterized baseline circulating tumor DNA in the blood showed a greater clinical benefit with ripretinib versus sunitinib in patients with gene mutations solely occurring in KIT exon 11 + 17 and/or 18 (exon 11 + 17/18). This article describes the rationale and design for a Phase III clinical trial called INSIGHT that will evaluate the benefit of ripretinib compared with sunitinib in patients with advanced GIST whose tumors have mutations in KIT exon 11 and KIT exon 17 and/or 18. Patients will receive ripretinib or sunitinib in 6-week cycles, and investigators will assess survival without cancer progression as the primary outcome, and overall survival, and response of the tumor to these two drugs as secondary outcomes. Tweetable Abstract This article describes the rationale and design for the INSIGHT Phase III trial evaluating patients with second-line advanced GIST who harbor primary KIT exon 11 mutations and secondary resistance mutations restricted to the activation loop (KIT exons 17/18). Executive summary Disease overview & management Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal sarcoma, with approximately 80% of cases driven by activating mutations in KIT. Sunitinib is a multitargeted tyrosine kinase inhibitor (TKI) approved as a second-line therapy for advanced GIST after disease progression on or intolerance to imatinib. Ripretinib is a broad-spectrum switch-control KIT/PDGFRA TKI approved as a fourth-line therapy for advanced GIST. Differential activity of ripretinib & sunitinib against secondary KIT mutations Exploratory baseline circulating tumor DNA (ctDNA) analysis from INTRIGUE determined that patients with KIT exon 11 + 13/14 mutations had improved progression-free survival (PFS) and objective response rate (ORR) with sunitinib versus ripretinib, while those with KIT exon 11 + 17/18 mutations had improved PFS, ORR and overall survival (OS) and a better safety profile with ripretinib versus sunitinib. Design INSIGHT is an international, Phase III, randomized, multicenter, open-label study evaluating the efficacy of ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib and who have KIT exon 11 mutations and co-occurring mutations exclusively in KIT exons 17/18, as identified by ctDNA. Approximately 54 patients will be randomized 2:1 to receive ripretinib 150 mg once daily (QD; continuous) or sunitinib 50 mg QD (4 weeks on/2 weeks off) in 6-week cycles. Eligible patients must have a histologic diagnosis of advanced GIST and co-occurring KIT exon 11 + 17/18 mutations confirmed by central laboratory ctDNA analysis, as well as radiologic progression on imatinib. The primary outcome measure is PFS based on blinded independent radiologic review (IRR) using modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST v1.1), while key secondary outcome measures are ORR based on blinded IRR using mRECIST v1.1 and OS. Infographic [ABSTRACT FROM AUTHOR]

In pharmaceutics, ingredients are classified as active ingredients and excipients. In topical/transdermal phytomedicines, an ingredient may serve both functions. Published information on these dual‐purpose ingredients and their pharmacological relevance is limited. An intriguing scenario arises in traditional Chinese medicine (TCM) formulations, where active ingredients and excipients are undifferentiated. This study analyzes ingredients in TCM topical/transdermal formulations, aiming at harmonization of understanding of TCMs. The most commonly recorded ingredients from such formulations in the Chinese pharmacopoeia 2020 (ChP 2020) are reviewed, aiming at developing innovative topical/transdermal phytomedicines. Current editions of Chinese historical documents were reviewed to explore the principles underlying the use of these ingredients. TCM formulations containing botanical drugs for topical/transdermal application were selected from the ChP 2020. The use of botanical materials in TCM formulations is guided by the "Jun‐Chen‐Zuo‐Shi" principle rooted in Yin‐Yang and the five elements' theories. In the ChP 2020, 155 botanical drugs, along with 40 excipients (from the "procedure" section, focusing on processing and technical parameters), were identified from 34 botanical formulations intended for topical/transdermal application. Pungent and aromatic botanical materials were the most frequently recorded. Adhesive plasters were the most commonly recorded TCM dosage form, employing specific matrix blends. This new perspective of study reveals the prevalence of pungent and aromatic botanical materials, the common use of adhesive plasters, multifunctional properties of botanical oils, and formulation adaptability in TCM topical/transdermal products. These insights should inform novel formulation designs for both pharmaceutical and phytopharmacological research. [ABSTRACT FROM AUTHOR]

The implementation of access and benefit-sharing (ABS) protocols, and especially the Nagoya Protocol, has created new hurdles for international collaborations around Indigenous Traditional Knowledge. Overall, these frameworks push for the development of novel collaborative North-South agendas to improve the fair distribution of benefits. The Green Health Project (Guatemala) aims to implement a culturally pertinent and mutually accepted framework for sustainable use, as well as ABS of traditional medicinal plants. It involves developing a consensus among Indigenous groups, government officials, industry, and academia. We describe steps undertaken to design and implement an intercultural transdisciplinary process that promotes trust building and advances herbal medicine research in a respectful and innovative way. This involves joint definition of goals and methods. The consortium co-researched Q'eqchi' Maya traditional medicine, collected voucher specimens of medicinal plants with traditional Healers, identified their taxa, and later developed a literature-based evaluation identifying species for potential product development. No samples for further research and development were collected. By applying the emic-etic concept, the project helped improve understanding of the main drivers of each stakeholder and the associated obstacles for reaching an ABS agreement. The project also explored the emergence of potential new drivers for developing evidence-based herbal medicine from the perspectives of academia, policy, cooperation, and grassroots Indigenous movements. Key words: Guatemala, access and benefit sharing, Q'eqchi', transdisciplinary process, traditional medicine, ethnopharmacology. La mise en oeuvre des protocoles sur l'accès et le partage des avantages (APA), et en particulier du protocole de Nagoya, a créé de nouveaux obstacles aux collaborations autour des savoirs traditionnels autochtones et aux collaborations internationales. Dans l'ensemble, ces cadres poussent à l'élaboration de nouveaux programmes de collaboration Nord-Sud afin d'améliorer la répartition équitable des avantages. Le projet Green Health (Guatemala) vise à mettre en oeuvre un cadre culturellement pertinent et mutuellement accepté pour l'utilisation durable, l'APA des plantes médicinales traditionnelles. Il implique de développer un consensus entre les groupes autochtones, les représentants du gouvernement, l'industrie et le monde universitaire. Les auteurs décrivent les étapes entreprises pour concevoir et mettre en oeuvre un processus interculturel transdisciplinaire qui favorise l'instauration d'un climat de confiance et fait progresser la recherche sur les plantes médicinales d'une manière respectueuse et innovante. Cela implique une définition conjointe des objectifs et des méthodes. Le consortium a effectué des recherches conjointes sur la médecine traditionnelle Maya Q'eqchi', a collecté des spécimens de référence de plantes médicinales avec des guérisseurs traditionnels, a identifié leurs taxons, et a ensuite développé une évaluation fondée sur la littérature identifiant les espèces pour le développement potentiel de produits. Aucun échantillon destiné à la recherche et au développement ultérieurs n'est collecté. En appliquant le concept émique-étique, le projet a pu comprendre les principaux moteurs de chaque partie prenante et les obstacles associés pour parvenir à un accord APA. Il en résulte l'émergence de nouveaux moteurs potentiels pour l'élaboration d'une phytothérapie fondée sur des preuves, du point de vue du monde universitaire, des politiques et de la coopération et des mouvements autochtones de base. [Traduit par la Rédaction] Mots-clés : Guatemala, accès et partage des avantages, Q'eqchi', processus transdisciplinaire, médecine traditionnelle, ethnopharmacologie., Introduction Recent years have seen a tremendous increase in research on certain traditional medical systems, albeit the drivers have been different in each region studied. This increase clearly results from [...]