دورية أكاديمية
Defining and Targeting Esophagogastric Cancer Genomic Subsets With Patient-Derived Xenografts.
| العنوان: | Defining and Targeting Esophagogastric Cancer Genomic Subsets With Patient-Derived Xenografts. |
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| المؤلفون: | Moy RH; Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY.; Department of Medicine, Weill Cornell Medical College, New York, NY.; Present address: Department of Medicine, Columbia University Medical Center, New York, NY., Walch HS; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY., Mattar M; Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY., Chatila WK; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.; Tri-Institutional Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, NY., Molena D; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY., Strong VE; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY., Tang LH; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY., Maron SB; Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY., Coit DG; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY., Jones DR; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY., Hechtman JF; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY., Solit DB; Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY.; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY., Schultz N; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY., de Stanchina E; Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY., Janjigian YY; Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY.; Department of Medicine, Weill Cornell Medical College, New York, NY. |
| المصدر: | JCO precision oncology [JCO Precis Oncol] 2022 Feb; Vol. 6, pp. e2100242. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society of Clinical Oncology Country of Publication: United States NLM ID: 101705370 Publication Model: Print Cited Medium: Internet ISSN: 2473-4284 (Electronic) Linking ISSN: 24734284 NLM ISO Abbreviation: JCO Precis Oncol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Alexandria, VA : American Society of Clinical Oncology, [2017]- |
| مواضيع طبية MeSH: | Esophageal Neoplasms*/drug therapy , Stomach Neoplasms*/drug therapy, Genomics ; Heterografts ; Humans ; Phosphatidylinositol 3-Kinases/metabolism ; Xenograft Model Antitumor Assays |
| مستخلص: | Purpose: Comprehensive genomic profiling has defined key oncogenic drivers and distinct molecular subtypes in esophagogastric cancer; however, the number of clinically actionable alterations remains limited. To establish preclinical models for testing genomically driven therapeutic strategies, we generated and characterized a large collection of esophagogastric cancer patient-derived xenografts (PDXs). Materials and Methods: We established a biobank of 98 esophagogastric cancer PDX models derived from primary tumors and metastases. Clinicopathologic features of each PDX and the corresponding patient sample were annotated, including stage at diagnosis, treatment history, histology, and biomarker profile. To identify oncogenic DNA alterations, we analyzed and compared targeted sequencing performed on PDX and parent tumor pairs. We conducted xenotrials in genomically defined models with oncogenic drivers. Results: From April 2010 to June 2019, we implanted 276 patient tumors, of which 98 successfully engrafted (35.5%). This collection is enriched for PDXs derived from patients with human epidermal growth factor receptor 2-positive esophagogastric adenocarcinoma (62 models, 63%), the majority of which were refractory to standard therapies including trastuzumab. Factors positively correlating with engraftment included advanced stage, metastatic origin, intestinal-type histology, and human epidermal growth factor receptor 2-positivity. Mutations in TP53 and alterations in receptor tyrosine kinases ( ERBB2 and EGFR ), RAS/PI3K pathway genes, cell-cycle mediators ( CDKN2A and CCNE1 ), and CDH1 were the predominant oncogenic drivers, recapitulating clinical tumor sequencing. We observed antitumor activity with rational combination strategies in models established from treatment-refractory disease. Conclusion: The Memorial Sloan Kettering Cancer Center PDX collection recapitulates the heterogeneity of esophagogastric cancer and is a powerful resource to investigate mechanisms driving tumor progression, identify predictive biomarkers, and develop therapeutic strategies for molecularly defined subsets of esophagogastric cancer. Competing Interests: Daniela MolenaHonoraria: Bristol Myers Squibb/Pfizer, MerckConsulting or Advisory Role: Johnson & Johnson, UroGen pharma, Boston Scientific, AstraZeneca/MedImmune Steven B. MaronStock and Other Ownership Interests: Calithera BiosciencesConsulting or Advisory Role: Natera, Basilea, Daichi Sankyo, Bicara Therapeutics, NovartisResearch Funding: Roche/Genentech (Inst), Guardant Health (Inst)Travel, Accommodations, Expenses: Bayer David R. JonesConsulting or Advisory Role: Merck, AstraZeneca Jaclyn F. HechtmanEmployment: NeoGenomics LaboratoriesStock and Other Ownership Interests: NeoGenomics LaboratoriesHonoraria: WebMD, Illumina, BayerConsulting or Advisory Role: Cor2Ed, Axiom Healthcare Strategies, BayerResearch Funding: Bayer, Lilly, Boehringer Ingelheim David B. SolitThis author is a member of the JCO Precision Oncology Editorial Board. Journal policy recused the author from having any role in the peer review of this manuscript.Stock and Other Ownership Interests: Scorpion Therapeutics, Vividion Therapeutics, Fore BiotherapeuticsConsulting or Advisory Role: Pfizer, Lilly, BridgeBio Pharma, Scorpion Therapeutics, Vividion Therapeutics, Syros Pharmaceuticals Yelena Y. JanjigianStock and Other Ownership Interests: RgenixConsulting or Advisory Role: Pfizer, Merck, Bristol Myers Squibb, Merck Serono, Daiichi Sankyo, Rgenix, Bayer, Imugene, AstraZeneca, Lilly, Zymeworks, Basilea Pharmaceutical, Michael J. Hennessy Associates, Paradigm, Seattle GeneticsResearch Funding: Bayer (Inst), Rgenix (Inst), Bristol Myers Squibb (Inst), Merck (Inst), Lilly (Inst), NCI (Inst), Department of Defense (Inst), Cycle for Survival (Inst), Fred's Team (Inst), Genentech/Roche (Inst)Other Relationship: Clinical Care Options, Axis Medical Education, Research to PracticeNo other potential conflicts of interest were reported. |
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| معلومات مُعتمدة: | U54 OD020355 United States OD NIH HHS; K08 CA263304 United States CA NCI NIH HHS; T32 CA009207 United States CA NCI NIH HHS; P30 CA008748 United States CA NCI NIH HHS; R01 CA150646 United States CA NCI NIH HHS; K12 CA184746 United States CA NCI NIH HHS |
| تواريخ الأحداث: | Date Created: 20220209 Date Completed: 20220404 Latest Revision: 20240214 |
| رمز التحديث: | 20240214 |
| مُعرف محوري في PubMed: | PMC8865520 |
| DOI: | 10.1200/PO.21.00242 |
| PMID: | 35138918 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 2473-4284 |
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| DOI: | 10.1200/PO.21.00242 |