Dataset Information

Next-Generation in vivo Modeling of Human Cancers.

ABSTRACT: Animal models of human cancers played a major role in our current understanding of tumor biology. In pre-clinical oncology, animal models empowered drug target and biomarker discovery and validation. In turn, this resulted in improved care for cancer patients. In the quest for understanding and treating a diverse spectrum of cancer types, technological breakthroughs in genetic engineering and single cell "omics" offer tremendous potential to enhance the informative value of pre-clinical models. Here, I review the state-of-the-art in modeling human cancers with focus on animal models for human malignant gliomas. The review highlights the use of glioma models in dissecting mechanisms of tumor initiation, in the retrospective identification of tumor cell-of-origin, in understanding tumor heterogeneity and in testing the potential of immuno-oncology. I build on the deep review of glioma models as a basis for a more general discussion of the potential ways in which transformative technologies may shape the next-generation of pre-clinical models. I argue that refining animal models along the proposed lines will benefit the success rate of translation for pre-clinical research in oncology.

SUBMITTER: Gargiulo G

PROVIDER: S-EPMC6192385 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Next-Generation <i>in vivo</i> Modeling of Human Cancers.

Gargiulo Gaetano G

Frontiers in oncology 20181010

Animal models of human cancers played a major role in our current understanding of tumor biology. In pre-clinical oncology, animal models empowered drug target and biomarker discovery and validation. In turn, this resulted in improved care for cancer patients. In the quest for understanding and treating a diverse spectrum of cancer types, technological breakthroughs in genetic engineering and single cell "omics" offer tremendous potential to enhance the informative value of pre-clinical models. ...[more]

PMID: 30364119

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Project description:BackgroundAppendiceal cancers (ACs) are rare. The genomic landscape of ACs has not been well studied. The aim of this study was to confirm the feasibility of next-generation sequencing (NGS) using circulating tumor DNA (ctDNA) in ACs and characterize common genomic alterations.Materials and methodsMolecular alterations in 372 plasma samples from 303 patients with AC using clinical-grade NGS of ctDNA (Guardant360) across multiple institutions were evaluated. Test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes.ResultsA total of 303 patients with AC were evaluated, of which 169 (56%) were female. Median age was 56.8 (25-83) years. ctDNA NGS testing was performed on 372 plasma samples; 48 patients had testing performed twice, 9 patients had testing performed three times, and 1 patient had testing performed four times. Genomic alterations were defined in 207 (n = 207/372, 55.6%) samples, and 288 alterations were identified excluding variants of uncertain significance and synonymous mutations. Alterations were identified in at least one sample from 184 patients; TP53-associated genes (n = 71, 38.6%), KRAS (n = 33, 17.9%), APC (n = 14, 7.6%), EGFR (n = 12, 6.5%), BRAF (n = 11, 5.9%), NF1 (n = 10, 5.4%), MYC (n = 9, 4.9%), GNAS (n = 8, 4.3%), MET (n = 6, 3.3%), PIK3CA (n = 5, 2.7%), and ATM (n = 5, 2.7%). Other low-frequency but clinically relevant genomic alterations were as follows: AR (n = 4, 2.2%), TERT (n = 4, 2.2%), ERBB2 (n = 4, 2.2%), SMAD4 (n = 3, 1.6%), CDK4 (n = 2, 1.1%), NRAS (n = 2, 1.1%), FGFR1 (n = 2, 1.1%), FGFR2 (n = 2, 1.1%), PTEN (n = 2, 1.1%), RB1 (n = 2, 1.1%), and CDK6, CDKN2A, BRCA1, BRCA2, JAK2, IDH2, MAPK, NTRK1, CDH1, ARID1A, and PDGFRA (n = 1, 0.5%).ConclusionEvaluation of ctDNA is feasible among patients with AC. The frequency of genomic alterations is similar to that previously reported in tissue NGS. Liquid biopsies are not invasive and can provide personalized options for targeted therapies in patients with AC.Implications for practiceThe complexity of appendiceal cancer and its unique genomic characteristics suggest that customized combination therapy may be required for many patients. Theoretically, as more oncogenic pathways are discovered and more targeted therapies are approved, customized treatment based on the patient's unique molecular profile will lead to personalized care and improve patient outcomes. Liquid biopsies are noninvasive, cost-effective, and promising methods that provide patients with access to personalized treatment.

Project description:Background and Objectives: Lung cancer is a leading cause of cancer mortality in Taiwan. With rapid advancement of targeted therapeutics in non-small cell lung cancers, next-generation sequencing (NGS) is becoming an important tool for biomarker testing. In this study, we describe institutional experience of NGS analysis in non-small cell carcinoma (NSCLC). Materials and Methods: A cohort of 73 cases was identified from the institutional pathology archive in the period between November 2020 and December 2022. Results: Adenocarcinoma was the most common histologic type (91.8%). Most patients presented with stage IIIB and beyond (87.7%). Twenty-nine patients (39.7%) were evaluated at the time of initial diagnosis, while the others had received prior chemotherapy or targeted therapy. The most frequently mutated gene was EGFR (63%), and this was followed by TP53 (50.7%), KRAS (13.7%), RB1 (13.7%), and CDKN2A (13.7%). Clinically actionable mutations associated with a guideline-suggested targeted therapy were identified in 55 cases (75.3%) overall, and in 47.1% of cases excluding EGFR TKI-sensitizing mutation. Biomarkers other than EGFR TKI-sensitizing mutations were compared. Cases without TKI-sensitizing EGFR mutation had more level 1 or 2 biomarkers (excluding EGFR TKI-sensitizing mutations) than cases with TKI-sensitizing EGFR mutations (47.1% versus 20.1%, p = 0.016). Progressive disease was associated with co-occurrence of clinically actionable mutations (20.5% versus 0%, p < 0.05). Eight of the nine cases with co-occurring actionable genetic alternations had an EGFR mutation. After an NGS test, 46.1% of actionable or potentially actionable genetic alternations led to patients receiving a matched therapy. Conclusions: Our study demonstrated that NGS analysis identifies therapeutic targets and may guide treatment strategies in NSCLC. NGS tests may be advantageous over multiple single-gene tests for optimization of treatment plans, especially for those with non-EGFR mutations or those with progressive disease.

Dataset Information

Next-Generation in vivo Modeling of Human Cancers.

Publications

Next-Generation <i>in vivo</i> Modeling of Human Cancers.

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