Emerging therapeutic targets and preclinical models for severe asthma

2020 ◽  
Vol 24 (9) ◽  
pp. 845-857
Author(s):  
Izabela Galvão ◽  
Richard Y. Kim ◽  
Sijie Shen ◽  
Kurtis F. Budden ◽  
Angélica T. Vieira ◽  
...  
Keyword(s):  
Severe Asthma ◽  
Therapeutic Targets ◽  
Preclinical Models

scholarly journals Comprehensive molecular characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Alvaro Quintanal-Villalonga ◽  
Hirokazu Taniguchi ◽  
Yingqian A. Zhan ◽  
Maysun M. Hasan ◽  
Shweta S. Chavan ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
Squamous Cell ◽  
Genetic Manipulation ◽  
Therapeutic Targets ◽  
Xenograft Model ◽  
Driver Mutations ◽  
Preclinical Models ◽  
Patient Derived Xenograft ◽  
Mixed Histology

Abstract Background Lineage plasticity, the ability to transdifferentiate among distinct phenotypic identities, facilitates therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon includes small cell and squamous cell (LUSC) histologic transformation in the context of acquired resistance to targeted inhibition of driver mutations. LUAD-to-LUSC transdifferentiation, occurring in up to 9% of EGFR-mutant patients relapsed on osimertinib, is associated with notably poor prognosis. We hypothesized that multi-parameter profiling of the components of mixed histology (LUAD/LUSC) tumors could provide insight into factors licensing lineage plasticity between these histologies. Methods We performed genomic, epigenomics, transcriptomics and protein analyses of microdissected LUAD and LUSC components from mixed histology tumors, pre-/post-transformation tumors and reference non-transformed LUAD and LUSC samples. We validated our findings through genetic manipulation of preclinical models in vitro and in vivo and performed patient-derived xenograft (PDX) treatments to validate potential therapeutic targets in a LUAD PDX model acquiring LUSC features after osimertinib treatment. Results Our data suggest that LUSC transdifferentiation is primarily driven by transcriptional reprogramming rather than mutational events. We observed consistent relative upregulation of PI3K/AKT, MYC and PRC2 pathway genes. Concurrent activation of PI3K/AKT and MYC induced squamous features in EGFR-mutant LUAD preclinical models. Pharmacologic inhibition of EZH1/2 in combination with osimertinib prevented relapse with squamous-features in an EGFR-mutant patient-derived xenograft model, and inhibition of EZH1/2 or PI3K/AKT signaling re-sensitized resistant squamous-like tumors to osimertinib. Conclusions Our findings provide the first comprehensive molecular characterization of LUSC transdifferentiation, suggesting putative drivers and potential therapeutic targets to constrain or prevent lineage plasticity.

Polycythemia vera: the current status of preclinical models and therapeutic targets

2020 ◽  
Vol 24 (7) ◽  
pp. 615-628
Author(s):  
Niccolò Bartalucci ◽  
Paola Guglielmelli ◽  
Alessandro M. Vannucchi
Keyword(s):  
Polycythemia Vera ◽  
Therapeutic Targets ◽  
Current Status ◽  
Preclinical Models

scholarly journals COPD: preclinical models and emerging therapeutic targets

2019 ◽  
Vol 23 (10) ◽  
pp. 829-838 ◽  
Author(s):  
Esther Barreiro ◽  
Xuejie Wang ◽  
Jun Tang
Keyword(s):  
Therapeutic Targets ◽  
Preclinical Models

scholarly journals TMOD-07. HUMAN DIFFUSE MIDLINE GLIOMA AVATARS AS A PLATFORM TO SEARCH FOR NOVEL THERAPEUTIC TARGETS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii229-ii229
Author(s):  
Tomoyuki Koga ◽  
Shunichiro Miki ◽  
Kasey R Skinner ◽  
Sriram Venneti ◽  
Denise Malicki ◽  
...  
Keyword(s):  
Histone Deacetylase Inhibitors ◽  
Genome Engineering ◽  
Pediatric Population ◽  
Therapeutic Targets ◽  
Genetic Alterations ◽  
Genetically Engineered ◽  
Preclinical Models ◽  
Pediatric Glioma ◽  
Novel Therapeutics ◽  
Diffuse Midline Glioma

Abstract Diffuse midline glioma is the leading cause of brain tumor death among the pediatric population. Drugs that show notable promise in preclinical models inevitably fail to demonstrate efficacy in clinical trials, likely due to the inadequacy of preclinical models. We have recently proposed glioblastoma models derived from human induced pluripotent stem cells (hiPSCs) genetically engineered with different combinations of glioblastoma-associated genetic alterations as a platform to search for therapeutic targets. These glioblastoma avatars authentically recapitulated the different pathobiology of glioblastoma subtypes, depending on what genetic alterations to be introduced. To investigate the biology and to develop novel therapeutics for diffuse midline glioma with H3K27M mutation, we have established a novel model by introducing H3.3 K27M mutation together with one of the most common concurrent genetic alterations, TP53 R248Q mutation, into hiPSCs through CRISPR/Cas9 genome engineering. Orthotopic engraftment of the neural progenitor cells derived from these edited hiPSCs formed diffusely invasive brainstem tumors with histological features of the diffuse midline glioma. These tumor avatars presented a global reduction in H3K27me3 accompanied by the expression of H3K27M. Transcriptome analyses of these models revealed that these avatars with H3K27M cluster apart from the pediatric glioma samples without this particular mutation, and that they present signatures of oligodendroglial progenitor differentiation as discovered in patient samples with this mutation. Using these models faithfully recapitulating histology and pathobiology of the patient tumors, we have performed drug screening and confirmed that their sensitivity to known drugs, including an EZH2 inhibitor and histone deacetylase inhibitors. On these faithful human avatars of diffuse midline glioma with H3K27M, we have applied bioinformatics algorithms of drug sensitivity prediction aiming at developing novel therapeutics for this devastating pediatric glioma.

scholarly journals Deubiquitinases in hematological malignancies

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Hu Lei ◽  
Jiaqi Wang ◽  
Jiacheng Hu ◽  
Qian Zhu ◽  
Yingli Wu
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Drug Targets ◽  
Hematological Malignancies ◽  
Therapeutic Targets ◽  
Cellular Proteins ◽  
Therapeutic Drug ◽  
Preclinical Models ◽  
Downstream Effectors ◽  
The Stability

AbstractDeubiquitinases (DUBs) are enzymes that control the stability, interactions or localization of most cellular proteins by removing their ubiquitin modification. In recent years, some DUBs, such as USP7, USP9X and USP10, have been identified as promising therapeutic targets in hematological malignancies. Importantly, some potent inhibitors targeting the oncogenic DUBs have been developed, showing promising inhibitory efficacy in preclinical models, and some have even undergone clinical trials. Different DUBs perform distinct function in diverse hematological malignancies, such as oncogenic, tumor suppressor or context-dependent effects. Therefore, exploring the biological roles of DUBs and their downstream effectors will provide new insights and therapeutic targets for the occurrence and development of hematological malignancies. We summarize the DUBs involved in different categories of hematological malignancies including leukemia, multiple myeloma and lymphoma. We also present the recent development of DUB inhibitors and their applications in hematological malignancies. Together, we demonstrate DUBs as potential therapeutic drug targets in hematological malignancies.

Osteosarcoma in the Post Genome Era: Preclinical Models and Approaches to Identify Tractable Therapeutic Targets

2019 ◽  
Vol 17 (5) ◽  
pp. 343-352 ◽  
Author(s):  
Wilson Castillo-Tandazo ◽  
Anthony J. Mutsaers ◽  
Carl R. Walkley
Keyword(s):  
Therapeutic Targets ◽  
Preclinical Models

scholarly journals Erratum: XIAP and survivin as therapeutic targets for radiation sensitization in preclinical models of lung cancer

Oncogene ◽  
2004 ◽  
Vol 23 (58) ◽  
pp. 9448-9448 ◽  
Author(s):  
Carolyn Cao ◽  
Yi Mu ◽  
Dennis E Hallahan ◽  
Bo Lu
Keyword(s):  
Lung Cancer ◽  
Therapeutic Targets ◽  
Preclinical Models ◽  
Radiation Sensitization

scholarly journals Present Status and Future Challenges of New Therapeutic Targets in Preclinical Models of Stroke in Aged Animals with/without Comorbidities

2018 ◽  
Vol 19 (2) ◽  
pp. 356 ◽  
Author(s):  
Aurel Popa-Wagner ◽  
Daniela-Gabriela Glavan ◽  
Andrei Olaru ◽  
Denissa-Greta Olaru ◽  
Otilia Margaritescu ◽  
...  
Keyword(s):  
Present Status ◽  
Therapeutic Targets ◽  
Preclinical Models ◽  
Future Challenges ◽  
New Therapeutic Targets

scholarly journals The Molecular Landscape Influencing Prognoses of Epithelial Ovarian Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 998
Author(s):  
Chao-Lien Liu ◽  
Ray-Hwang Yuan ◽  
Tsui-Lien Mao
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Delayed Diagnosis ◽  
Therapeutic Targets ◽  
Gene Mutations ◽  
Molecular Characteristics ◽  
Preclinical Models ◽  
Gene Expression Microarrays ◽  
Expression Microarrays ◽  
Molecular Landscape

Epithelial ovarian cancer (EOC) is one of the major increasing lethal malignancies of the gynecological tract, mostly due to delayed diagnosis and chemoresistance, as well as its very heterogeneous genetic makeup. Application of high-throughput molecular technologies, gene expression microarrays, and powerful preclinical models has provided a deeper understanding of the molecular characteristics of EOC. Therefore, molecular markers have become a potent tool in EOC management, including prediction of aggressiveness, prognosis, and recurrence, and identification of novel therapeutic targets. In addition, biomarkers derived from genomic/epigenomic alterations (e.g., gene mutations, copy number aberrations, and DNA methylation) enable targeted treatment of affected signaling pathways in advanced EOC, thereby improving the effectiveness of traditional treatments. This review outlines the molecular landscape and discusses the impacts of biomarkers on the detection, diagnosis, surveillance, and therapeutic targets of EOC. These findings focus on the necessity to translate these potential biomarkers into clinical practice.

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