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5 results on '"Straehla J"'

1. Glioblastoma and the search for non-hypothesis driven combination therapeutics in academia

Author

Johanssen, T, McVeigh, L, Erridge, S, Higgins, G, Straehla, J, Frame, M, Aittokallio, T, Carragher, NO, Ebner, D, Helsinki Institute for Information Technology, Tero Aittokallio / Principal Investigator, Bioinformatics, Institute for Molecular Medicine Finland, University of Helsinki, Research Programs Unit, and Helsinki Institute of Life Science HiLIFE

Subjects
Cancer Research, Temozolamide, glioblastoma stem cell, Radiotherapy, drug targer combination, hypoxia, high throughput screening (HTS), 3122 Cancers, glioblastoma, radiothereapy, Oncology, temozolamide, Glioblastoma stem cell, Glioblastoma, Hypoxia, Drug target combination
Abstract

Glioblastoma (GBM) remains a cancer of high unmet clinical need. Currentstandard of care for GBM, consisting of maximal surgical resection, followed byionisation radiation (IR) plus concomitant and adjuvant temozolomide (TMZ),provides less than 15-month survival benefit. Efforts by conventional drugdiscovery to improve overall survival have failed to overcome challengespresented by inherent tumor heterogeneity, therapeutic resistance attributed toGBM stem cells, and tumor niches supporting self-renewal. In this review wedescribe the steps academic researchers are taking to address these limitations in high throughput screening programs to identify novel GBM combinatorial targets.We detail how they are implementing more physiologically relevant phenotypicassays which better recapitulate key areas of disease biology coupled with morefocussed libraries of small compounds, such as drug repurposing, target discovery, pharmacologically active and novel, more comprehensive anti-cancer targetannotated compound libraries. Herein, we discuss the rationale for current GBM combination trials and the need for more systematic and transparent strategies for identification, validation and prioritisation of combinations that lead to clinical trials. Finally, we make specific recommendations to the preclinical, small compound screening paradigm that could increase the likelihood of identifying tractable, combinatorial, small molecule inhibitors and better drug targets specific to GBM.

Published
2023
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4. Embryonic stem cell secreted factors decrease invasiveness of triple-negative breast cancer cells through regulome modulation.

Author

Tarasewicz E, Oakes RS, Aviles MO, Straehla J, Chilton KM, Decker JT, Wu J, Shea LD, and Jeruss JS

Subjects
Animals, Biological Factors therapeutic use, Cell Culture Techniques methods, Cell Line, Tumor, Cell Movement drug effects, Cellular Reprogramming drug effects, Culture Media, Conditioned pharmacology, Epithelial-Mesenchymal Transition drug effects, Female, GATA3 Transcription Factor metabolism, Gene Expression Profiling, Humans, Mice, Neoplasm Invasiveness pathology, Neoplasm Invasiveness prevention & control, Phosphorylation drug effects, Signal Transduction drug effects, Smad3 Protein metabolism, Spheroids, Cellular, Triple Negative Breast Neoplasms pathology, Tumor Microenvironment drug effects, Biological Factors pharmacology, Cellular Reprogramming Techniques methods, Gene Expression Regulation, Neoplastic drug effects, Mouse Embryonic Stem Cells metabolism, Triple Negative Breast Neoplasms drug therapy
Abstract

Stem cell microenvironments decrease the invasiveness of cancer cells, and elucidating the mechanisms associated with disease regression could further the development of targeted therapies for aggressive cancer subtypes. To this end, we applied an emerging technology, TRanscriptional Activity CEll aRray (TRACER), to investigate the reprogramming of triple-negative breast cancer (TNBC) cells in conditions that promoted a less aggressive phenotype. The repressive environment was established through exposure to mouse embryonic stem cell conditioned media (mESC CM). Assessment of carcinogenic phenotypes indicated that mESC CM exposure decreased proliferation, invasion, migration, and stemness in TNBC cells. Protein expression analysis revealed that mESC CM exposure increased expression of the epithelial protein E-cadherin and decreased the mesenchymal protein MMP9. Gene expression analysis showed that mESC CM decreased epithelial to mesenchymal transition (EMT) markers fibronectin, vimentin, and Snail. Over a period of 6 d, TRACER quantified changes in activity of 11 transcription factors (TFs) associated with oncogenic progression. The EMT profile was decreased in association with the activity of 7 TFs (Smad3, NF-κΒ, MEF2, GATA, Hif1, Sp1, and RXR). Further examination of Smad3 and GATA expression and phosphorylation revealed that mESC CM exposure decreased noncanonical Smad3 phosphorylation and Smad3-mediated gene expression, increased GATA3 expression and phosphorylation, and resulted in a synergistic decrease in migration of GATA3 overexpressing MDA-MB-231 cells. Collectively, the application of TRACER to examine TF activity associated with the transition of cancer cells to a less aggressive phenotype, as directed by mESC CM, identified novel mechanistic events linking the embryonic microenvironment to both favorable changes and cellular plasticity in TNBC cell phenotypes.

Published
2018
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5. CDK4 inhibition and doxorubicin mediate breast cancer cell apoptosis through Smad3 and survivin.

Author

Tarasewicz E, Hamdan R, Straehla J, Hardy A, Nunez O, Zelivianski S, Dokic D, and Jeruss JS

Subjects
Apoptosis Regulatory Proteins genetics, Breast Neoplasms metabolism, Cell Proliferation drug effects, Cyclin D1 genetics, Cyclin-Dependent Kinase 4 metabolism, Drug Synergism, Humans, Inhibitor of Apoptosis Proteins genetics, MCF-7 Cells drug effects, Mutation, Phosphorylation, Signal Transduction drug effects, Smad3 Protein genetics, Survivin, X-Linked Inhibitor of Apoptosis Protein metabolism, Antibiotics, Antineoplastic pharmacology, Apoptosis drug effects, Breast Neoplasms pathology, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Doxorubicin pharmacology, Inhibitor of Apoptosis Proteins metabolism, Protein Kinase Inhibitors pharmacology, Smad3 Protein metabolism
Abstract

Cyclin D1/CDK4 activity is upregulated in up to 50% of breast cancers and CDK4-mediated phosphorylation negatively regulates the TGFβ superfamily member Smad3. We sought to determine if CDK4 inhibition and doxorubicin chemotherapy could impact Smad3-mediated cell/colony growth and apoptosis in breast cancer cells. Parental and cyclin D1-overexpressing MCF7 cells were treated with CDK4 inhibitor, doxorubicin, or combination therapy and cell proliferation, apoptosis, colony formation, and expression of apoptotic proteins were evaluated using an MTS assay, TUNEL staining, 3D Matrigel assay, and apoptosis array/immunoblotting. Study cells were also transduced with WT Smad3 or a Smad3 construct resistant to CDK4 phosphorylation (5M) and colony formation and expression of apoptotic proteins were assessed. Treatment with CDK4 inhibitor/doxorubicin combination therapy, or transduction with 5M Smad3, resulted in a similar decrease in colony formation. Treating cyclin D overexpressing breast cancer cells with combination therapy also resulted in the greatest increase in apoptosis, resulted in decreased expression of anti-apoptotic proteins survivin and XIAP, and impacted subcellular localization of pro-apoptotic Smac/DIABLO. Additionally, transduction of 5M Smad3 and doxorubicin treatment resulted in the greatest change in apoptotic protein expression. Collectively, this work showed the impact of CDK4 inhibitor-mediated, Smad3-regulated tumor suppression, which was augmented in doxorubicin-treated cyclin D-overexpressing study cells.

Published
2014
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