The Experts below are selected from a list of 189228 Experts worldwide ranked by ideXlab platform
John A. Hassell - One of the best experts on this subject based on the ideXlab platform.
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antagonists of the serotonin receptor 5a target human Breast Tumor initiating cells
BMC Cancer, 2020Co-Authors: William D. Gwynne, Craig Aarts, Mirza S Shakeel, Adele Girgisgabardo, Emily Ford, Anna Dvorkingheva, Methvin Isaac, Rima Alawar, John A. HassellAbstract:Breast Tumor initiating cells (BTIC) are stem-like cells that initiate and sustain Tumor growth, and drive disease recurrence. Identifying therapies targeting BTIC has been hindered due primarily to their scarcity in Tumors. We previously reported that BTIC frequency ranges between 15% and 50% in multiple mammary Tumors of 3 different transgenic mouse models of Breast cancer and that this frequency is maintained in Tumor cell populations cultured in serum-free, chemically defined media as non-adherent Tumorspheres. The latter enabled high-throughput screening of small molecules for their capacity to affect BTIC survival. Antagonists of several serotonin receptors (5-HTRs) were among the hit compounds. The most potent compound we identified, SB-699551, selectively binds to 5-HT5A, a Gαi/o protein coupled receptor (GPCR). We evaluated the activity of structurally unrelated selective 5-HT5A antagonists using multiple orthogonal assays of BTIC frequency. Thereafter we used a phosphoproteomic approach to uncover the mechanism of action of SB-699551. To validate the molecular target of the antagonists, we used the CRISPR-Cas9 gene editing technology to conditionally knockout HTR5A in a Breast Tumor cell line. We found that selective antagonists of 5-HT5A reduced the frequency of Tumorsphere initiating cells residing in Breast Tumor cell lines and those of patient-derived xenografts (PDXs) that we established. The most potent compound among those tested, SB-699551, reduced the frequency of BTIC in ex vivo assays and acted in concert with chemotherapy to shrink human Breast Tumor xenografts in vivo. Our phosphoproteomic experiments established that exposure of Breast Tumor cells to SB-699551 elicited signaling changes in the canonical Gαi/o-coupled pathway and the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) axis. Moreover, conditional mutation of the HTR5A gene resulted in the loss of Tumorsphere initiating cells and BTIC thus mimicking the effect of SB-699551. Our data provide genetic, pharmacological and phosphoproteomic evidence consistent with the on-target activity of SB-699551. The use of such agents in combination with cytotoxic chemotherapy provides a novel therapeutic approach to treat Breast cancer.
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Serotonergic system antagonists target Breast Tumor initiating cells and synergize with chemotherapy to shrink human Breast Tumor xenografts
Oncotarget, 2017Co-Authors: William D. Gwynne, Robin M. Hallett, Adele Girgis-gabardo, Bojana Bojovic, Anna Dvorkin-gheva, Craig Aarts, Kay Dias, Anita Bane, John A. HassellAbstract:Breast Tumors comprise an infrequent Tumor cell population, termed Breast Tumor initiating cells (BTIC), which sustain Tumor growth, seed metastases and resist cytotoxic therapies. Hence therapies are needed to target BTIC to provide more durable Breast cancer remissions than are currently achieved. We previously reported that serotonergic system antagonists abrogated the activity of mouse BTIC resident in the mammary Tumors of a HER2-overexpressing model of Breast cancer. Here we report that antagonists of serotonin (5-hydroxytryptamine; 5-HT) biosynthesis and activity, including US Federal Food and Drug Administration (FDA)-approved antidepressants, targeted BTIC resident in numerous Breast Tumor cell lines regardless of their clinical or molecular subtype. Notably, inhibitors of tryptophan hydroxylase 1 (TPH1), required for 5-HT biosynthesis in select non-neuronal cells, the serotonin reuptake transporter (SERT) and several 5-HT receptors compromised BTIC activity as assessed by functional sphere-forming assays. Consistent with these findings, human Breast Tumor cells express TPH1, 5-HT and SERT independent of their molecular or clinical subtype. Exposure of Breast Tumor cells ex vivo to sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), reduced BTIC frequency as determined by transplanting drug-treated Tumor cells into immune-compromised mice. Moreover, another SSRI (vilazodone; Viibryd) synergized with chemotherapy to shrink Breast Tumor xenografts in immune-compromised mice by inhibiting Tumor cell proliferation and inducing their apoptosis. Collectively our data suggest that antidepressants in combination with cytotoxic anticancer therapies may be an appropriate treatment regimen for testing in clinical trials.
Kurt R. Zinn - One of the best experts on this subject based on the ideXlab platform.
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DCE-MRI detects early vascular response in Breast Tumor xenografts following anti-DR5 therapy.
Molecular imaging and biology, 2010Co-Authors: Hyunki Kim, Karri Folks, Lingling Guo, Cecil R. Stockard, Naomi Fineberg, William E. Grizzle, James F. George, Donald J. Buchsbaum, Desiree E. Morgan, Kurt R. ZinnAbstract:Purpose Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measured the early vascular changes after administration of TRA-8, bevacizumab, or TRA-8 combined with bevacizumab in Breast Tumor xenografts.
Shuichi Takayama - One of the best experts on this subject based on the ideXlab platform.
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Studying Adipose Tissue in the Breast Tumor Microenvironment In Vitro: Progress and Opportunities
Tissue Engineering and Regenerative Medicine, 2020Co-Authors: David Mertz, Jason Sentosa, Gary Luker, Shuichi TakayamaAbstract:Background: The Breast cancer microenvironment contains a variety of stromal cells that are widely implicated in worse patient outcomes. While many in vitro models of the Breast Tumor microenvironment have been published, only a small fraction of these feature adipocytes. Adipocytes are a cell type increasingly recognized to have complex functions in Breast cancer. Methods: In this review, we examine findings from recent examples of in vitro experiments modeling adipocytes within the local Breast Tumor microenvironment. Results: Both two-dimensional and three-dimensional models of adipocytes in the Breast Tumor microenvironment are covered in this review and both have uncovered interesting phenomena related to Breast Tumor progression. Conclusion: Certain aspects of Breast cancer and associated adipocyte biology: extracellular matrix effects, cell-cell contact, and physiological mass transport can only be examined with a three-dimensional culture platform. Opportunities remain for innovative improvements to be made to in vitro models that further increase what is known about adipocytes during Breast cancer progression.
Ashraf B. Abdel-naim - One of the best experts on this subject based on the ideXlab platform.
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2-Methoxyestradiol reverses doxorubicin resistance in human Breast Tumor xenograft.
Cancer chemotherapy and pharmacology, 2008Co-Authors: Samar S. Azab, Salama A. Salama, Memy H. Hassan, Amani E. Khalifa, Ebtehal El-demerdash, Hala Fouad, Ayman Al-hendy, Ashraf B. Abdel-naimAbstract:Purpose 2-Methoxyestradiol (2ME), an endogenous estradiol metabolite, was developed as a novel agent based on its antiTumor activity and lack of toxicity. This study was designed to investigate the modulatory effect of 2ME on the antiTumor effect of doxorubicin (Dox) in resistant Breast Tumor xenograft. Resistant MCF-7/Dox cells were implanted subcutaneously in nude mice
William D. Gwynne - One of the best experts on this subject based on the ideXlab platform.
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antagonists of the serotonin receptor 5a target human Breast Tumor initiating cells
BMC Cancer, 2020Co-Authors: William D. Gwynne, Craig Aarts, Mirza S Shakeel, Adele Girgisgabardo, Emily Ford, Anna Dvorkingheva, Methvin Isaac, Rima Alawar, John A. HassellAbstract:Breast Tumor initiating cells (BTIC) are stem-like cells that initiate and sustain Tumor growth, and drive disease recurrence. Identifying therapies targeting BTIC has been hindered due primarily to their scarcity in Tumors. We previously reported that BTIC frequency ranges between 15% and 50% in multiple mammary Tumors of 3 different transgenic mouse models of Breast cancer and that this frequency is maintained in Tumor cell populations cultured in serum-free, chemically defined media as non-adherent Tumorspheres. The latter enabled high-throughput screening of small molecules for their capacity to affect BTIC survival. Antagonists of several serotonin receptors (5-HTRs) were among the hit compounds. The most potent compound we identified, SB-699551, selectively binds to 5-HT5A, a Gαi/o protein coupled receptor (GPCR). We evaluated the activity of structurally unrelated selective 5-HT5A antagonists using multiple orthogonal assays of BTIC frequency. Thereafter we used a phosphoproteomic approach to uncover the mechanism of action of SB-699551. To validate the molecular target of the antagonists, we used the CRISPR-Cas9 gene editing technology to conditionally knockout HTR5A in a Breast Tumor cell line. We found that selective antagonists of 5-HT5A reduced the frequency of Tumorsphere initiating cells residing in Breast Tumor cell lines and those of patient-derived xenografts (PDXs) that we established. The most potent compound among those tested, SB-699551, reduced the frequency of BTIC in ex vivo assays and acted in concert with chemotherapy to shrink human Breast Tumor xenografts in vivo. Our phosphoproteomic experiments established that exposure of Breast Tumor cells to SB-699551 elicited signaling changes in the canonical Gαi/o-coupled pathway and the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) axis. Moreover, conditional mutation of the HTR5A gene resulted in the loss of Tumorsphere initiating cells and BTIC thus mimicking the effect of SB-699551. Our data provide genetic, pharmacological and phosphoproteomic evidence consistent with the on-target activity of SB-699551. The use of such agents in combination with cytotoxic chemotherapy provides a novel therapeutic approach to treat Breast cancer.
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Serotonergic system antagonists target Breast Tumor initiating cells and synergize with chemotherapy to shrink human Breast Tumor xenografts
Oncotarget, 2017Co-Authors: William D. Gwynne, Robin M. Hallett, Adele Girgis-gabardo, Bojana Bojovic, Anna Dvorkin-gheva, Craig Aarts, Kay Dias, Anita Bane, John A. HassellAbstract:Breast Tumors comprise an infrequent Tumor cell population, termed Breast Tumor initiating cells (BTIC), which sustain Tumor growth, seed metastases and resist cytotoxic therapies. Hence therapies are needed to target BTIC to provide more durable Breast cancer remissions than are currently achieved. We previously reported that serotonergic system antagonists abrogated the activity of mouse BTIC resident in the mammary Tumors of a HER2-overexpressing model of Breast cancer. Here we report that antagonists of serotonin (5-hydroxytryptamine; 5-HT) biosynthesis and activity, including US Federal Food and Drug Administration (FDA)-approved antidepressants, targeted BTIC resident in numerous Breast Tumor cell lines regardless of their clinical or molecular subtype. Notably, inhibitors of tryptophan hydroxylase 1 (TPH1), required for 5-HT biosynthesis in select non-neuronal cells, the serotonin reuptake transporter (SERT) and several 5-HT receptors compromised BTIC activity as assessed by functional sphere-forming assays. Consistent with these findings, human Breast Tumor cells express TPH1, 5-HT and SERT independent of their molecular or clinical subtype. Exposure of Breast Tumor cells ex vivo to sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), reduced BTIC frequency as determined by transplanting drug-treated Tumor cells into immune-compromised mice. Moreover, another SSRI (vilazodone; Viibryd) synergized with chemotherapy to shrink Breast Tumor xenografts in immune-compromised mice by inhibiting Tumor cell proliferation and inducing their apoptosis. Collectively our data suggest that antidepressants in combination with cytotoxic anticancer therapies may be an appropriate treatment regimen for testing in clinical trials.