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  • 1
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    The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade
    Elsevier BV ; 2018
    In:  Cell Reports Vol. 22, No. 11 ( 2018-03), p. 2978-2994
    Details
    In: Cell Reports, Elsevier BV, Vol. 22, No. 11 ( 2018-03), p. 2978-2994
    Type of Medium: Online Resource
    ISSN: 2211-1247
    URL: Article
    DOI: 10.1016/j.celrep.2018.02.053
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2018
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  • 2
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    Obtaining Functional Proteomics Insights From Thermal Proteome Profiling Through Optimized Melt Shift Calculation and Statistical Analysis With InflectSSP
    Elsevier BV ; 2023
    In:  Molecular & Cellular Proteomics Vol. 22, No. 9 ( 2023-09), p. 100630-
    Details
    In: Molecular & Cellular Proteomics, Elsevier BV, Vol. 22, No. 9 ( 2023-09), p. 100630-
    Type of Medium: Online Resource
    ISSN: 1535-9476
    URL: Article
    DOI: 10.1016/j.mcpro.2023.100630
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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    SSG: 12
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  • 3
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    Data_Sheet_1.docx
    Frontiers Media SA ; 2023
    In:  Frontiers in Medicine Vol. 10 ( 2023-4-27)
    Details
    In: Frontiers in Medicine, Frontiers Media SA, Vol. 10 ( 2023-4-27)
    Abstract: Pancreatic cancer or pancreatic ductal adenocarcinoma (PDAC) is characterized by a profound inflammatory tumor microenvironment (TME) with high heterogeneity, metastatic propensity, and extreme hypoxia. The integrated stress response (ISR) pathway features a family of protein kinases that phosphorylate eukaryotic initiation factor 2 (eIF2) and regulate translation in response to diverse stress conditions, including hypoxia. We previously demonstrated that eIF2 signaling pathways were profoundly affected in response to Redox factor-1 (Ref-1) knockdown in human PDAC cells. Ref-1 is a dual function enzyme with activities of DNA repair and redox signaling, responds to cellular stress, and regulates survival pathways. The redox function of Ref-1 directly regulates multiple transcription factors including HIF-1α, STAT3, and NF-κB, which are highly active in the PDAC TME. However, the mechanistic details of the crosstalk between Ref-1 redox signaling and activation of ISR pathways are unclear. Following Ref-1 knockdown, induction of ISR was observed under normoxic conditions, while hypoxic conditions were sufficient to activate ISR irrespective of Ref-1 levels. Inhibition of Ref-1 redox activity increased expression of p-eIF2 and ATF4 transcriptional activity in a concentration-dependent manner in multiple human PDAC cell lines, and the effect on eIF2 phosphorylation was PERK-dependent. Treatment with PERK inhibitor, AMG-44 at high concentrations resulted in activation of the alternative ISR kinase, GCN2 and induced levels of p-eIF2 and ATF4 in both tumor cells and cancer-associated fibroblasts (CAFs). Combination treatment with inhibitors of Ref-1 and PERK enhanced cell killing effects in both human pancreatic cancer lines and CAFs in 3D co-culture, but only at high doses of PERK inhibitors. This effect was completely abrogated when Ref-1 inhibitors were used in combination with GCN2 inhibitor, GCN2iB. We demonstrate that targeting of Ref-1 redox signaling activates the ISR in multiple PDAC lines and that this activation of ISR is critical for inhibition of the growth of co-culture spheroids. Combination effects were only observed in physiologically relevant 3D co-cultures, suggesting that the model system utilized can greatly affect the outcome of these targeted agents. Inhibition of Ref-1 signaling induces cell death through ISR signaling pathways, and combination of Ref-1 redox signaling blockade with ISR activation could be a novel therapeutic strategy for PDAC treatment.
    Type of Medium: Online Resource
    ISSN: 2296-858X
    URL: Article
    URL: Article
    DOI: 10.3389/fmed.2023.1146115
    DOI: 10.3389/fmed.2023.1146115.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
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  • 4
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    IRAK4 Kinase Activity Is Required for Th17 Differentiation and Th17-Mediated Disease
    The American Association of Immunologists ; 2009
    In:  The Journal of Immunology Vol. 183, No. 1 ( 2009-07-01), p. 568-577
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 183, No. 1 ( 2009-07-01), p. 568-577
    Abstract: Both IL-23- and IL-1-mediated signaling pathways play important roles in Th17 cell differentiation, cytokine production, and autoimmune diseases. The IL-1R-associated kinase 4 (IRAK4) is critical for IL-1/TLR signaling. We show here that inactivation of IRAK4 kinase in mice (IRAK4 KI) results in significant resistance to experimental autoimmune encephalomyelitis due to a reduction in infiltrating inflammatory cells into the CNS and reduced Ag-specific CD4+ T cell-mediated IL-17 production. Adoptive transfer of myelin oligodendrocyte glycoprotein 35–55-specific IRAK4 KI Th17 cells failed to induce experimental autoimmune encephalomyelitis in either wild-type or IRAK4 KI recipient mice, indicating the lack of autoantigen-specific Th17 cell activities in the absence of IRAK4 kinase activity. Furthermore, the absence of IRAK4 kinase activity blocked induction of IL-23R expression, STAT3 activation by IL-23, and Th17 cytokine expression in differentiated Th17 cells. Importantly, blockade of IL-1 signaling by IL-1RA inhibited Th17 differentiation and IL-23-induced cytokine expression in differentiated Th17 cells. The results of these studies demonstrate that IL-1-mediated IRAK4 kinase activity in T cells is essential for induction of IL-23R expression, Th17 differentiation, and autoimmune disease.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.0802361
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2009
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  • 5
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    Abstract 6231: Activation of GCN2 by HC-7366 results in significant antitumor efficacy as monotherapy and in combination with multiple standard of care agents in various solid cancer models
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6231-6231
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6231-6231
    Abstract: The integrated stress response (ISR) is an adaptive signaling pathway that cells utilize to respond to a wide range of extrinsic and intrinsic stresses, which are important for tumorigenesis. Activation of ISR is suggested to play a dual role in cell fate decisions. While the ISR promotes survival, prolonged activation of ISR induces apoptosis. We are developing HC-7366, a first-in-class, first-in-human GCN2 activator, and are currently evaluating it in a phase 1 clinical trial in solid tumors (NCT05121948). In this study, we present the characterization of the antitumor effects of HC-7366 in solid tumors. In vivo efficacy studies using HC-7366 montherapy showed significant tumor growth inhibition (TGI%) in preclinical cancer models of colorectal (78-95%), head and neck (33% regression), sarcoma (80%) and prostate (65%). HC-7366 activated the ISR in tumors from treated mice as evidenced by induction of the ATF4 target genes ASNS and PSAT1. Additionally, HC-7366 induced the proapoptotic protein PUMA and reduced HIF1⍺ and HIF2⍺ levels. Furthermore, HC-7366 showed significant benefit in colorectal models when combined with DC101 (anti-VEGFR2 antibody), 5-fluorouracil (chemotherapy), alpelisib (PI3Kα inhibitor), or trametinib (MEK1/2 inhibitor). Using GCN2 CRISPR-knockout cells, we confirmed that the HC-7366 mediated reduction of cell growth and induction of ISR markers was dependent on GCN2. We performed multi-omics analyses to further understand the mechanism of action. Metabolomics analysis of tumors treated with HC-7366 revealed that HC-7366 altered several metabolites involved in amino acid metabolism, oxidative stress, the urea cycle, and pyrimidine biosynthesis. Additionally, proteomics analysis showed that HC-7366 significantly reduced proteins involved in oxidative phosphorylation. Analysis of the transcriptome in tumors from treated mice demonstrated that HC-7366 reduced the activity of HIF and E2F1-driven transcription, including expression of metaphase-anaphase transition genes, consistent with decreased Ki67 staining in tumors. ATF4 and JUN transcriptional activity was enhanced with HC-7366 treatment consistent with activation of ISR. Collectively, our in vitro and in vivo results demonstrate that HC-7366 is a potent GCN2 activator with strong antitumor activity across multiple solid tumor models as a monotherapy or in combination with standard of care agents. Citation Format: Feven Tameire, Paulina Wojnarowicz, Crissy Dudgeon, Sho Fujisawa, Sharon Huang, Owen B. Reilly, Nicholas Collette, Jeremy Drees, Kathryn Bieging-Rolett, Takashi O. Kangas, Weiyu Zhang, Maria Fumagalli, Iman Dewji, Yunfang Li, Anissa SH Chan, Xiaohong Qiu, Ben Harrison, Ashley LaCayo, Ricardo A. Cordova, Kirk A. Staschke, Alan C. Rigby, Savithri Ramurthy, Eric S. Lightcap, David Surguladze, Nandita Bose. Activation of GCN2 by HC-7366 results in significant antitumor efficacy as monotherapy and in combination with multiple standard of care agents in various solid cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6231.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-6231
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 6
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    Abstract 4818: GCN2 eIF2 kinase and p53 coordinate amino acid homeostasis and metabolism in prostate cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4818-4818
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4818-4818
    Abstract: Activation of the integrated stress response (ISR) contributes to the progression of many cancers, including prostate cancer (PCa). The ISR features a family of protein kinases that phosphorylate the eukaryotic translation initiation factor 2 (eIF2) during different stress conditions, resulting in repression of global protein synthesis. In parallel, eIF2 phosphorylation also enhances the translation of select gene transcripts, such as ATF4, which directs the transcription of ISR-target genes that are critical for cancer stress adaptation. We recently reported (Cordova et al., 2022 eLife) that the eIF2 kinase GCN2 is a driver of the ISR in PCa and is critical for the maintenance of essential amino acid (EAA) homeostasis. GCN2 is activated in PCa due to EAA limitations, resulting in increased expression of key amino acid transporters which provide for nutrient import to facilitate protein synthesis and metabolism that drive PCa proliferation. Genetic loss or pharmacological inhibition of GCN2 results in lowered expression of amino acid transporters, leading to severe depletion of intracellular essential amino acids and reduced proliferation in PCa cell lines and xenograft models. These results support the therapeutic potential of targeting GCN2 in PCa.We recently determined that loss of GCN2 in PCa triggers a G1 nutrient-sensitive cell cycle checkpoint that is dependent on p53 and its target gene CDKN1A, encoding p21 inhibitor of cell cycle. Induced G1 arrest and p53/p21 signaling by GCN2 inhibition is reversed by supplementation with EAAs, suggesting amino acid limitation is critical for activation of p53. Metabolic stresses, such as amino acid starvation, have been suggested to activate p53 in different cancers and p53 regulates metabolic pathways that are critical for cancer cells adaptation to stresses. We also showed that depletion of specific amino acids activates GCN2 and p53 in cultured PCa cells. Using transcriptomic and metabolomic analyses, we determined that loss of GCN2 or p53 in PCa cells impacted multiple metabolic pathways, specifically those involved in amino acid and nucleotide metabolism, supporting the importance of GCN2 and p53 in metabolic homeostasis. In addition, deletion of p53 in PCa cells exacerbates the activation of GCN2 and the ISR, suggesting that loss of p53 results in amino acid imbalances that further activate GCN2. Importantly, inhibition of GCN2 in combination with loss of p53 resulted in increased cell death and apoptosis in PCa. Our study suggests that GCN2 and p53 can be activated in parallel in PCa and these stress response pathways are crucial for PCa cells to maintain homeostasis and adapt to metabolic stress. We propose that GCN2 and p53 function to coordinate PCa growth and progression by regulating metabolism and cell cycle control. Targeting these stress pathways in combination may provide enhanced efficacy for the treatment of PCa. Citation Format: Ricardo A. Cordova, Noah R. Sommers, Angela J. Klunk, Haroon M. Mohiuddin, Roberto Pili, Ronald C. Wek, Kirk A. Staschke. GCN2 eIF2 kinase and p53 coordinate amino acid homeostasis and metabolism in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4818.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-4818
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 7
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    GCN2 inhibition sensitizes prostate cancer cells to loss of p21 cell cycle control
    IUPUI University Library ; 2023
    In:  Proceedings of IMPRS Vol. 5, No. 1 ( 2023-01-26)
    Details
    In: Proceedings of IMPRS, IUPUI University Library, Vol. 5, No. 1 ( 2023-01-26)
    Abstract: Background: Activation of the Integrated Stress Response (ISR) by GCN2 is crucial for cells to survive in amino acid-depleted environments. We recently demonstrated in prostate cancer (PCa) that the GCN2 protein kinase that serves as a nutrient sensor in the ISR is critical for the regulation of transport of essential amino acids (EAAs) and for PCa growth and tumor progression. Inhibition of GCN2 results in lowered expression of amino acid transporters and a severe depletion of intracellular EAAs. Although loss of GCN2 in PCa cells reduces proliferation, this leads only in cell stasis and not cell death. We hypothesize that the senescent phenotype induced by GCN2 inhibition in PCa cells will render these cells vulnerable to cell cycle modulation and is a potential therapeutic target.Methods: Immunoblot analyses was used to measure protein levels. Cell cycle analysis was performed by flow cytometry, and cell death/apoptosis was measured by Annexin-V and Cytotox-Red using an Incucyte.Results: We determined that GCN2 inhibition in PCa cell lines results in G1-cell cycle arrest accompanied by induced p21 expression. p21 is a major regulator of the cell cycle by inhibition of cyclin/CDK complexes. Induced G1 arrest and p21 by GCN2 inhibition can be reversed by supplementation with EAAs, suggesting amino acid limitations is critical for the p21-dependent cell cycle checkpoint control. Combinations of GCN2 and p21 knockdowns using siRNAs resulted in cell death and apoptosis in PCa cells.Conclusions: Our results suggest that inhibition of GCN2 in PCa cells causes severe starvation for EAAs, triggering the cell cycle checkpoint by a p21-dependent mechanism. Although PCa cells survive and undergo growth stasis following loss of GCN2, these cells are vulnerable to loss of p21 cell cycle control. We propose that GCN2 inhibition in combination with cell cycle modulators is novel therapy for the treatment of PCa.
    Type of Medium: Online Resource
    ISSN: 2641-2470
    URL: Article
    DOI: 10.18060/26701
    Language: Unknown
    Publisher: IUPUI University Library
    Publication Date: 2023
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  • 8
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    GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis
    eLife Sciences Publications, Ltd ; 2022
    In:  eLife Vol. 11 ( 2022-09-15)
    Details
    In: eLife, eLife Sciences Publications, Ltd, Vol. 11 ( 2022-09-15)
    Abstract: Prostate cancer is the fourth most common cancer worldwide, affecting over a million people each year. Existing drug treatments work by blocking the effects or reducing the levels of the hormone testosterone. However, these drug regimens are not always effective, so finding alternative treatments is an important area of research. One option is to target the 'integrated stress response', a pathway that acts as a genetic switch, turning on a group of genes that counteract cellular stress and are essential for the survival of cancer cells. The reason cancer cells are under stress is because they are hungry. They need to make a lot of proteins and other metabolic intermediates to grow and divide, which means they need plenty of amino acids, the building blocks that make up proteins and fuel metabolism. Amino acids enter cells through molecular gates called amino acid transporters, and scientists think the integrated stress response might play a role in this process. One of the integrated stress response components is a protein called General Control Nonderepressible 2, or GCN2 for short. In healthy cells, this protein helps to boost amino acid levels when supplies start to run low. Cordova et al. examined human prostate cancer cells to find out what role GCN2 plays in this cancer. In both lab-grown cells and tissue from patients, GCN2 was active and played a critical role in prostate tumor growth by turning on the genes for amino acid transporters to increase the levels of amino acids entering the cancer cells. Deleting the gene for GCN2, or blocking its effects with an experimental drug, slowed the growth of cultured prostate cancer cells and reduced tumor growth in mice. In these early experiments, Cordova et al. did not notice any toxic side effects to healthy tissues. If GCN2 works in the same way in humans as it does in mice, blocking it might help to control prostate cancer growth. The integrated stress response is also active in other cancer types, so the same logic might apply to different tumors. However, before GCN2 blockers can become treatments, researchers need a more complete understanding of their molecular effects.
    Type of Medium: Online Resource
    ISSN: 2050-084X
    URL: Article
    DOI: 10.7554/eLife.81083
    Language: English
    Publisher: eLife Sciences Publications, Ltd
    Publication Date: 2022
    detail.hit.zdb_id: 2687154-3
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  • 9
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    Abstract 4816: Targeting GCN2 regulation of amino acid homeostasis sensitizes prostate cancer cells to senolytic therapies
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4816-4816
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4816-4816
    Abstract: The integrated stress response (ISR) features a family of eIF2 kinases that sense cellular stress, triggering translational and transcriptional modes of gene expression that enhance cell adaptation to the underlying stress. Previously we reported (Cordova et al., 2022 eLife) that prostate cancer (PCa) cells rely on one of these eIF2 kinases, GCN2, for maintenance of amino acid homeostasis and sustained proliferation. GCN2 functions to enhance expression of amino acid transporters and subsequent import of essential amino acids (EAAs) that are necessary to sustain PCa growth. Genetic loss or pharmacological inhibition of GCN2 results in decreased expression of amino acid transporters, severe depletion of intracellular EAAs, and decreased proliferation of PCa cells in culture and mouse xenograft models. Although loss of GCN2 in PCa cells reduces proliferation, depletion of this eIF2 kinase is suggested to lead to cell stasis and modest cell death. We hypothesize that the static phenotype by GCN2 inhibition in PCa cells renders these cells vulnerable to senolytic treatment and is a potential therapeutic target in combination therapies. To address this idea, we utilized models of androgen-sensitive and castration-resistant PCa and non-tumorigenic prostate epithelial cells. GCN2 inhibition induced a static phenotype in PCa cell lines, but not non-tumorigenic prostate epithelial cells, and this was accompanied by increased expression of the senescent markers p53, p21, p27, and MCL-1. Furthermore, induction of senescent markers following GCN2 inhibition in PCa cells was reversed by supplementation with EAAs, suggesting that limitation of EAAs is critical to the induction of cell stasis. Of importance, treatment of PCa cells with Navitoclax, a senolytic agent that targets Bcl-2 family of anti-apoptotic proteins, in combination with GCN2 inhibition resulted in enhanced cell death and apoptosis compared to each single treatment alone. Our results suggest that GCN2 inhibition in PCa cells leads to depletion of EAAs and induction of a static phenotype, rendering these cells vulnerable to targeting the Bcl-2 family of proteins to expedite cell death. As such, therapies integrating GCN2 inhibition and senolytic agents are proposed to be effective strategies for treatment of PCa. Citation Format: Noah R. Sommers, Ricardo A. Cordova, Angela J. Klunk, Roberto Pili, Ronald C. Wek, Kirk A. Staschke. Targeting GCN2 regulation of amino acid homeostasis sensitizes prostate cancer cells to senolytic therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4816.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-4816
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 10
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    Abstract A45: PERK-Inhibition as a possible therapy for hypoxia-induced solitary dormant tumor cells
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 7_Supplement ( 2016-04-01), p. A45-A45
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 7_Supplement ( 2016-04-01), p. A45-A45
    Abstract: Disseminated tumor cells (DTCs) travel to secondary organs, where they may remain viable for extended amounts of time (years to decades). This state, known as cellular dormancy, is defined as a state of quiescence and cells remain solitary. Preliminary data from our group strongly suggests that single DTCs originating from hypoxic microenvironments within the primary tumor may be more prone to enter a prolonged cellular dormancy at secondary sites. Hypoxic stress also leads to the activation of the endoplasmic reticulum (ER) stress sensor PKR-like ER Kinase (PERK), which promotes the activation of survival genes through the unfolded protein response (UPR). We hypothesize that hypoxia-induced dormant cells require PERK for survival and that through PERK inhibition we can target dormancy. Here, we evaluate PERK inhibition as a way to selectively eliminate quiescent head and neck squamous cell carcinoma (HNSCC) tumor cells. To determine whether hypoxia induces dormancy and PERK activation we cultured HNSCC tumorigenic HEp3 (T-HEp3) cells in normoxic (21% O2) and hypoxic (1% O2) conditions for 8 and 24 hours, and measured the expression of quiescence markers (p27), dormancy markers (DEC2 & NR2F1), and PERK activation (ATF4) via western blot. We found that only at 8 hours p27, DEC2 and NR2F1 are higher expressed in HNSCC in hypoxic conditions in comparison to normoxic conditions. NR2F1 and DEC2 have been shown to promote dormancy by limiting proliferation via p27 induction and mediating the expression of pluripotency genes. After 8 and 24 hours, ATF4, a downstream target of PERK, was upregulated in hypoxic over normoxic cells. These findings support that hypoxic cells express dormancy markers simultaneously with active PERK signaling. To test HNSCC cell sensitivity to PERK inhibition, we seeded T-HEp3-TET-On-H2B-GFP cells at single cell level in a 3D Matrigel. These cells express a green fluorescent protein (GFP) in the presence of doxycycline (Dox). By seeding at a single cell level the solitary cells enter a quiescent phenotype. H2B-GFP was induced with Dox in 2D tissue culture for 3 days, prior to seeding in the Matrigel. Cells were then cultured in Dox free Matrigel in normoxic conditions for 10 days, daily treatment with PERK inhibitor LY4 was started at day 4. As a marker for quiescence, we monitored over time the retention of the H2B-GFP label in the nucleosomes. Treatment with 2μM and 6μM LY4 led to a significant decrease (p = 0.03, 0.0003, respectively) in the percentage of green label retaining cells at day 10 and 7, respectively. The total number of live cells did not increase over time (p = 0.17), arguing that the loss of H2B-GFP+ cells was not due to an increase in proliferation and dilution of the label but rather due to cell death of the quiescent, GFP positive cells. Further experiments will confirm the effect of such treatment on the hypoxic cells and the rate of death. These results indicate that dormant cells, either induced through hypoxic conditioning or single cell state, upregulate a set of dormancy markers as well as PERK. Quiescent cells seem to be dependent on PERK activity for their survival. The PERK inhibition selectively affected the survival of the quiescent, dormant-like H2B-GFP positive cells. This initial data suggests that PERK might represent a novel therapeutic target against disseminated DTCs, for which no therapeutic strategy is currently available. Citation Format: Miguel Vizarreta Sandoval, Georg Fluegen, Kirk A. Staschke, Veronica Calvo-Vidal, Julio A. Aguirre-Ghiso. PERK-Inhibition as a possible therapy for hypoxia-induced solitary dormant tumor cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A45.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TUMMET15-A45
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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