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  • 1
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    EXTH-37. TARGETING EPIGENETIC VULNERABILITIES IDENTIFIED FROM A CRISPR SCREEN IN H3.3K27M DIPG
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii95-ii95
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii95-ii95
    Abstract: Children diagnosed with diffuse intrinsic pontine glioma (DIPG), a type of high grade glioma in the brainstem, currently have a dismal 5-year overall survival of only 2%. The majority of DIPG patients harbor a K27M mutation in histone 3.3 encoding genes (H3.3K27M). To understand if the aberrant epigenetic landscape induced by H3.3K27M provides an opportunity for novel targeted therapies, we conducted the first CRISPR/Cas9 screen using a focused library of 1,350 epigenetic regulatory and cancer related genes in six H3.3K27M DIPG patient-derived primary neurosphere cell lines. We identified gene dependencies in chromatin regulators, polycomb repressive complexes 1 and 2 (PRC1 and PRC2), histone demethylases, acetyltransferases and deacetylators as novel tumor cell dependencies in DIPG. We hypothesized that targeting dysregulated functions of chromatin regulators by genetically deleting and chemically targeting these epigenetically induced vulnerabilities, we could ameliorate, or even reverse the downstream oncogenic effects of the aberrant epigenetic landscape of DIPG. In our secondary CRISPR nanoscreen, we first used six single guide RNAs (sgRNA) to knockout each gene using CRISPR/Cas9 ribonucleoprotein nucleofections, followed by use of three best sgRNAs combined with homology directed repair templates. Compared to lentiviral delivery, nucleofection is a rapid method, with reduced off-target toxicity, suitable for single gene knockouts in DIPG neurospheres. Secondary CRISPR validations confirmed dependencies in BMI1, CBX4, KDM1A, EZH2, EED, SUZ12, HDAC2, and EP300. Next, we conducted a chemical screen using 20 inhibitors and degraders to target the aberrant activity of HDAC, KDM1A, P300/CBP, PRC1 and PRC2. We identified eight chemical compounds that were effective in H3.3K27M DIPG neurosphere cell lines at low drug concentrations. Among these, an inhibitor and degrader targeting P300/CBP activity indicates a novel strategy of epigenetic therapy in DIPG. Through our combinatorial testing, we will identify a synergistic combination of epigenetic therapy for treating children diagnosed with H3.3K27M DIPG.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa215.391
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 2
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    DIPG-19. BAF COMPLEX PERTURBATION AS A NOVEL THERAPEUTIC OPPORTUNITY IN H3K27M PEDIATRIC GLIOMA
    Oxford University Press (OUP) ; 2023
    In:  Neuro-Oncology Vol. 25, No. Supplement_1 ( 2023-06-12), p. i16-i17
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 25, No. Supplement_1 ( 2023-06-12), p. i16-i17
    Abstract: Epigenetic dysregulation resulting in stalled development plays a crucial role in pediatric cancer tumorigenesis. Diffuse midline gliomas (DMG) are universally fatal pediatric brain cancers refractory to standard of care treatment modalities. These malignancies are driven by heterozygous mutations in genes encoding histone 3 (H3K27M) which create an aberrant epigenetic landscape that keeps glioma cells in an undifferentiated stem-like state. Consequently, targeting epigenetic regulators to restore the epigenome and force glioma cells to exit this stem-like cell state represents a promising new therapeutic strategy for H3K27M-DMG. To interrogate for epigenetic dependencies, we performed a CRISPR/Cas9 inactivation screen in patient-derived H3K27M-DMG neurospheres using an epigenetically focused sgRNA library and identified several core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex as genetic vulnerabilities. Validation assays revealed that knockout of the BAF catalytic subunit BRG1 results in decreased glioma cell proliferation and tumor growth in orthotopic mouse models. Mechanistically, genome wide localization and DNA accessibility studies combined with regulatory network analysis demonstrated that BRG1 controls the transcription factor and enhancer landscapes that maintain H3K27M-DMG cells in a cycling, oligodendrocyte precursor cell-like state. Single cell transcriptome analysis in vitro and immunofluorescence studies in vivo confirmed that genetic perturbation of this chromatin remodeler promotes progression of differentiation along the astrocytic lineage. Similarly, pharmacological suppression of BRG1 activity, using both catalytic inhibitors as well as recently developed degraders, opposes tumor cell proliferation, stimulates cell state transition, and improves overall survival of patient-derived xenograft models. Interestingly, these effects seem to be restricted to H3K27M mutant glioma, as H3 wildtype glioma cells were less sensitive to BRG1 inhibition both in vitro and in vivo. In summary, we demonstrate that the BAF complex contributes to the maintenance of glioma cells in a proliferative stem-like state and that its therapeutic inhibition has translational potential for children bearing H3K27M-DMG.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noad073.066
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 3
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    Abstract B10: Rhabdomyosarcoma requires MYC family genomic events to pathogenically subvert core-regulatory circuitry
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 14_Supplement ( 2020-07-15), p. B10-B10
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 14_Supplement ( 2020-07-15), p. B10-B10
    Abstract: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood. Despite multimodality therapy and trials of molecularly targeted agents, limited improvements in overall survival have been realized for patients with high-risk disease. Thus, we aimed to determine the landscape of tumor-specific gene dependencies that underlie tumorigenesis in RMS and therefore provide a valuable group of targets for the development of novel therapeutics. Using unbiased genome-scale CRISPR-Cas9 approaches, we identified a set of RMS-specific tumor dependencies involved in tumor cell growth and survival. RMS dependencies were enriched for nucleic acid binding proteins, including transcription factors (TFs). We then used genome-wide chromatin-immunoprecipitation coupled to high-throughput sequencing analysis to demonstrate that a small number of essential TFs—MYCN, MYOD1, TCF12, SOX8, ZEB2, ZNF217, and SIX1—are members of the transcriptional core regulatory circuitry (CRC) that maintains the malignant cell state of RMS. Both c-MYC and MYCN were associated with gene and enhancer copy number increases in cell lines and primary tumors and represented strong dependencies in the RMS cell lines screened. c-MYC and MYCN function to similarly invade and regulate the CRC in respectively dependent cells. To disable the CRC, we tested A485, an inhibitor of the histone acetyltransferase enzymes involved in the establishment of super-enhancer elements that are associated with high level expression of the CRC factors. A485 caused a reversible and rapid loss of CRC factor and c-MYC and/or MYCN expression, and prolonged treatment resulted in cell cycle arrest, differentiation, and apoptosis in vitro and in vivo. This phenotype is rescued by exogenous re-expression of either c-MYC or MYCN in a manner insensitive to A485, indicating a mechanism by which these genes subvert a myogenic CRC to produce an oncogenic fate. This study defines a common set of critical dependency genes in RMS and identifies key genomic events surrounding the c-MYC and MYCN loci that lead to elevated expression and tumorigenesis. Citation Format: Adam D. Durbin, Guillaume Kugener, Mark W. Zimmerman, Chuan Yan, Neekesh V. Dharia, Elizabeth S. Frank, Xiang Chen, Ken N. Ross, Brenton Paolella, Michael Krill-Burger, David E. Root, Jesse S. Boehm, Francisca Vazquez, Andrew L. Hong, Aviad Tsherniak, David M. Langenau, William C. Hahn, Todd R. Golub, Brian J. Abraham, Richard A. Young, A. Thomas Look, Kimberly Stegmaier. Rhabdomyosarcoma requires MYC family genomic events to pathogenically subvert core-regulatory circuitry [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B10.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PEDCA19-B10
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 4
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    Abstract B50: Targeting EWS/FLI fusion oncoprotein stability/degradation in Ewing sarcoma
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 14_Supplement ( 2020-07-15), p. B50-B50
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 14_Supplement ( 2020-07-15), p. B50-B50
    Abstract: Fusion-transcription factors (fusion-TFs) represent a class of oncoproteins that drive tumorigenesis by activating an aberrant transcriptional program to promote the development and survival of cancer cells. Unlike fusion oncoproteins involving readily druggable proteins such as kinases, fusion-TFs are difficult to therapeutically target. Recent studies have suggested protein degradation as a novel strategy in targeting oncogenic transcription factors. However, the molecular and functional mechanisms that regulate fusion-TFs’ degradation/stability are unknown. Ewing sarcoma is the second most common bone cancer in children and is driven by EWS-ETS fusion-TFs, most commonly EWS/FLI (~85%). EWS/FLI acts as a pioneer transcription factor to activate oncogenic gene expression by chromatin remodeling that drives the tumorigenesis and survival of Ewing sarcoma tumors. Despite this, there are no clinically validated targeted therapies against EWS/FLI. Ewing sarcoma has a relatively quiet genome and lacks recurrent mutations, which hinders target identification for therapeutic intervention. Thus, we examined whether a protein degradation strategy can be exploited to target EWS/FLI by investigating the molecular and functional mechanisms by which EWS/FLI protein stability/degradation is regulated. In a genome-scale, flow cytometry-based CRISPR-Cas9 screen, we discovered that tripartite motif containing 8 (TRIM8) is a novel E3 ubiquitin for EWS/FLI. Biochemical studies showed that TRIM directly binds and ubiquitinates EWS/FLI for proteasome-dependent degradation. Moreover, we identified TRIM8 as a top enriched and selective dependency in Ewing sarcoma in a genome-scale CRISPR-Cas9 depletion screen. We determined that TRIM8 knockout increased EWS/FLI protein levels and induced apoptosis of Ewing sarcoma cells in vitro and reduced tumor growth in vivo. Consistent with TRIM8 as an E3 ligase for EWS/FLI, overexpression of TRIM8 reduced EWS/FLI protein levels and decreased growth. TRIM8 lacking the E3 ligase domain (TRIM8E3) functioned as a dominant negative, leading to increased EWS/FLI and decreased growth of Ewing sarcoma cells. To investigate whether upregulated EWS/FLI protein expression is mediating the TRIM8 knockout phenotype, we engineered Ewing sarcoma cell line by concurrently knocking out endogenous EWS/FLI using CRISPR and expressing degradable EWS/FLI (FKBP12F36V-EWS/FLI) using the dTAG system. The dTAG molecule is a heterobifunctional molecule that specifically binds to FKBP12F36V and an E3 ligase complex for targeted protein degradation. Using this degradable EWS/FLI cell model, we showed that TRIM8 suppression phenotype can be rescued by degrading the upregulated EWS/FLI protein expression to control levels. Our results demonstrate that the protein stability of fusion-TF oncoproteins is highly regulated to maintain the expression at a precise level and highlight the critical importance of oncogene dosage in cancer cell survival. Citation Format: Bo Kyung Alex Seong, Shan Lin, Katherine Donovan, Amanda Robichaud, Bjorn Stolte, Emily Wang, Neekesh Dharia, Behnam Nabet, Federica Piccioni, Nathanael Gray, Eric Fischer, Kimberly Stegmaier. Targeting EWS/FLI fusion oncoprotein stability/degradation in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B50.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PEDCA19-B50
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
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    Abstract LB076: Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. LB076-LB076
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. LB076-LB076
    Abstract: Leukemic blasts are immune cells gone awry. We thus hypothesized that dysregulation of inflammatory pathways can maintain a leukemic state. In contrast to traditional cancer immunotherapy, we exploited inflammatory signaling within AML blasts as cell-intrinsic, self-directed immunotherapy. Corroborating the hypothesis that AML cells depend on proper regulation of inflammatory networks, we identified an AML subgroup enriched for inflammatory pathways, associated with a monocytic lineage signature. To discover AML selective, immune-modulating vulnerabilities, we integrated data from the Cancer Dependency Map on 789 cancer cell lines with independent genome-wide screens, identifying Interferon regulatory factor 2 binding protein 2 (IRF2BP2). We validated AML cell dependency on IRF2BP2 with orthogonal genetic approaches in vitro and in vivo and studied acute IRF2BP2 degradation. Perturbation of IRF2BP2 resulted in cell death with hallmarks of apoptosis. To decipher how IRF2BP2 relates to inflammatory signaling, we studied IRF2BP2 localization on chromatin. We found genome-wide IRF2BP2 binding in promoter and in enhancer regions. Global gene expression studies following degradation of IRF2BP2 showed an increase in expression of the majority of IRF2BP2 bound genes, supporting a role for IRF2BP2 as a transcriptional repressor. Gene set enrichment analyses identified NF-κB-related immune response signatures as the most significantly altered leading us to hypothesize that IRF2BP2 represses NF-κB-mediated TNFα signaling that, when acutely perturbed, leads to leukemia cell death. Indeed, we confirmed an activation of NF-κB-signaling, an increase in nuclear RELA protein, and gain in RELA chromatin binding following degradation of IRF2BP2. Moreover, a mutant “super-repressor” allele of IκBα rescued the impaired cell growth upon IRF2BP2 perturbation, supporting cell death associated with IRF2BP2 loss being mediated through activation of NF-κB signaling. In addition, we identified IL-1ß as an enhancer of the inflammatory response repressed by IRF2BP2. Using patient-derived xenograft models, we demonstrated a significant reduction in leukemia burden and an increase in median survival in mice that had received patient-derived AML cells with IRF2BP2-targeting CRISPR guides compared to control guides. Importantly, loss of IRF2BP2 in normal bone marrow-derived hCD34+ cells had no effect on colony forming capacity. In summary, we demonstrate that IRF2BP2 represses IL-1ß/TNFα signaling via NF-κB, and IRF2BP2 perturbation results in hyperinflammation leading to AML cell death. These findings elucidate a hitherto unexplored AML dependency, reveal cell-intrinsic inflammatory signaling as a mechanism priming leukemic blasts for cell death, and motivate the exploration of alternative immune-mediated therapies in cancers that have yet to reap the benefits of the immunotherapy revolution. Citation Format: Jana M. Ellegast, Gabriela Alexe, Amanda Hamze, Shan Lin, Hannah J. Uckelmann, Philipp J. Rauch, Maxim Pimkin, Linda Ross, Neekesh V. Dharia, Amanda L. Robichaud, Amy Conway Saur, Delan Khalid, Mark Wunderlich, Lina Benajiba, Behnam Nabet, Nathanael S. Gray, Stuart H. Orkin, Kimberly Stegmaier. Unleashing cell-intrinsic inflammation as a strategy to kill AML blasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB076.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-LB076
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
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    Gene Fusions Create Partner and Collateral Dependencies Essential to Cancer Cell Survival
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 15 ( 2021-08-01), p. 3971-3984
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 15 ( 2021-08-01), p. 3971-3984
    Abstract: Gene fusions frequently result from rearrangements in cancer genomes. In many instances, gene fusions play an important role in oncogenesis; in other instances, they are thought to be passenger events. Although regulatory element rearrangements and copy number alterations resulting from these structural variants are known to lead to transcriptional dysregulation across cancers, the extent to which these events result in functional dependencies with an impact on cancer cell survival is variable. Here we used CRISPR-Cas9 dependency screens to evaluate the fitness impact of 3,277 fusions across 645 cell lines from the Cancer Dependency Map. We found that 35% of cell lines harbored either a fusion partner dependency or a collateral dependency on a gene within the same topologically associating domain as a fusion partner. Fusion-associated dependencies revealed numerous novel oncogenic drivers and clinically translatable alterations. Broadly, fusions can result in partner and collateral dependencies that have biological and clinical relevance across cancer types. Significance: This study provides insights into how fusions contribute to fitness in different cancer contexts beyond partner-gene activation events, identifying partner and collateral dependencies that may have direct implications for clinical care.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-21-0791
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 7
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    Abstract 2318: EP300 selectively controls the enhancer landscape of high risk neuroblastoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2318-2318
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2318-2318
    Abstract: Gene expression is regulated by promoters and enhancers marked by histone H3-lysine-27 acetylation (H3K27ac) and established by the paralogous histone acetyltransferases (HATs), EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma depend on EP300, while CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2β, a transcription factor member of the lineage-defining core-regulatory transcriptional circuitry (CRC). To disrupt EP300, we developed a proteolysis-targeted-chimaera (PROTAC) compound “JQAD1” that selectively targets EP300 for degradation. This results in loss of H3K27ac at CRC enhancers and neuroblastoma apoptosis, with limited toxicity to untransformed cells where CBP compensates. EP300 physically interacts with the MYCN oncoprotein, promoting its chromatin localization in neuroblastoma. EP300 degradation therefore capitalizes on EP300 dependency in neuroblastoma by controlling MYCN localization and preventing MYCN from sustaining the malignant cell state. Citation Format: Adam D. Durbin, Tingjian Wang, Virangika K. Wimalasena, Mark W. Zimmerman, Deyao Li, Neekesh V. Dharia, Luca Mariani, Paul M. Park, Logan H. Sigua, Ken Morita, Amy S. Conway, Amanda L. Robichaud, Antonio Perez-Atayde, Melissa Bikowitz, Taylor Quinn, Olaf Wiest, Ernst Schonbrunn, Martha Bulyk, Brian J. Abraham, Kimberly Stegmaier, A. Thomas Look, Jun Qi. EP300 selectively controls the enhancer landscape of high risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2318.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2318
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 8
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    A Combination CDK4/6 and IGF1R Inhibitor Strategy for Ewing Sarcoma
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 4 ( 2019-02-15), p. 1343-1357
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 4 ( 2019-02-15), p. 1343-1357
    Abstract: Novel targeted therapeutics have transformed the care of subsets of patients with cancer. In pediatric malignancies, however, with simple tumor genomes and infrequent targetable mutations, there have been few new FDA-approved targeted drugs. The cyclin-dependent kinase (CDK)4/6 pathway recently emerged as a dependency in Ewing sarcoma. Given the heightened efficacy of this class with targeted drug combinations in other cancers, as well as the propensity of resistance to emerge with single agents, we aimed to identify genes mediating resistance to CDK4/6 inhibitors and biologically relevant combinations for use with CDK4/6 inhibitors in Ewing. Experimental Design: We performed a genome-scale open reading frame (ORF) screen in 2 Ewing cell lines sensitive to CDK4/6 inhibitors to identify genes conferring resistance. Concurrently, we established resistance to a CDK4/6 inhibitor in a Ewing cell line. Results: The ORF screen revealed IGF1R as a gene whose overexpression promoted drug escape. We also found elevated levels of phospho-IGF1R in our resistant Ewing cell line, supporting the relevance of IGF1R signaling to acquired resistance. In a small-molecule screen, an IGF1R inhibitor scored as synergistic with CDK4/6 inhibitor treatment. The combination of CDK4/6 inhibitors and IGF1R inhibitors was synergistic in vitro and active in mouse models. Mechanistically, this combination more profoundly repressed cell cycle and PI3K/mTOR signaling than either single drug perturbation. Conclusions: Taken together, these results suggest that IGF1R inhibitors activation is an escape mechanism to CDK4/6 inhibitors in Ewing sarcoma and that dual targeting of CDK4/6 inhibitors and IGF1R inhibitors provides a candidate synergistic combination for clinical application in this disease.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-0372
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 9
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    A Chemical Genomic Analysis of Decoquinate, a Plasmodium falciparum Cytochrome b Inhibitor
    American Chemical Society (ACS) ; 2011
    In:  ACS Chemical Biology Vol. 6, No. 11 ( 2011-11-18), p. 1214-1222
    Details
    In: ACS Chemical Biology, American Chemical Society (ACS), Vol. 6, No. 11 ( 2011-11-18), p. 1214-1222
    Type of Medium: Online Resource
    ISSN: 1554-8929 , 1554-8937
    URL: Article
    DOI: 10.1021/cb200105d
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2011
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    A Systems-Based Analysis of Plasmodium vivax Lifecycle Transcription from Human to Mosquito
    Public Library of Science (PLoS) ; 2010
    In:  PLoS Neglected Tropical Diseases Vol. 4, No. 4 ( 2010-4-6), p. e653-
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    In: PLoS Neglected Tropical Diseases, Public Library of Science (PLoS), Vol. 4, No. 4 ( 2010-4-6), p. e653-
    Type of Medium: Online Resource
    ISSN: 1935-2735
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    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2010
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