GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • American Association for Cancer Research (AACR)  (4)
  • 1
    Online Resource
    Online Resource
    Abstract LB190: Modulation of SPI1 transcriptional program contributes to the preclinical anti-tumor activity of SMARCA4/SMARCA2 ATPase inhibitors in AML
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. LB190-LB190
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. LB190-LB190
    Abstract: SPI1 (PU.1) is an ETS family transcription factor that plays a critical role in hematopoietic development and differentiation. Regulation of SPI1 expression has also been implicated in Acute Myeloid Leukemia (AML) oncogenesis, though its mechanism is incompletely understood. Previously we have identified and characterized a series of novel dual inhibitors of the SMARCA4/SMARCA2 ATPases (also referred to as BRG1/BRM), critical components of the BAF (mSWI/SNF) family of chromatin remodeling complexes; and FHD-286, a related SMARCA4/SMARCA2 ATPase inhibitor, is currently being explored clinically for the treatment of metastatic uveal melanoma and AML (NCT04879017 and NCT04891757). Here we show that AML cell lines are sensitive to BAF ATPase inhibition, resulting in both cell cycle arrest and apoptosis. We demonstrate that BAF ATPase inhibition primarily affects the SPI1 transcriptional profile by regulating SPI1 genomic occupancy at various enhancer elements, resulting in downregulation of key target genes. Using in vivo mouse models of AML, we demonstrate dose-dependent tumor growth inhibition and pharmacodynamic modulation of SPI1 target genes. Together, these data suggest that modulation of SPI1 function may, in part, provide a mechanistic basis for the clinical development of FHD-286 in AML. Citation Format: Gabriel J. Sandoval, Katharine Feldman, Sal Topal, Ammar Adam, Hsin-Jung Wu, Darshan Sappal, Luis M. Soares, David L. Lahr, Lan Xu, Rishi G. Vaswani, Jordana Muwanguzi, Liyue Huang, Jessica Piel, Mike Collins, Ho Man Chan, Michael J. Thomenius, Steven F. Bellon, Ryan G. Kruger, Carl P. Decicco, Richard C. Centore, Martin Hentemann. Modulation of SPI1 transcriptional program contributes to the preclinical anti-tumor activity of SMARCA4/SMARCA2 ATPase inhibitors in AML [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 LB190.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-LB190
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract 1950: The eIF4A inhibitors didesmethylrocaglamide and rocaglamide as effective treatments for pediatric bone and soft-tissue sarcomas
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 1950-1950
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 1950-1950
    Abstract: Background: Development of an effective medical therapy for osteosarcoma and Ewing sarcoma, the two most common aggressive forms of pediatric bone and soft-tissue sarcomas, is urgently needed as current treatments are inadequate particularly for those with recurrent or metastatic diseases. To achieve this goal, we have identified two natural eIF4A inhibitors, rocaglamide (Roc) and didesmethylrocaglamide (DDR), which potently inhibit proliferation of a series of commonly-used osteosarcoma and Ewing sarcoma cell lines. We also demonstrated that Roc effectively suppresses tumor growth in patient-derived xenograft (PDX) models of osteosarcoma and Ewing sarcoma. Both Roc- and DDR-treated sarcoma cells show decreased levels of multiple oncogenic kinases, including insulin-like growth factor-1 receptor (IGF-1R). Importantly, these rocaglamides are not sensitive to multidrug resistance 1 (MDR1) efflux. In addition, Roc exhibits 50% oral bioavailability, is well-tolerated in mice, and does not induce pulmonary toxicity in dogs as found with another eIF4A inhibitor silvestrol (Chang et al. Mol Cancer Ther. 2019; In Revision). Methods: Various osteosarcoma and Ewing sarcoma cell lines were treated with DDR and Roc, followed by cell proliferation assay, flow cytometry, and immunoblotting. Mesenchymal stem cells (MSCs) were used as a control for comparing the expression levels of the eIF4F components important for translation initiation. RNA interference (RNAi) and CRISPR/Cas9 techniques were used to verify eIF4A dependency. An orthotopic cell line-derived xenograft (CDX), a metastatic xenograft, and a PDX models for osteosarcoma and immunohistochemistry were used to assess antitumor efficacy. Results: We hypothesize that osteosarcoma and Ewing sarcoma cells are highly addicted to active protein synthesis and that Roc and DDR, by acting as potent eIF4A inhibitors with an ability to induce apoptosis and the DNA damage response, effectively eliminate these malignant sarcomas. We found that various osteosarcoma and Ewing sarcoma cell lines expressed higher levels of eIF4A2, but not eIF4A1, eIF4E, and eIF4G, than MSCs, suggesting a role of eIF4A2 in enhancing protein translation in these sarcoma cells. RNAi knockdown and CRISPR/Cas9 knockout experiments are being evaluated to verify this finding. Both DDR and Roc effectively blocked tumor growth in an orthotopic CDX model. As found with Roc previously, DDR also potently inhibited the growth of an osteosarcoma PDX model. Both rocaglamides were well tolerated at 3 mg/kg by IP every other day and did not cause any significant changes in body weight, compared with vehicle-treated controls. We are presently determining the effects of Roc and DDR on osteosarcoma metastasis. Conclusions: The potent anti-tumor activity and favorable toxicity profile of Roc and DDR suggest that these rocaglamides should be further evaluated as potential treatments for osteosarcomas and Ewing sarcomas. Citation Format: Long-Sheng Chang, Janet L. Oblinger, Garima Agarwal, Tyler A. Wilson, Ryan Roberts, James Fuchs, Barry R. O'Keefe, A. Douglas Kinghorn, Jerry M. Collins. The eIF4A inhibitors didesmethylrocaglamide and rocaglamide as effective treatments for pediatric bone and soft-tissue sarcomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1950.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-1950
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Abstract A058: Investigating the molecular role of BRD9 in synovial sarcoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics Vol. 22, No. 12_Supplement ( 2023-12-01), p. A058-A058
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 12_Supplement ( 2023-12-01), p. A058-A058
    Abstract: Bromodomain-containing protein 9 (BRD9) represents a potential selective vulnerability for tumors with specific alterations in the Brahma-associated factor (BAF) chromatin remodeling complex.  One example of such a modification is the incorporation of the SS18-SSX fusion into BAF complexes.  This alteration is a hallmark of synovial sarcoma, and thought to drive tumorigenesis. As BRD9 is a subunit unique to ncBAF, tumors that depend on ncBAF for survival may be susceptible to BRD9 degradation.  Accordingly, selective BRD9 degradation is a potential therapeutic approach to treat such diseases. Previous work has shown that loss of BRD9 causes cell and tumor proliferation defects (Brien et al. 2018, Michel et al. 2018).  To explore the mechanism by which degradation of BRD9 causes cell and tumor proliferation defects in synovial sarcoma, we utilized a multi-omic approach using RNA-seq, ATAC-seq, and ChIP-seq data to understand the molecular impact of loss of BRD9 on relevant cell lines and animal model tumors. ChIP-seq revealed genome-wide colocalization of BRD9 and Myc on chromatin, and BRD9 degradation can lead to MYC loss at the majority of these co-bound regions.  Genes commonly regulated in synovial cell lines treated with a BRD9 degrader in vitro and/or in vivo are enriched in MYC target genes, ribosome biogenesis genes and cell cycle genes. Furthermore, the genes commonly downregulated in synovial cell lines treated with a BRD9 degrader have notable MYC binding at their promoter regions. Therefore, we propose that these downregulated genes might be potential MYC targets, specifically in synovial sarcoma, and that downregulation leads to observed proliferation defects. Citation Format: Salih Topal, Claudia Dominici, Michael Collins, David L Lahr, Qianhe Zhou, Flore Uzan, David Mayhew, Ammar Adam, Victoria Garbitt-Amaral, Brandon Antonakos, Oliver Mikse, Hafiz Ahmad, Salonee Parikh, Mei Yun Lin, Hsin-Jung Wu, Gabriel Sandoval, Luis M. M. Soares, Jordana Muwanguzi, Huawei Chen, Zhaoxia Yang, Jason T. Lowe, Matt Netherton, Laura Zawadzke, Johannes Voigt, Liyue Huang, Sabine Ruppel, Ho Man Chan, Ryan Kruger, David S. Millan, Scott Innis, Steven F. Bellon. Investigating the molecular role of BRD9 in synovial sarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abst ract nr A058.
    Type of Medium: Online Resource
    ISSN: 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-23-A058
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2062135-8
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Targeting Protein Translation by Rocaglamide and Didesmethylrocaglamide to Treat MPNST and Other Sarcomas
    American Association for Cancer Research (AACR) ; 2020
    In:  Molecular Cancer Therapeutics Vol. 19, No. 3 ( 2020-03-01), p. 731-741
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 19, No. 3 ( 2020-03-01), p. 731-741
    Abstract: Malignant peripheral nerve sheath tumors (MPNST) frequently overexpress eukaryotic initiation factor 4F components, and the eIF4A inhibitor silvestrol potently suppresses MPNST growth. However, silvestrol has suboptimal drug-like properties, including a bulky structure, poor oral bioavailability ( & lt;2%), sensitivity to MDR1 efflux, and pulmonary toxicity in dogs. We compared ten silvestrol-related rocaglates lacking the dioxanyl ring and found that didesmethylrocaglamide (DDR) and rocaglamide (Roc) had growth-inhibitory activity comparable with silvestrol. Structure–activity relationship analysis revealed that the dioxanyl ring present in silvestrol was dispensable for, but may enhance, cytotoxicity. Both DDR and Roc arrested MPNST cells at G2–M, increased the sub-G1 population, induced cleavage of caspases and PARP, and elevated the levels of the DNA-damage response marker γH2A.X, while decreasing the expression of AKT and ERK1/2, consistent with translation inhibition. Unlike silvestrol, DDR and Roc were not sensitive to MDR1 inhibition. Pharmacokinetic analysis confirmed that Roc had 50% oral bioavailability. Importantly, Roc, when administered intraperitoneally or orally, showed potent antitumor effects in an orthotopic MPNST mouse model and did not induce pulmonary toxicity in dogs as found with silvestrol. Treated tumors displayed degenerative changes and had more cleaved caspase-3–positive cells, indicative of increased apoptosis. Furthermore, Roc effectively suppressed the growth of osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma cells and patient-derived xenografts. Both Roc- and DDR-treated sarcoma cells showed decreased levels of multiple oncogenic kinases, including insulin-like growth factor-1 receptor. The more favorable drug-like properties of DDR and Roc and the potent antitumor activity of Roc suggest that these rocaglamides could become viable treatments for MPNST and other sarcomas.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-19-0809
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...