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  • American Association for Cancer Research (AACR)  (4)
  • 1
    Online Resource
    Online Resource
    Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Discovery ( 2023-09-11), p. OF1-OF24
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), ( 2023-09-11), p. OF1-OF24
    Abstract: Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle–related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. Significance: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction.
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-23-0131
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2607892-2
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  • 2
    Online Resource
    Online Resource
    Abstract NTOC-087: DYNAMIC REPROGRAMMING OF THE KINOME OVERCOMES BET PROTEIN INHIBITION IN OVARIAN CANCER
    American Association for Cancer Research (AACR) ; 2017
    In:  Clinical Cancer Research Vol. 23, No. 11_Supplement ( 2017-06-01), p. NTOC-087-NTOC-087
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 11_Supplement ( 2017-06-01), p. NTOC-087-NTOC-087
    Abstract: High-grade serous ovarian carcinoma (HGS-OvCa) is the most common and deadly form of ovarian cancer, and currently lacks effective targeted therapies. Recently, proteins involved in chromatin remodeling such as the BET bromodomain protein BRD4 have emerged as an exciting new class of targets for the treatment of cancer. Targeted BRD4 inhibition has been shown to cause tumor regression and apoptosis in a number of cancers, including HGS-OvCa. Consequently, small molecule BET bromodomain inhibitors (BETi) are actively being pursued in clinical trials. In our preliminary studies, we discovered that the BET inhibitor JQ1 dramatically reduced MYC protein levels resulting in inhibited cell growth and survival in a panel of HGS-OvCa cell lines. Importantly, although JQ1 initially caused significant growth arrest and apoptosis, the majority of HGS-OvCa cell lines acquired drug resistance. Detailed molecular characterization of JQ1- resistant HGS-OvCa cells showed the return of MYC protein levels accompanied by elevated PI3K-AKT activity, suggesting the acquired resistance stems from activated kinase signaling. Our laboratory has designed a novel mass spectrometry approach that globally measures kinase activity to identify the kinase networks responsible for drug resistance. Using this technology, we analyzed global kinase activity in JQ1-resistant cells and observed the activation of several receptor-tyrosine kinases (RTKs), including EGFR, FGFRs and IGF1R known to strongly drive PI3K-AKT pro-survival signaling pathways. These findings suggest that BETi therapies may have limited success as single agent therapies due to “adaptive kinome reprogramming” and will likely require combination strategies involving inhibitors targeting protein kinases and BET bromodomain proteins. Citation Format: Alison M. Kurimchak, Claude Shelton, Kelly E. Duncan, Katherine J. Johnson, Jennifer Brown, Shane O'Brien, Rashid Gabbasov, Lauren S. Fink, Yuesheng Li, Nicole Lounsbury, Magid Abou-Gharbia, Wayne E. Childers, Denise C. Connolly, Jonathan Chernoff, Jeffrey R. Peterson, James S. Duncan. DYNAMIC REPROGRAMMING OF THE KINOME OVERCOMES BET PROTEIN INHIBITION IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-087.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.OVCASYMP16-NTOC-087
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
    Online Resource
    Online Resource
    Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Lesions
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Discovery Vol. 13, No. 6 ( 2023-06-02), p. 1324-1345
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 13, No. 6 ( 2023-06-02), p. 1324-1345
    Abstract: The adult healthy human pancreas has been poorly studied given the lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors, thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathologic analysis of the samples revealed pancreatic intraepithelial neoplasia (PanIN) lesions in most individuals irrespective of age. Using a combination of multiplex IHC, single-cell RNA sequencing, and spatial transcriptomics, we provide the first-ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. Significance: Precursor lesions to pancreatic cancer are poorly characterized. We analyzed donor pancreata and discovered that precursor lesions are detected at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell-intrinsic factors that restrain or, conversely, promote malignant progression. See related commentary by Hoffman and Dougan, p. 1288. This article is highlighted in the In This Issue feature, p. 1275
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-23-0013
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2607892-2
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  • 4
    Online Resource
    Online Resource
    CDK2-Mediated Upregulation of TNFα as a Mechanism of Selective Cytotoxicity in Acute Leukemia
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 10 ( 2021-05-15), p. 2666-2678
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 10 ( 2021-05-15), p. 2666-2678
    Abstract: Although inhibitors of the kinases CHK1, ATR, and WEE1 are undergoing clinical testing, it remains unclear how these three classes of agents kill susceptible cells and whether they utilize the same cytotoxic mechanism. Here we observed that CHK1 inhibition induces apoptosis in a subset of acute leukemia cell lines in vitro, including TP53-null acute myeloid leukemia (AML) and BCR/ABL–positive acute lymphoid leukemia (ALL), and inhibits leukemic colony formation in clinical AML samples ex vivo. In further studies, downregulation or inhibition of CHK1 triggered signaling in sensitive human acute leukemia cell lines that involved CDK2 activation followed by AP1-dependent TNF transactivation, TNFα production, and engagement of a TNFR1- and BID-dependent apoptotic pathway. AML lines that were intrinsically resistant to CHK1 inhibition exhibited high CHK1 expression and were sensitized by CHK1 downregulation. Signaling through this same CDK2–AP1–TNF cytotoxic pathway was also initiated by ATR or WEE1 inhibitors in vitro and during CHK1 inhibitor treatment of AML xenografts in vivo. Collectively, these observations not only identify new contributors to the antileukemic cell action of CHK1, ATR, and WEE1 inhibitors, but also delineate a previously undescribed pathway leading from aberrant CDK2 activation to death ligand–induced killing that can potentially be exploited for acute leukemia treatment. Significance: This study demonstrates that replication checkpoint inhibitors can kill AML cells through a pathway involving AP1-mediated TNF gene activation and subsequent TP53-independent, TNFα-induced apoptosis, which can potentially be exploited clinically.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-20-1504
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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