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  • 1
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    Online Resource
    Inhibition of RNA Polymerase I Transcription by CX-5461 As a Therapeutic Strategy for the Cancer-Specific Activation of p53 in MLL-Rearranged Acute Myeloid Leukemias
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 1548-1548
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1548-1548
    Abstract: Abstract 1548 Increased transcription of the ribosomal genes (rDNA) by RNA Polymerase I (Pol I) is a common feature of human cancer1. Inhibition of Pol I transcription causes nucleolar stress that leads to the release of ribosomal proteins from the nucleolus into the nucleoplasm where they can sequester the p53 inhibitory protein MDM2, causing activation of p53 and induction of apoptosis2. We have developed a potent and selective small molecule inhibitor of Pol I transcription (CX-5461) that is non-genotoxic3. When evaluated for anti-proliferative activity against genetically diverse cancer cell lines, CX-5461 exhibited its greatest potency against wild-type (wt) p53 cells derived from hematological malignancies (median IC50 = 12 nM), while the median IC50s in cells derived from p53 mutated hematological, p53wt and p53 mutated solid tumors and normal cells were less sensitive to CX-5461 (median IC50s = 94 nM, 164 nM, 265 nM and 5 mM respectively), indicating CX-5461 selectively kills p53-wild type malignant hematopoietic cells. Consistent with the nucleolar stress model, p53 wt human leukemia cell lines exhibited robust activation of p53 signaling and apoptotic death in response to low nanomolar doses of CX-5461. To explore the therapeutic potential of Pol I transcription inhibition in vivo in hematological malignancies wt for p53 that are refractory to cytotoxic therapies we tested CX-5461 in mouse models of human acute myeloid leukemia (AML) expressing MLL fusion proteins4. Mice transplanted with 5×106 leukemia cells expressing MLL/ENL or MLL/AF9 together with oncogenic NRAS linked to GFP and luciferase biomarkers by virtue of bicistronic retroviral vectors, rapidly developed aggressive leukemia characterized by anemia, leukocytosis, hepatosplenomegaly and within 7–10 days (Mac1+, Gr-1) leukemic cell counts in peripheral blood. Treatment of recipient mice harboring MLL/ENL+NRAS leukemia with CX-5461 (40mg/kg Q3D) significantly increased median survival (17 days for vehicle vs 36 days for drug, P 〈 0.0001), and reduced leukemic burden, as determined by leukemic cell luminescence imaging, peripheral white blood cell counts (20.77×103cells/ml±2.25 for vehicle vs 6.2×103cells/ml±0.68 for drug, P 〈 0.0001) at sacrifice and FACS analysis of the peripheral blood (24.36% GFP leukemic cells±1.84 for vehicle vs 6.30% leukemic cells±0.5 for drug, P 〈 0.0001) after 3 doses of treatment. The reduction in tumour burden was associated with in vivo activation of p53 signaling and apoptosis. In marked contrast, treatment of MLL/ENL+NRAS leukemic mice with a combination regimen of cytarabine (50 mg/kg 5XQD IP) and doxorubicin (1.5 mg/kg 3XQD IP) at the combined MTD dose failed to provide a significant survival advantage. Treatment of recipient mice harboring the highly aggressive MLL/AF9 + NRAS leukemia with CX-5461 (40mg/kg Q3D) was also able to increased overall survival (15 days for vehicle vs 23 days for drug, P 0.0009), with this delay accompanied by a significant decrease in leukemic burden as determined by peripheral white blood cell counts (114×103cells/ml±12.24 for vehicle vs 4.68×103cells/ml±0.7 for drug) and FACS analysis of the peripheral blood (65% GFP leukemic cells±4.9 for vehicle vs 0.26% leukemic cells±0.05 for drug) after 2 respectively 3 doses of treatment. Critically, in murine xenograft of human AML MV 4;11 that carries the MLL/AF4 fusion, treatment with CX-5461 (125 mg/kg Q7D IP) inhibited tumour growth by 93% and extended time to sacrifice from 21 to 36 days. Together this work demonstrates that CX-5461, which selectively inhibits Pol I transcription and non-genotoxically activates p53, may be used to therapeutically treat aggressive p53-wild type AMLs that are highly refractory to standard cytotoxic therapies. The fact that mutations or deletions of the p53 gene are relatively rare in AML, coupled with our data that p53-wt AML cancer cells are particularly sensitive to CX-5461, provides a compelling rationale for evaluating CX-5461 in this patient population. Disclosures: Drygin: Cylene Pharmaceuticals Inc: Employment. Huser:Cylene Pharmaceuticals Inc: Employment. Bliesath:Cylene Pharmaceuticals Inc: Employment. Ryckman:Cylene Pharmaceuticals Inc: Employment. Rice:Cylenen Pharmaceuticals Inc: Employment. Hannan:Cylene Pharmaceuticals Inc: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.1548.1548
    RVK:
    XA 33000
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 2
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    Online Resource
    CX-4945, an Orally Bioavailable Selective Inhibitor of Protein Kinase CK2, Inhibits Prosurvival and Angiogenic Signaling and Exhibits Antitumor Efficacy
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 24 ( 2010-12-15), p. 10288-10298
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 24 ( 2010-12-15), p. 10288-10298
    Abstract: Malignant transformation and maintenance of the malignant phenotype depends on oncogenic and non-oncogenic proteins that are essential to mediate oncogene signaling and to support the altered physiologic demands induced by transformation. Protein kinase CK2 supports key prosurvival signaling pathways and represents a prototypical non-oncogene. In this study, we describe CX-4945, a potent and selective orally bioavailable small molecule inhibitor of CK2. The antiproliferative activity of CX-4945 against cancer cells correlated with expression levels of the CK2α catalytic subunit. Attenuation of PI3K/Akt signaling by CX-4945 was evidenced by dephosphorylation of Akt on the CK2-specific S129 site and the canonical S473 and T308 regulatory sites. CX-4945 caused cell-cycle arrest and selectively induced apoptosis in cancer cells relative to normal cells. In models of angiogenesis, CX-4945 inhibited human umbilical vein endothelial cell migration, tube formation, and blocked CK2-dependent hypoxia-induced factor 1 alpha (HIF-1α) transcription in cancer cells. When administered orally in murine xenograft models, CX-4945 was well tolerated and demonstrated robust antitumor activity with concomitant reductions of the mechanism-based biomarker phospho-p21 (T145). The observed antiproliferative and anti-angiogenic responses to CX-4945 in tumor cells and endothelial cells collectively illustrate that this compound exerts its antitumor effects through inhibition of CK2-dependent signaling in multiple pathways. Finally, CX-4945 is the first orally bioavailable small molecule inhibitor of CK2 to advance into human clinical trials, thereby paving the way for an entirely new class of targeted treatment for cancer. Cancer Res; 70(24); 10288–98. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-10-1893
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 3
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    Online Resource
    Abstract 5494: CX-4945, an inhibitor of protein kinase CK2, potentiates the antitumor activity of platinum chemotherapy in models of ovarian cancer by preventing phosphorylation of XRCC1 and MDC1 and disrupting DNA damage repair
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5494-5494
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5494-5494
    Abstract: Platinum-based chemotherapeutics are commonly used to treat solid tumors but may be restricted in their application by dose limiting toxicity and inherent or acquired resistance. Because efficient DNA damage repair mechanisms contribute to resistance, targeting components of the repair machinery has emerged as a strategy to increase the effectiveness of these and other DNA-damaging anti-cancer drugs. Protein kinase CK2 is a serine/threonine kinase that has emerged as an attractive molecular target due to its overexpression in cancer and regulatory role in key cellular processes including the cell cycle, apoptosis and DNA damage repair. Multiple lines of evidence suggest an increasingly important role for CK2 in the DNA damage response, including the phosphorylation and activation of the mediator/adaptor proteins XRCC1 and MDC1. XRCC1 is an essential component for nucleotide excision repair which is the major repair pathway responsible for removing platinum adducts. MDC1 is the predominant γ-H2AX recognition factor in mammalian cells and is essential for homologous recombination repair. CX-4945 is a first-in-class, selective, oral inhibitor of CK2 currently in Phase 1 clinical trials. We sought to determine if inhibiting CK2 activity with CX-4945 would prevent phosphorylation of XRCC1 and MDC1 and potentiate the activity of platinum-based drugs by preventing DNA damage repair. Treatment of the ovarian cancer cell lines A2780 and SKOV3 with CX-4945 led to decreased phosphorylation of XRCC1 at the CK2 specific phosphorylation sites and reduced total XRCC1 protein levels. Likewise, immunoprecipitation of MDC1 from SKOV3 cells treated with CX-4945 revealed significant reductions in phosphorylation at the CK2 specific sites, while in A2780 cells MDC1 protein levels were decreased. The reduction of MDC1 protein levels was reproduced by CK2 siRNA, confirming that CK2 activity supports MDC1 expression levels. Combined treatment of A2780 cells with CX-4945 and cycloheximide revealed a faster rate of MDC1 degradation than with cycloheximide alone but did not affect MDC1 mRNA levels, indicating that CK2 regulates MDC1 protein stability. When combined with cisplatin, CX-4945 enhanced the activation of CHK2 and increased levels of γ-H2AX and cleaved PARP. In antiproliferative experiments, CX-4945 exhibited synergy with cisplatin in A2780 and SKOV3 cell lines. The combination of CX-4945 with cisplatin or carboplatin significantly enhanced antitumor activity in ovarian xenograft models and was well tolerated. Thus, the inhibition of CK2 by CX-4945 enhanced the antitumor activity of platinum agents by preventing DNA damage repair and inducing apoptosis. These data provide compelling preclinical support for pursuing CX-4945 in combination with platinum chemotherapy in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5494. doi:10.1158/1538-7445.AM2011-5494
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-5494
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 4
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    Abstract C198: CX-4945, a novel small molecule inhibitor of CK2 protein kinase, reduces hyperactivated Akt signaling and synergizes with Akt inhibitors in breast cancer cells
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 12_Supplement ( 2009-12-10), p. C198-C198
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. C198-C198
    Abstract: Akt, a critical protein kinase in the PI3K signaling pathway regulates multiple biological processes that are important in tumorigenesis. This “Master Regulator Kinase” is often hyperactivated in cancer through various mechanisms, including mutations or deletions in Akt, PI3K or PTEN tumor suppressor. The last decade witnessed the emergence of another “Master Regulator Kinase” - CK2. Like Akt, CK2 controls the growth, proliferation and survival of cancer cells. Ironically, CK2 regulates Akt through phosphorylation and down regulation of PTEN and via direct and specific phosphorylation of Akt at Ser129. This phosphorylation event by CK2 further stimulates the activity of Akt, thereby enhancing the “driver effect” of Akt in promoting oncogenic signaling. Unlike Akt, CK2 does not require phosphorylation for activation but rather its activity appears to be regulated through expression levels. Due to the unique shape of the ATP-binding site and an incomplete understanding of the regulation of CK2 expression, pharmacological targeting of CK2 has proven to be very challenging. To date only one small molecule inhibitor of CK2, CX-4945, has advanced into clinical development. Herein, we describe the pharmacological characterization of CX-4945, its impact on Akt signaling and implications for combination therapies. The high incidence of abnormalities found in the PI3K pathway in breast cancers and the distinct roles that CK2 and Akt play in this disease have made it an attractive tumor type to study the effects of CX-4945. A cell viability screen of 16 diverse but genetically well-characterized breast cancer lines revealed that cells carrying mutations causing Akt-activation were significantly more sensitive to CX-4945 than those that did not. Western blot analyses of these cell lines demonstrated good correlation between the phosphorylation of Akt at Ser129 and expression of catalytic subunits of CK2. Treatment with CX-4945 resulted in dramatic reductions of phosphorylation of Akt at Ser129 and reductions in phosphorylation of the downstream targets of Akt, e.g. p21. Upon combination of CX-4945 with inhibitors that targeted the PI3K/Akt pathway, we observed synergistic antiproliferative activity in breast cancer cells. Thus, evaluation of the effects of CX-4945 on the Akt pathway in breast cancer cell lines may allow for the identification of patient populations more sensitive to CX-4945 and guide the selection of more effective combination therapies for cancer patients. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C198.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-09-C198
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 5
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    Online Resource
    Discovery of CX-5461, the First Direct and Selective Inhibitor of RNA Polymerase I, for Cancer Therapeutics
    American Chemical Society (ACS) ; 2012
    In:  ACS Medicinal Chemistry Letters Vol. 3, No. 7 ( 2012-07-12), p. 602-606
    Details
    In: ACS Medicinal Chemistry Letters, American Chemical Society (ACS), Vol. 3, No. 7 ( 2012-07-12), p. 602-606
    Type of Medium: Online Resource
    ISSN: 1948-5875 , 1948-5875
    URL: Article
    DOI: 10.1021/ml300110s
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2012
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    SSG: 15,3
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  • 6
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    Abstract 2560: The CK2 inhibitor CX-4945 enhances the antitumor activity of EGFR-targeted agents by attenuating signaling in the PI3K/AKT/mTOR pathway
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2560-2560
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2560-2560
    Abstract: The epidermal growth factor receptor (EGFR) regulates several oncogenic signaling pathways including PI3K/AKT/mTOR, MEK/ERK, and STAT. A number of EGFR antagonists have been approved for treatment of late-stage tumors of epithelial origin. Despite these advances, there are several limitations to these therapies, including primary and acquired resistance, prompting the need to combine EGFR antagonists with agents that target pathways downstream of EGFR. CK2 modulates multiple pro-proliferative and pro-survival signals through many of these same signaling pathways, and co-overexpression of EGFR and CK2 has been frequently observed in solid tumors. Here we present the combination of EGFR-targeted agents with CX-4945, a first-in-class selective CK2 inhibitor currently under evaluation in a Phase I clinical trial. CK2 phosphorylates several key proteins at multiple levels within the PI3K/AKT/mTOR signaling pathway including AKT, PTEN, and p70S6K1. CK2 also regulates the Hsp90/Cdc37 machinery, whose clients include EGFR, AKT, and Src. We proposed that top-down inhibition of EGFR, combined with lateral inhibition of the PI3K/ATK/mTOR pathway by CX-4945, would result in an improved cancer therapy compared to EGFR antagonism alone. This hypothesis was tested in vitro and in vivo in A431 squamous cell carcinoma (SCC) and non-small cell lung carcinoma (NSCLC) models of various genetic backgrounds. Signaling pathways and induction of apoptosis were analyzed by western blot and cell proliferation was measured in a 96-hour cell viability assay. The combination of CX-4945 and erlotinib resulted in enhanced reduction in phosphorylation of AKT (T308), AKT (S473), PRAS40 (S246), mTOR (S2481), mTOR (S2448), p70S6K1 (T389), S6 (S235/6), S6 (240/4), and 4E-BP1 (T37/46), and decreased Mcl-1 levels. These effects were accompanied by decreased cell proliferation and synergistic induction of apoptosis. CX-4945 plus erlotinib exhibited enhanced antitumor activity in A431 SCC and NCI-H2170 NSCLC xenograft models; moreover, in the erlotinib-resistant NCI-H1975 NSCLC xenograft model, CX-4945 plus cetuximab resulted in enhanced efficacy. These data suggest that CX-4945 in combination with EGFR-targeted agents may improve clinical outcomes in patients with EGFR and CK2-driven cancers by inhibiting multiple nodes of the EGFR signaling pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2560. doi:10.1158/1538-7445.AM2011-2560
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-2560
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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