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  • 1
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    Online Resource
    Targeting CK2 overexpression and hyperactivation as a novel therapeutic tool in chronic lymphocytic leukemia
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 15 ( 2010-10-14), p. 2724-2731
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 15 ( 2010-10-14), p. 2724-2731
    Abstract: Expression of protein kinase CK2 is frequently deregulated in cancer and mounting evidence implicates CK2 in tumorigenesis. Here, we show that CK2 is overexpressed and hyperactivated in chronic lymphocytic leukemia (CLL). Inhibition of CK2 induces apoptosis of CLL cells without significantly affecting normal B and T lymphocytes. Importantly, this effect is not reversed by coculture with OP9 stromal cells, which are otherwise capable of rescuing CLL cells from in vitro spontaneous apoptosis. CLL cell death upon CK2 inhibition is mediated by inactivation of PKC, a PI3K downstream target, and correlates with increased PTEN activity, indicating that CK2 promotes CLL cell survival at least in part via PI3K-dependent signaling. Although CK2 antagonists induce significant apoptosis of CLL cells in all patient samples analyzed, sensitivity to CK2 blockade positively correlates with the percentage of CLL cells in the peripheral blood, β2 microglobulin serum levels and clinical stage. These data suggest that subsets of patients with aggressive and advanced stage disease may especially benefit from therapeutic strategies targeting CK2 function. Overall, our study indicates that CK2 plays a critical role in CLL cell survival, laying the groundwork for the inclusion of CK2 inhibitors into future therapeutic strategies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2010-04-277947
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 2
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    KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with advanced/metastatic non–small cell lung cancer (NSCLC) harboring a KRAS G12C mutation.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 9002-9002
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 9002-9002
    Abstract: 9002 Background: KRAS is a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRAS G12C mutation occurs in ̃14% of NSCLC. Adagrasib, an investigational agent, is a KRAS G12C inhibitor that irreversibly and selectively binds KRAS G12C , locking it in its inactive state. Adagrasib is optimized for favorable pharmacokinetic (PK) properties, including long half-life (̃24 h), dose-dependent PK, and central nervous system penetration; it has demonstrated objective response and favorable tolerability in the Phase 1/1b setting. Methods: KRYSTAL-1 (NCT03785249) is a multicohort Phase 1/2 study evaluating adagrasib as monotherapy or in combination regimens in patients with advanced solid tumors harboring a KRAS G12C mutation. Here we report the first disclosure from all patients enrolled in Cohort A, a Phase 2 cohort with registrational intent, evaluating adagrasib given 600 mg orally BID in patients with NSCLC previously treated with platinum-based chemotherapy and anti-PD-1/L1 therapy. Study objectives include evaluating efficacy (objective response rate [ORR], duration of response [DOR] , progression-free survival [PFS], overall survival [OS] ), safety, PK, and exploratory correlative analyses. Objective tumor response was assessed per RECIST v1.1 by blinded independent central review (BICR). Results: As of the 15 October 2021 data cutoff, 116 patients with NSCLC harboring a KRAS G12C mutation were enrolled and treated, with a median follow-up of 12.5 months. Baseline characteristics include median age 64 years, 65% female, and 15.5%/83.6% with ECOG PS 0/1; 98.3% of patients received adagrasib following prior treatment with immunotherapy and chemotherapy, with a median of 2 prior systemic therapies. The ORR (by BICR) was 42.9% (48/112) and the disease control rate was 79.5% (89/112); 31 patients remain on treatment. Median DOR was 8.5 months (95% CI 6.2–13.8), median PFS was 6.5 months (95% CI 4.7–8.4), median OS was 12.6 months (95% CI 9.2–NE). Treatment-related AEs (TRAEs) of any grade occurred in 97.4% of patients, grade ≥3 TRAEs in 45.7%, 2 grade 5 TRAEs, and 8 (6.9%) TRAEs led to discontinuation. The most commonly reported (≥25%) TRAEs (any grade) were diarrhea (62.9%), nausea (62.1%), vomiting (47.4%), fatigue (40.5%), ALT/AST increased (27.6%/25%), blood creatinine increased (25.9%); the most commonly reported (≥5%) TRAEs (grade 3/4) were lipase increased (6%) and anemia (5.2%). Additional subgroup analyses will be presented, including selected demographics, molecular markers and sites of metastases. Conclusions: Adagrasib is well tolerated and demonstrates promising efficacy in pretreated patients with NSCLC harboring a KRAS G12C mutation. A Phase 3 trial evaluating adagrasib monotherapy versus docetaxel in previously treated patients with KRAS G12C -mutant NSCLC is ongoing (NCT04685135). Clinical trial information: NCT03785249.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.9002
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 3
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    Anticancer Activity of CX-3543: A Direct Inhibitor of rRNA Biogenesis
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 19 ( 2009-10-01), p. 7653-7661
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 19 ( 2009-10-01), p. 7653-7661
    Abstract: Hallmark deregulated signaling in cancer cells drives excessive ribosome biogenesis within the nucleolus, which elicits unbridled cell growth and proliferation. The rate-limiting step of ribosome biogenesis is synthesis of rRNA (building blocks of ribosomes) by RNA Polymerase I (Pol I). Numerous kinase pathways and products of proto-oncogenes can up-regulate Pol I, whereas tumor suppressor proteins can inhibit rRNA synthesis. In tumorigenesis, activating mutations in certain cancer-associated kinases and loss-of-function mutations in tumor suppressors lead to deregulated signaling that stimulates Pol I transcription with resultant increases in ribosome biogenesis, protein synthesis, cell growth, and proliferation. Certain anticancer therapeutics, such as cisplatin and 5-fluorouracil, reportedly exert, at least partially, their activity through disruption of ribosome biogenesis, yet many prime targets for anticancer drugs within the ribosome synthetic machinery of the nucleolus remain largely unexploited. Herein, we describe CX-3543, a small molecule nucleolus-targeting agent that selectively disrupts nucleolin/rDNA G-quadruplex complexes in the nucleolus, thereby inhibiting Pol I transcription and inducing apoptosis in cancer cells. CX-3543 is the first G-quadruplex interactive agent to enter human clinical trials, and it is currently under evaluation against carcinoid/neuroendocrine tumors in a phase II clinical trial. [Cancer Res 2009;69(19):7653–61]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-09-1304
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 4
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    Abstract A079: Subpopulation heterogeneity demonstrated in circulating tumor cells isolated from breast cancer patients using ApoStream, an antibody-independent cancer cell recovery device
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Research Vol. 11, No. 10_Supplement ( 2013-10-01), p. A079-A079
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 11, No. 10_Supplement ( 2013-10-01), p. A079-A079
    Abstract: Background: Current established methods of circulating tumor cell (CTC) isolation and identification rely on antibodies against epithelial specific markers such as epithelial cell adhesion molecule (EpCAM) and cytokeratin (CK). The classical phenotypic definition of a CTC is a CK positive, CD45 negative, nucleated cell, yet several reports have shown that EpCAM and CK detect only a fraction of CTCs and are not sufficient to detect the heterogeneous subpopulations of CTCs. Moreover, subsets of primary tumor cells acquire features of invasiveness and transform into an aggressive phenotype. During this process, EpCAM and CK are down regulated or lost leaving a lethal population of CTCs undetectable and unstudied using antibody dependent CTC technologies. It is imperative to isolate CTCs in an unbiased, EpCAM independent manner and expand the phenotypic characterization of CTCs to elucidate the subpopulation heterogeneity. Here we used ApoStream™, a novel, antibody-independent device which exploits differences in the dielectric properties between cancer cells and normal blood cells to enrich CTCs from the blood of cancer patients. We demonstrate device performance and integration with additional methods to perform subsequent phenotyping and molecular marker analysis. Methods: The performance of ApoStream™ was assessed using SKOV3 (ovarian cancer) and MDA-MB-231 (breast cancer) cell lines that have a high and low expression level of EpCAM, respectively, to demonstrate linearity and precision of recovery independent of EpCAM receptor levels. A side-by-side comparison of CellSearch® and ApoStream™ was performed on 10 metastatic breast cancer patients. A multiplexed immunofluorescent assay and laser scanning cytometry (LSC) analyses were applied to identify multiple combinations of positive and/or negative staining for CK/CD45/DAPI cells, expression of EpCAM and vimentin. Results: In system precision performance studies, the average recovery of SKOV3 and MDA-MB-231 cancer cells spiked into approximately 12 million peripheral blood mononuclear cells obtained from 7.5 mL normal donor blood was 75.4 ± 3.1% (n=12) and 71.2 ± 1.6% (n=6), respectively. The intra-day and inter-day precision coefficients of variation (CVs) of the device were both less than 3%. Linear regression analysis yielded a correlation coefficient (R2) of more than 0.99 for a spiking range of 4-2600 cells. ApoStream™ consistently recovered significantly higher numbers of CTCs compared to CellSearch® (p=0.024). ApoStream™ recovered varying numbers of CK+/CD45–/DAPI+, CK+/CD45+/DAPI+, CK–/CD45–/DAPI+ cells from each cancer patient sample tested. ApoStream™ recovered both EpCAM+ and EpCAM– CTCs in 50% and 90% of patients, respectively. Vimentin+ CTCs were isolated from 90% of patients. Conclusions: The ApoStream™ technology circumvents dependence on expression of EpCAM and recovers CTCs in high percentage of patients. ApoStream™ coupled with LSC analysis is a sensitive method for phenotyping and detecting biomarker expression in CTCs. These results demonstrate the broad applicability of ApoStream™ for enrichment and molecular characterization of CTCs as a foundation for improved clinical applications of CTCs. Citation Format: Kenna L. Anderes, Vladislava O. Melnikova, Vishal Gupta, Dave K. Hasegawa, Darren W. Davis. Subpopulation heterogeneity demonstrated in circulating tumor cells isolated from breast cancer patients using ApoStream, an antibody-independent cancer cell recovery device. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A079.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1557-3125.ADVBC-A079
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 5
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    Abstract 1449: ApoStream™, a new dielectrophoretic device for antibody-independent isolation and recovery of circulating tumor cells from blood of patients with metastatic pancreatic adenocarcinoma.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1449-1449
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1449-1449
    Abstract: Pancreatic adenocarcinoma (PAC) remains the fourth most common cause of cancer-related mortality with a 5-year survival rate of less than 5%. The available diagnostic tools and biomarkers for PAC fail at early detection and suffer from low specificity and sensitivity. Advances in the isolation, recovery, and characterization of circulating tumor cells (CTCs) offer hope for the development of noninvasive techniques for disease detection, monitoring, and biomarker discovery. While CTC enumeration provides prognostic information in patients with various cancer types, the biological characterization of CTCs may offer insight into the molecular determinants of disease progression. Epithelial cell adhesion molecule (EpCAM) and cytokeratin (CK) dependent CTC technologies fare poorly in the metastatic PAC setting, due to altered phenotypes acquired during epithelial mesenchymal transition (EMT). The links between EMT, plectin-1, mesothelin and metastatic progression of PAC are emerging and underscore the need for biomarker information in real time. Here we used ApoStream™, a novel, antibody-independent device which uses dielectrophoretic (DEP) technology in a continuous flow system to isolate CTCs from the blood of patients with metastatic PAC and expand their phenotypic characterization in order to elucidate the population heterogeneity and characterize pancreatic specific markers (CA19-9, KRAS, plectin-1 and mesothelin). This prospective study will evaluate thirty patients. Paired blood samples from 11 metastatic PAC patients were analyzed by CellSearch® and ApoStream™. Collected cells were immunostained using antibodies against CK, CD45, DAPI, CA19-9, plectin-1 and mesothelin. CTC enumeration was performed using laser scanning cytometry (LSC). A multiplexed immunofluorescent assay and LSC analysis were applied to identify cell phenotypes based on combinations of CK, CD45, plectin-1 and mesothelin marker expression. Results:The detection of CK+/CD45−/DAPI+ cells was comparable between CellSearch® and ApoStream™ with counts ranging from 1-10 CTCs/7.5 mL blood in 50% of patients. In addition, ApoStream™, recovered CK−/CD45−/DAPI+ cells in 100% of patients with counts in the range of 12-166 cells/7.5 mL of blood. CA19-9+ cells were identified in both CK+/CD45−/DAPI+ and CK−/CD45−/DAPI+ subpopulations isolated by ApoStream™. KRAS, plectin-1 and mesothelin analysis is pending. Conclusions: ApoStream™ recovers putative CTCs with multiple phenotypes in patients with metastatic PAC. Preliminary data is encouraging and if confirmed in a larger sample size of PAC patients, ApoStream™ could prove to be a sensitive method for isolating and detecting biomarkers in CTCs of PAC patients. Acknowledgments: Supported in part by the Lockton Fund. Citation Format: Gauri Varadhachary, James Abbruzzese, Rachna Shroff, Vladislava Melnikova, Vishal Gupta, Chris Neal, Miguel Garza, David K. Hasegawa, Kenna L. Anderes, Darren Davis, Robert A. Wolff. ApoStream™, a new dielectrophoretic device for antibody-independent isolation and recovery of circulating tumor cells from blood of patients with metastatic pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1449. doi:10.1158/1538-7445.AM2013-1449
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-1449
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 6
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    Early Changes in Circulating Cell-Free KRAS G12C Predict Response to Adagrasib in KRAS Mutant Non–Small Cell Lung Cancer Patients
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 16 ( 2023-08-15), p. 3074-3080
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 16 ( 2023-08-15), p. 3074-3080
    Abstract: Non-invasive monitoring of circulating tumor DNA (ctDNA) has the potential to be a readily available measure for early prediction of clinical response. Here, we report on early ctDNA changes of KRAS G12C in a Phase 2 trial of adagrasib in patients with advanced, KRAS G12C-mutant lung cancer. Experimental Design: We performed serial droplet digital PCR (ddPCR) and plasma NGS on 60 KRAS G12C-mutant patients with lung cancer that participated in cohort A of the KRYSTAL-1 clinical trial. We analyzed the change in ctDNA at 2 specific intervals: Between cycles 1 and 2 and at cycle 4. Changes in ctDNA were compared with clinical and radiographic response. Results: We found that, in general, a maximal response in KRAS G12C ctDNA levels could be observed during the initial approximately 3-week treatment period, well before the first scan at approximately 6 weeks. 35 patients (89.7%) exhibited a decrease in KRAS G12C cfDNA & gt;90% and 33 patients (84.6%) achieved complete clearance by cycle 2. Patients with complete ctDNA clearance at cycle 2 showed an improved objective response rate (ORR) compared with patients with incomplete ctDNA clearance (60.6% vs. 33.3%). Furthermore, complete ctDNA clearance at cycle 4 was associated with an improved overall survival (14.7 vs. 5.4 months) and progression-free survival (HR, 0.3). Conclusions: These results support using early plasma response of KRAS G12C assessed at approximately 3 weeks to anticipate the likelihood of a favorable objective clinical response.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-23-0795
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 7
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    CK2 Inhibitor CX-4945 Suppresses DNA Repair Response Triggered by DNA-Targeted Anticancer Drugs and Augments Efficacy: Mechanistic Rationale for Drug Combination Therapy
    American Association for Cancer Research (AACR) ; 2012
    In:  Molecular Cancer Therapeutics Vol. 11, No. 4 ( 2012-04-01), p. 994-1005
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 11, No. 4 ( 2012-04-01), p. 994-1005
    Abstract: Drug combination therapies are commonly used for the treatment of cancers to increase therapeutic efficacy, reduce toxicity, and decrease the incidence of drug resistance. Although drug combination therapies were originally devised primarily by empirical methods, the increased understanding of drug mechanisms and the pathways they modulate provides a unique opportunity to design combinations that are based on mechanistic rationale. We have identified protein kinase CK2 as a promising therapeutic target for combination therapy, because CK2 regulates not just one but many oncogenic pathways and processes that play important roles in drug resistance, including DNA repair, epidermal growth factor receptor signaling, PI3K/AKT/mTOR signaling, Hsp90 machinery activity, hypoxia, and interleukin-6 expression. In this article, we show that CX-4945, a clinical stage selective small molecule inhibitor of CK2, blocks the DNA repair response induced by gemcitabine and cisplatin and synergizes with these agents in models of ovarian cancer. Mechanistic studies show that the enhanced activity is a result of inactivation of XRCC1 and MDC1, two mediator/adaptor proteins that are essential for DNA repair and that require phosphorylation by CK2 for their function. These data position CK2 as a valid pharmacologic target for intelligent drug combinations and support the evaluation of CX-4945 in combination with gemcitabine and platinum-based chemotherapeutics in the clinical setting. Mol Cancer Ther; 11(4); 994–1005. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-11-0613
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 8
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    Abstract B51: ApoStream™ isolated circulating tumor cells from primary breast cancer patients reveals heterogeneous phenotypes related to epithelial-mesenchymal transition and stem cell markers.
    American Association for Cancer Research (AACR) ; 2013
    In:  Molecular Cancer Therapeutics Vol. 12, No. 11_Supplement ( 2013-11-01), p. B51-B51
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 11_Supplement ( 2013-11-01), p. B51-B51
    Abstract: Background: Detection of circulating tumor cells (CTCs) is an indicator of poor prognosis in patients with metastatic breast cancer and not in primary breast cancer (PBC). The classical phenotypic definition of a CTC is a nucleated cell that is cytokeratin (CK) positive but CD45 negative. Several reports have shown that EpCAM based capture methods detect only a fraction of CTCs and not the heterogeneous subpopulations of CTCs. Moreover, subsets of CTCs may acquire a more aggressive phenotype with features of invasiveness and motility by undergoing an epithelial to mesenchymal transition (EMT) and down regulate the epithelial cell adhesion molecule, EpCAM. EMT is a hallmark of cellular invasion and metastasis and CTCs undergoing EMT may express the putative cancer stem cell like phenotype, CD24lowCD44+. CTCs undergoing EMT (CTC-EMT) are not readily detected by current CTC detection technologies. Thus, it is desirable to isolate CTCs using capture methods independent of EpCAM to recover a heterogeneous CTC population for more extensive characterization. Here we use ApoStream™, a novel antibody-free CTC isolation device that does not rely on EpCAM to capture circulating rare cells, to evaluate the molecular heterogeneity of CTCs. Methods: Baseline blood samples from 14 newly diagnosed PBC patients were collected and processed using ApoStream™. Isolated cells were stained with anti-CK and anti-CD45, and DAPI. In addition, a multiplexed immunofluorescence assay and laser scanning cytometry analysis were applied to identify multiple combinations of CK+CD45− cells for the expression and distribution of EpCAM, vimentin, CD44, CD24, β-catenin and E-cadherin. Results: ApoStream™ recovered both EpCAM+ and EpCAM− cells. CK+CD45− cells were detected in 9 out of 14 PBC patients. The expression of EpCAM− vimentin+ in the CK+CD45− population was heterogeneous across the patient population. E-cadherin and β-catenin were detected in 0-94% (Mean 52 %) and 0-37% (Mean 8 %), respectively of the CK+CD45− population. All patients with CK+CD45− cells had a subset of cells with the putative phenotype of CD44+CD24low cells. Conclusions: Heterogeneous CTC phenotypes with CD44+CD24lowin both EpCAM+ and EpCAM− cells were observed in patients with PBC. Our aim is to correlate ApoStream™ EMT-CTC counts in patients with PBC with the pathological clinical response (pCR). This study will continue to enroll PBC patients and test the hypothesis that low EMT-CTC count patients have higher pCR rates compared to high EMT-CTC count patients. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B51. Citation Format: Kenna L. Anderes, Insiya Jafferji, Vladislava O. Melnikova, Jackson A. Summer, Darren W. Davis, James M. Reuben, Naoto T. Ueno. ApoStream™ isolated circulating tumor cells from primary breast cancer patients reveals heterogeneous phenotypes related to epithelial-mesenchymal transition and stem cell markers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B51.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-13-B51
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 9
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    Abstract 3110: RNA Polymerase I: A novel target in the treatment of Myc-driven malignancy
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3110-3110
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 3110-3110
    Abstract: c-MYC plays a prominent role in cancer. Intriguingly, many of the genes regulated by this oncoprotein are associated with ribosome biogenesis and we have previously demonstrated that Myc regulates a major rate limiting step in this pathway, transcription of the 45S rRNA genes by RNA Polymerase I (Pol I). These observations lead us to hypothesize that cMyc's regulation of rRNA synthesis may contribute to its oncogenic properties. We have tested this hypothesis in a mouse model of Myc-driven lymphoma, the EμMyc transgenic mouse. B-cells purified from EμMyc mice display an increased growth rate in comparison to their wild-type littermates, with increased cell volume, total RNA and protein per cell. This phenotype is characterized by higher rates of 45S rRNA transcription and increased expression of factors specific for Pol I transcription. Knockdown of one of these factors, UBF, by RNAi in EμMyc lymphoma cell lines results in a selective proliferative disadvantage of cells in vitro, in a competition assay, and in vivo, in a transplant model. This phenotype is driven by an increased rate of apoptosis associated with a reduction in 45S rRNA transcription. Based on these findings we explored the potential therapeutic effectiveness in this model of a novel specific small molecule inhibitor of Pol I, CX-5461, currently in preclinical development. Transplanted EμMyc tumors showed marked sensitivity to CX-5461 in vivo, with a dramatic reduction in tumor burden in the peripheral blood (97.54%±0.56) and lymph nodes (94.96%±0.90) due to induction of apoptosis 24hrs following a single oral dose at 75mg/kg. Importantly a normal B-cell population was preferentially maintained in treated mice (13%±1.39 wt B220+ cells versus 1.04%±0.24 tumor B220+ cells, as a percentage of total WBC) indicating specificity of the compound for tumor cells. Four doses of CX-5461, 75mg/kg orally every third day, significantly delayed time to endpoint by 9.5 days (P & lt;0.0001) compared to untreated animals. This delay was accompanied by a period of complete remission with normal white blood cell counts (6.76±0.48 ×10^9cells/L) and no identifiable tumor cells in the peripheral blood. Interestingly, in vitro dose curves indicate a dependence of CX-5461 sensitivity on wild-type p53 function (p53 wt and ARF−/− cell line IC50=9.28nM±1.53 in comparison to p53 mutant and p53−/− IC50=1.70uM±0.03), which can be reduced with over expression of Bcl2 (Bcl2 IC50=2.33uM±1.3). Notably even in the more resistant p53 mutant and p53−/− cell lines, cell death also occurred via apoptosis, suggesting p53-dependent and independent mechanisms to be involved in CX-5461 mediated cell death. In summary, this work with UBF RNAi and CX-5461 identifies inhibition of RNA Pol I transcription as a novel and effective target in the treatment of cMyc-driven malignancies, and for the first time establishes that dysregulation of rDNA transcription can directly contribute to malignant transformation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3110.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-3110
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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    Abstract 3611: Identifying gene expression markers of anticancer drug response using large scale genomic and drug response databases established from patient derived tumors
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3611-3611
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3611-3611
    Abstract: Chemotherapy has a well-established history of checkered success for treatment in a number of solid and hematological malignancies alike. Numerous reports have demonstrated heightened levels of response to some of these agents within subpopulations of cancer patients, leading to the notion that we have effective pharmaceuticals; however, we lack reliable means to identify these subpopulations prior to administering therapy. We report here an integrated series of preclinical and translational research studies aimed at identifying those populations by capturing predictive markers of response to specific anticancer agents. Our approach to identifying molecular markers of response relies on a biobank of more than 140,000 patient derived tumor samples, and an accompanying database of ex-vivo drug resistance and sensitivity profiles for a broad range of chemotherapeutic agents. Briefly, the drug response database was created by dissociating fresh tumor into single cell suspension, and treating each cell preparation in an anchorage independent growth matrix with antineoplastic agents relevant to tumor type. Drug resistance was scored as Extreme (E), Intermediate (I), or Low (L), with the Low score providing a correlative measure of sensitivity. We identified subsets of tumors featuring differential drug response profiles, and performed Affymetrix gene expression microarray profiling to create data sets that could be interrogated to identify gene expression markers predictive of response. In all, more than 300 tumors were profiled covering 7 indications: prostate, lung, colon, breast, melanoma, ovarian, and lymphoma. Statistical analysis and biological interpretation of genomic data was performed using Ingenuity iReport. iReport, powered by the Ingenuity® Knowledge Base, identified biological processes, pathways, and cellular phenotypes most perturbed in the tumor samples, providing insight into the molecular basis of drug response in these tumor cells. This focused the analysis down to a subset of genes anchored on pathways representative of the drug response and cellular properties of the tumor samples and prioritized a set of candidate markers for further study. We were able to identify gene expression markers predictive of drug response and evaluate those markers based on functional roles consistent with pathways and processes. Additional studies are on-going to validate these potentially novel markers in a series of primary tumor cell models established directly from patient tumor biopsies registered in the Molecular Response tumor bank. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3611. doi:1538-7445.AM2012-3611
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-3611
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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