bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B50: Regulation of non-small cell lung cancer stem cells by STAT3 and WNT pathways.
Authors: Shao Chunli , DeSevo Chris , Girard Luc , Yenerall Paul , Behrens Carmen , Wistuba Ignacio , Minna John D. 
Published: August 2014

Abstract
Background: Accumulating evidence demonstrates that the malignant phenotype is driven and maintained by cancer stem cells (CSCs), which can self-renew, differentiate, and contribute to drug resistance and tumor metastasis. Our group has identified CSCs in both non-small cell lung cancer cell (NSCLC) lines and patient tumor samples by their enhanced ALDH activity and demonstrated that ALDH+ lung cancer cells are highly tumorigenic and clonogenic. We also found that ALDH1A3 is the major isozyme responsible for the ALDH activity and functionally important for lung CSCs.
Aims and Methods: The purpose of our study is to elucidate the mechanisms by which lung CSCs are regulated. We performed a siRNA screen of 40 stem cell pathway genes in a panel of NSCLC lines to identify potential targets related to stem cell self-renewal pathways and other regulators. qRT-PCR, western blot and flow cytometry based Aldefluor assay were used to validate the promising hits. To further explore their biological function in lung CSCs we manipulated their expression genetically or pharmacologically followed by colony formation and tumor formation assays.
Results: siRNA screen revealed that knocking down ALDH1A3, Signal Transducers and Activators of Transcription 3 (STAT3), or certain components of WNT and Notch pathway caused a reduction of cell viability in many NSCLC lines. Western blot analysis confirmed that ALDH+ cells contained more activated STAT3 compared to ALDH− lung cancer cells. Inhibition of STAT3 activation by Stattic (a specific STAT3 inhibitor), GSK126 (an EZH2 inhibitor), or siRNA attenuated ALDH1A3 expression, ALDH+ lung cancer cells and tumor cell clonogenicity. In addition, FZD2, DVL3 and LBH were more commonly upregulated in ALDH+ cells across the penal of NSCLC lines. shRNA mediated knockdown of DVL3 in NSCLCs resulted in a significant reduction in ALDH activity, clonogenicity, and tumorigenicity.
Conclusions: Our data suggest that ALDH1A3 expression, STAT3 pathway activation (via EZH2), and an active WNT pathway are all essential for maintenance of lung CSCs. Blocking ALDH1A3, WNT or STAT3 pathways appear to be rationale therapeutic strategies for eliminating NSCLC stem cells.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B50.
Citation Format: Chunli Shao, Chris DeSevo, Luc Girard, Paul Yenerall, Carmen Behrens, Ignacio Wistuba, John D. Minna. Regulation of non-small cell lung cancer stem cells by STAT3 and WNT pathways. [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 B50.
Abstract B56: Human PIF1 helicase depletion sensitizes RAS-transformed human fibroblasts to gemcitabine and suppresses DNA replication fork progression and initiation efficiency.
Authors: Gagou Mary E. , Ganesh Anil , Meuth Mark 
Published: August 2014

Abstract
Pif1 helicase is implicated in a wide range of DNA transactions that are required for orderly replication and genome stability in lower and higher eukaryotes. While mouse pif1-/- knockouts show no phenotype and PIF1 is dispensable in non-cancerous human cells, Pif1 knockdowns sensitize many tumor cell lines to replication inhibitors, slow S-phase progression, and trigger apoptosis. Here we investigated the effects of PIF1 depletion on a non-tumor cell line, MRC5-SV2, and HRAS-transformed derivatives. We show that PIF1 depletion reduces the growth and viability of RAS-transformed MRC5-SV2 cells relative to parental and increases sensitivity to the therapeutic DNA replication inhibitor gemcitabine. Since previous work suggested that PIF1 depletion affected S-phase entry and transition in cultured tumor cells, we used single fiber analysis of pulse-labeled DNA to investigate the potential role of PIF1 in these events. Here we show that PIF1 depletion triggers replication stress characterized by slower fork rates and increased fork arrest during normal cycling conditions in non-tumor MRC5-SV2 cells. These effects were enhanced in the RAS-transformed derivative. Impaired fork movement upon PIF1-depletion did not augment DNA double-stranded break formation or trigger DNA damage responses. However PIF1 depletion affected resumption of DNA synthesis after prolonged replication inhibitor exposure, accompanied by diminished new origin firing and S-phase entry. Taken together, our data establish a novel functional role for human PIF1 in DNA replication that becomes critical for cell growth during oncogenic stress.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B56.
Citation Format: Mary E. Gagou, Anil Ganesh, Mark Meuth. Human PIF1 helicase depletion sensitizes RAS-transformed human fibroblasts to gemcitabine and suppresses DNA replication fork progression and initiation efficiency. [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 B56.
Abstract B65: Antitumor activity of imatinib in GIST is attenuated by FGFR signaling.
Authors: Li Fang , Growney Joseph , Battalagine Linda , Qiu Shumei , Manley Paul , Schlegel Robert , Monahan John 
Published: August 2014

Abstract
Activating mutations in either KIT or PDGFR are present in approximately 90% of gastrointestinal stromal tumors (GISTs). Treatment with the KIT and PDGFR inhibitor imatinib can control advanced disease in about 80% of GIST patients. However, the beneficial effect is not durable with more than 50% of patients progressing after 2 years of imatinib first line therapy. Gene expression data has revealed that FGF2 and FGFR1 are highly expressed in all primary GIST samples examined and at significantly higher levels than the other forty tumor types tested, suggesting that FGFR signaling may limit the antitumor response of imatinib. The effect of inhibiting FGFR signaling in GIST cell lines was tested by combining imatinib with BGJ398, a potent and selective small-molecule inhibitor of FGFR1, FGFR2, and FGFR3. This combination showed increased growth inhibition in imatinib-sensitive GIST cell lines. This effect was observed in the presence or absence of added FGF2. The degree of synergy generated by imatinib and BGJ398 combination correlated with the level of added FGF2. In addition, inhibition of mitogen-activated protein kinase (MAPK) was transient in GIST cells treated with imatinib. The re-activation of extracellular signal-regulated kinase (ERK) in GIST cells was accompanied by increased FGFR signaling, and can be suppressed by BGJ398 treatment. These results suggest that imatinib treatment induces feedback activation of FGFR signaling that can attenuate the antitumor effects of imatinib. This provides a rationale for combining imatinib and FGFR inhibitors, such as BGJ398, in the first line therapy of GIST.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B65.
Citation Format: Fang Li, Joseph Growney, Linda Battalagine, Shumei Qiu, Paul Manley, Robert Schlegel, John Monahan. Antitumor activity of imatinib in GIST is attenuated by FGFR signaling. [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 B65.
Abstract B66: A novel cre-versible approach for identifying synthetic lethal interactions in the DNA damage response in vivo.
Authors: Morandell Sandra , Reinhardt H.-Christian , Cannell Ian G. , Yaffe Michael B. 
Published: August 2014

Abstract
A fundamental limitation in the ability to devise new therapeutic strategies for manipulating the DNA damage response to treat cancer is the identification of synthetic lethal interactions that function in tumors in vivo. We recently identified the stress activated p38MAPK/MK2 pathway as a critical component of the DNA damage response network in tumor cells in vitro. When treated with genotoxic chemotherapy, MK2 is essential for the survival of tumor cell lines that lack functional p53, but is dispensable in p53-proficient cells. A critical function of MK2 in p53-deficient cells is the post-transcriptional regulation of gene expression, namely the stabilization of the mRNA of cell cycle regulators such as Gadd45α. Intriguingly, MK2 also plays an essential role in the biosynthesis of inflammatory cytokines, including IL-1, IL-6 and TNFα that are key signaling components in the tumor microenvironment. These MK2-regulated cytokines are likely to play important roles in promoting tumor development, as many cancers arise in setting of chronic inflammation, as well as in the creation of chemo-resistant niches where therapeutic resistance develops. The fact that p53 is commonly lost in tumors suggests that the therapeutic targeting of MK2 may be a useful strategy to enhance destruction of tumors by genotoxic chemotherapy.
To explore the role of the p38MAPK/MK2 pathway in the integration of the DNA damage response and cytokine signaling during tumor development and chemotherapeutic response in vivo, we have generated a novel mouse model in which Cre-mediated recombination can be used to create MK2-proficient and deficient tumors within a single animal. This strategy allows direct comparison of MK2 synthetic lethality with genetic mutations that promote tumor development and with the tumor response to DNA damaging chemotherapy in a novel internally controlled setting in vivo. Furthermore, this approach potentially allows tumor autonomous signaling events after DNA damage to be distinguished from signaling events within the stromal microenvironment. Using this approach in a murine autochthonous model of non-small-cell lung cancer (NSCLC) we demonstrate that synthetic lethality between p53 and MK2 can successfully be exploited for enhanced chemo-sensitization of tumors to DNA damaging chemotherapy in vivo.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B66.
Citation Format: Sandra Morandell, H.-Christian Reinhardt, Ian G. Cannell, Michael B. Yaffe. A novel cre-versible approach for identifying synthetic lethal interactions in the DNA damage response in vivo. [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 B66.
Abstract B8: Targeting CXCR4/CXCL12 axis by AMD3100 inhibits ECTC-associated metastasis in hepatocellular carcinoma.
Authors: Yan Jing , Liang Jing , Xu Jing , Zheng Limin 
Published: August 2014

Abstract
Background: Hepatocellular carcinoma (HCC) is characterized by high incidence of blood-borne metastasis. We have recently found that endothelium-coated tumor cell cluster (ECTC), a distinct vascular morphology, is significantly correlated with micrometastatic emboli and might represent a novel metastatic pathway of HCC. The aim of this study is to uncover the mechanisms of ECTC formation and the therapeutic potential of ECTC inhibition.
Methods: ECTC was evaluated by immunohistochemical staining (IHC) of CD34. CXCR4 and CXCL12 expression in tumor vessels were examined by immunofluorescence staining. Human umbilical venous endothelial cells (HUVEC) were treated with CXCL12 and cell branches were assessed. HUVEC migration towards CXCL12 was tested by transwell assay. Orthotopic HCC was induced by intrahepatic injection of Hepa1-6 in male C57/BL6 mice. To block CXCR4/CXCL12 interaction, AMD3100 was injected i.p. every other day one week after the implantation. Tumor volumes and intrahepatic metastases were evaluated at the 3rd week after the injection. Endothelial cell branching and ECTC formation were measured by IHC.
Results: ECTC-associated endothelial cells specifically expressed CXCR4 while endothelial cells from non-ECTC samples did not. Furthermore, CXCL12 (the unique CXCR4 ligand) was more abundant in ECTC vessels in comparison to non-ECTC vessels, suggesting a possible involvement of CXCR4/CXCL12 axis in ECTC formation. In vitro experiments revealed that CXCL12 promoted the branching and chemotactic migration of HUVEC. Mouse orthotopic HCC model showed that the intrahepatic metastasis incidence was inhibited by the specific CXCR4 antagonist AMD3100 (25% vs. 100%), accompanied with smaller tumor volumes. Moreover, endothelial cell branching (34% reduction, P&lt;0.05) and ECTC formation (62% reduction, P&lt;0.01) were significantly reduced by AMD3100 administration.
Conclusion: CXCR4/CXCL12 interaction may promote ECTC formation by facilitating endothelial cell branching and directional migration. Disrupting CXCR4-CXCL12 interaction with AMD3100 reduced tumor metastasis by decreasing ECTC formation. Therefore, remodeling tumor vascular morphology by targeting CXCR4/CXCL12 axis may serve as a novel therapy for HCC treatment.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B8.
Citation Format: Jing Yan, Jing Liang, Jing Xu, Limin Zheng. Targeting CXCR4/CXCL12 axis by AMD3100 inhibits ECTC-associated metastasis in hepatocellular carcinoma. [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 B8.
Abstract B84: Can propensity score analyses be alternatives to randomized trials.
Authors: Ishizuka Naoki , Yamanaka Takeharu 
Published: August 2014

Abstract
Introduction: The use of propensity Score (PS) in oncology is increasing. Previous reports have, however, shown that, in the case of a normal or binary response, the inclusion of variables which affect treatment choice but do not correlate with the response into the statistical model for calculating PS needs a caution because the statistical power to detect the association between treatment and response gets decreased. In this study, we evaluated the PS method for survival response in terms of power loss under various scenarios.
Method: We conducted simulation studies to compare statistical power between the Cox models with and without PS. We assumed 4 strata, each having a unique PS (a probability of choosing test drug) as in Table 1. Patients belong to one of the 4 strata and received either test drug or control drug according to his/her PS. Every stratum has an exponential survival distribution with a mean of 1.25 years for the test drug and 1 year for the control drug. Of the 3 scenarios we considered, Scenario 1 is closest to the condition of "clinical equipoise," while Scenario 3 reflects the situation that variables unrelated to survival strongly affect treatment choice.
Result: See Table 2. Statistical power was decreased in any scenario and Scenario 3 was most serious.
Conclusion: The indiscriminate inclusion of variables into PS will lead to a power loss. It would be inevitable in an evaluation for anti-cancer drugs where it is not easy to exclude variables which are unrelated to survival because the choice of drug depends on risk as well as benefit for each patient.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B84.
Citation Format: Naoki Ishizuka, Takeharu Yamanaka. Can propensity score analyses be alternatives to randomized trials. [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 B84.
Abstract B93: Preclinical evaluation of BMN 673 in combination with temozolomide (TMZ) in various tumor types including small cell lung cancer (SCLC) cells.
Authors: Feng Ying , Post Leonard , Wang Bing , Shen Yuqiao 
Published: August 2014

Abstract
BMN 673 is a potent, specific PARP1/2 inhibitor that shows promising clinical activity as a monotherapy agent against cancers that harbor BRCA1 or BRCA2 mutations (de Bono et al. 2013). A large body of evidence also indicates PARP inhibitors may be combined with cytotoxic chemotherapy agents (such as TMZ, topoisomerase inhibitors, platinum drugs, etc.) for greater antitumor activity.
In this study, BMN 673 was evaluated in combination with TMZ against solid tumor cell lines representing breast cancer, small cell lung cancer (SCLC), and other cancer types. The breast cancer cell lines include those that carry BRCA1/2 mutations (MX-1, MDA-MB-436) and cell lines that are wild-type for BRCA1/2 (MDA-MB-231, MDA-MB-468). None of the SCLC lines have been reported to have BRCA1/2 mutations. Cells were treated for 5-7 days with single agent TMZ or BMN 673, or in combination. Cell viability was assessed by CellTiter-Glo. In all the cell lines we have tested, regardless of their BRCA1/2 mutation status, BMN 673 markedly sensitized tumor cell cells to TMZ cytotoxicity. Compared to cells that are relatively resistant to BMN 673, cells that are sensitive to single-agent BMN 673 are more likely to show complete growth inhibition when treated with BMN 673/TMZ combination. Similarly, a fixed concentration of TMZ (10 μM) reduced IC50 of BMN 673 in the tested cell lines by as much as 1,000 fold. This dose of TMZ by itself had no effect in cultured cells under the assay condition. These observations support a treatment scheme in which small doses of TMZ may be combined with full dose BMN 673 for potent antitumor activity. Encouraged by the in vitro assay results, we are currently evaluating BMN 673 in combination with TMZ in vivo using various subcutaneous xenograft mouse models. Data will be presented at the 2013 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B93.
Citation Format: Ying Feng, Leonard Post, Bing Wang, Yuqiao Shen. Preclinical evaluation of BMN 673 in combination with temozolomide (TMZ) in various tumor types including small cell lung cancer (SCLC) cells. [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 B93.
Abstract B94: Discovery of and first disclosure of the clinical candidate AZD9291, a potent and selective third-generation EGFR inhibitor of both activating and T790M resistant mutations that spares the wild type form of the receptor.
Authors: Finlay M. Raymond V. , Anderton Mark , Ashton Susan , Ballard Peter G. , Bradbury Rob H. , Butterworth Sam , Chuaqui Claudio E. , Colclough Nicola , Cross Darren A. E. , McFarland Heather L. , Mellor Martine J. , Ward Richard A. , Waring Mike J. 
Published: August 2014

Abstract
Small molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase such as gefitinib and erlotinib have been employed successfully in the treatment of non-small cell lung cancer (NSCLC) patients harboring an activating mutation (EGFRm+). However, resistance to these inhibitors in the form of additional mutations in the kinase domain such as T790M is emerging as a growing clinical issue. This presentation will describe the discovery of AZD9291, an orally bioavailable, irreversible EGFR inhibitor of both the resistance (NCI-H1975, cell phosphorylation IC50 &lt;0.025 μM) and activating mutations (PC9, cell phosphorylation IC50&lt;0.025 μM) that also spares inhibition of the wild type form of the receptor (A431, cell phosphorylation IC50&gt;0.5 μM). Wild type EGFR inhibition is believed to drive the observed dose limiting toxicities (such as skin rash and diarrhea) for these first generation therapies in the clinic. New data will be discussed for the first time including the medicinal chemistry program that led to the identification of AZD9291, details of significant in vivo oral activity in pre-clinical xenograft models (including tumor regression in the L858R/T790M double mutant setting at a dose of 5 mpk) and the first disclosure of the candidate drug structure. The pre-clinical findings from this work strongly supported selection of AZD9291 as a clinical candidate, and first dose in man was achieved with AZD9291 in March 2013.
L858R/T790M Double Mutant (resistance) cell IC50 (μM)EGFRm+ Single Mutant (activating) cell IC50 (μM)EGFR Wild Type cell IC50 (μM)Aqueous solubility, (salt) (pH=6.8, μg/mL)L858R/T790M Double Mutant efficacy (% TGI at 5mpk PO QD for 14 days)AZD9291&lt;0.025&lt;0.025&gt;0.5&gt;490119
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B94.
Citation Format: M. Raymond V. Finlay, Mark Anderton, Susan Ashton, Peter G. Ballard, Rob H. Bradbury, Sam Butterworth, Nicola Colclough, Darren A. E. Cross, Heather L. McFarland, Martine J. Mellor, Richard A. Ward, Mike J. Waring. Discovery of and first disclosure of the clinical candidate AZD9291, a potent and selective third-generation EGFR inhibitor of both activating and T790M resistant mutations that spares the wild type form of the receptor. [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 B94.
Abstract B99: Discovery of 2,4-diarylaminopyrimidine SOMCL-12-81 as a potent inhibitor targeting both wild and mutant ALK kinases.
Authors: Song Zilan , Ai Jing , Liu Zhiqing , Peng Xia , Chen Yi , Ding Jian , Geng Meiyu , Zhang Ao 
Published: August 2014

Abstract
Anaplastic lymphoma kinase (ALK) is an orphan receptor tyrosine kinase (RTK), structurally belonging to the insulin receptor family. The identification of ALK fusion genes NPM-ALK and EML4-ALK in ALCL and NSCLC respectively, and clinical outcomes resulting from aberrant ALK signalling in different human cancers has confirmed the emergence of ALK as a novel and promising ‘personalized’ anticancer drug target. The development of small molecule ALK inhibitors has been accelerated and validated by the recent approval of crizotinib. Unfortunately, similar to other RTK inhibitors, resistance to crizotinib has been reported within a year of starting therapy. Different from the acquired resistance to EGFR inhibitors, the resistance to crizotinib was much more complex and driven by more than twenty secondary mutations, including the gate-keeper L1196M, and the C1156Y near the α-C-helix. In the course of our drug discovery program toward the discovery of novel ALK inhibitors, we took advantage of the 2,4-diarylaminopyrimidine (DAAP) scaffold that has long been recognized as a classical kinase inhibitor motif (TAE684) by introducing an amino acid side chain to the solvent interaction region to bring in additional H-bondings. Therefore, a series of new DAAP analogues (DAAPalogues) were developed and one compound SOMCL-12-81 was identified with high potency against both wild type ALK and L1196M mutations with IC50 values of 2.7 nM and 15.3 nM, respectively. In cellular assay, SOMCL-12-81 displayed an IC50 value of 3.0 nM against the proliferation of EML4-ALK dependent Karpass-299 cells. It was relatively selective (&gt;10-fold) against a panel of in-house 20 RTKs. Dose-dependent tumor growth inhibition was observed in the BF3 rat xenograft model carrying the EML4-ALK fusion gene with daily administration of SOMCL-12-81. The high potency of SOMCL-12-81 both in vitro and in vivo allows it for further investigation.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B99.
Citation Format: Zilan Song, Jing Ai, Zhiqing Liu, Xia Peng, Yi Chen, Jian Ding, Meiyu Geng, Ao Zhang. Discovery of 2,4-diarylaminopyrimidine SOMCL-12-81 as a potent inhibitor targeting both wild and mutant ALK kinases. [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 B99.