bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 749: Highly potent and orally available SIK2 inhibitors block growth of human ovarian cancer cells in culture and xenografts
Authors: Alfredi Albandri , Zhang Shu , Mao Weiqu , Wang Yan , Takemori Hiroshi , Lu Zhen , Bast Robert C. , Vankayalapati Hariprasad 
Published: May 2015

Abstract
Salt Inducible Kinase 2 (SIK2) is a Ser/Thr kinase required for centrosome splitting and bipolar mitotic spindle formation. SIK2 is overexpressed in 30% of ovarian cancers associated with a poor prognosis. Knockdown of SIK2 with siRNA has inhibited ovarian cancer cell growth and enhanced paclitaxel sensitivity in cell culture and in xenografts. Given the challenges of delivering siRNA to cancer cells in vivo, we have sought small molecule inhibitors of SIK2 to permit clinical trials, alone and in combination with paclitaxel. Fragment-based design strategies utilizing SIK2 ATP-binding site residues, scaffold-hopping, SIK2 binding assay and subsequent SAR have led to the discovery of potent, selective, orally bioavailable first-in-class SIK2 inhibitors. Here we describe the identification and the preclinical characterization of ARN-3236 and its novel analogue ARN-3252 belonging to the same chemical class, suitable for oral administration. ARN-3236 and ARN-3252 compounds are highly potent (IC50: 1 and 5 nM), ATP competitive SIK2 inhibitors, characterized by high selectivity when tested against a panel of more than 456 kinases. ARN-3236 and ARN-3252 potently blocked proliferation of human ovarian cancer cell lines with endogenous SIK2 activation including OVCAR-3, SKOv3, HEY and ES-2 with an IC50 between 0.5 to 3.0 nM. Inhibition of proliferation has been observed in 9 additional ovarian cancer cell lines. The ARN-3236 and ARN-3252 exhibit a promising in vitro ADME profile and favorable in vivo PK parameters in mice and rats, including oral bioavailability. When tested in vivo in three murine subcutaneous xenograft models employing OVCAR-3, SKOv3 and ES-2 cells, ARN-3236 displayed dose-dependent tumor growth inhibition following daily oral administration at 30, 60 and 100 mg/Kg, with tumor regression observed at these dose levels. The lead identification, optimization, SAR, PK, single agent efficacy, efficacy in combination with paclitaxel and dose-dependent target modulation and the maintenance of SIK2 phosphorylation inhibition data will be presented. Given these specific small molecule inhibitors, SIK2 may provide a valuable target for treatment of a subset of human ovarian cancers.
Citation Format: Albandri Alfredi, Shu Zhang, Weiqu Mao, Yan Wang, Hiroshi Takemori, Zhen Lu, Robert C. Bast, Hariprasad Vankayalapati. Highly potent and orally available SIK2 inhibitors block growth of human ovarian cancer cells in culture and xenografts. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 749. doi:10.1158/1538-7445.AM2014-749
Abstract 75: PKR cooperates with an MDS driver mutation to worsen cytopenias and promote acute leukemia
Authors: Byrne Michael T. , Bennett Richard L. , Cheng Xiaodong , May W. Stratford 
Published: May 2015

Abstract
The interferon-inducible, dsRNA-dependent protein kinase, PKR, is activated by cellular stresses to inhibit protein synthesis and initiate apoptosis. Recently, we reported that expressing human PKR (TgPKR) in mouse hematopoietic tissues induced peripheral blood cytopenias and dysplastic changes in the bone marrow. Additionally, these findings were associated with reduced numbers of hematopoietic stem/progenitor cells (HSPCs) consistent with a myelodysplastic syndrome (MDS)-like phenotype. We have now tested whether TgPKR expression in HSPCs may cooperate with the Nup98-HoxD13 (NHD13) driver transgene. This NHD13 transgene induces a highly penetrant form of MDS with progression to acute leukemia in mice. TgPKR or PKR knockout (PKRKO) mice were crossed with the NHD13 transgenic mouse to generate TgPKR-NHD13 and PKRKO-NHD13 mice that were aged. The development of pancytopenia/MDS and evolution to acute leukemia were compared to NHD13 mice or to normal WT control mice.
Beginning at 5 months and persisting through 8 months of age, the TgPKR-NHD13 mice developed reduced WBC and platelet counts compared to NHD13 controls (WBC mean 2.6 vs. 3.5 x103 cells/µl, [p: &lt; 0.01], and mean platelet counts of 576.9 vs. 814.3 x103 platelets/µl). Both cell types were significantly lower than WT controls. By contrast, PKRKO-NHD13 mice maintained higher WBC counts beginning at age 6 months (n=4) compared to NHD13 controls (n=13) (mean 7 vs. 2.5 x103 cells/µl, [6 mos.], 11.6 vs. 3.7 x103 cells/µl [7 mos.], 9.62 vs. 3.5 x103 cells/µl [8 mos.], p: &lt;0.05).
To date, 1 of 13 of the NHD13 mice, aged 7-10 months, has developed acute leukemia. Of the TgPKR-NHD13 mice, 7 of 18 have died due to either acute leukemia (4/7), MDS with anemia requiring euthanasia (1/7), or due to unknown causes (2/7). By contrast, none of the PKRKO-NHD13 (n = 19) or WT mice (n= 11), both aged up to 9 months, have developed symptomatic MDS requiring euthanasia or acute leukemia
These data indicate that PKR may cooperate with the NHD13 driver oncogenic mutation to create a more aggressive MDS-like phenotype characterized by deeper peripheral blood cytopenias and an increased rate of evolution to AML. Alternatively, inhibition of PKR expression/activation may delay or forestall evolution of MDS/AML in the NHD13 background.
These findings suggest that PKR may be a potential novel therapeutic target in the treatment of MDS and its evolution to acute leukemia.
Citation Format: Michael T. Byrne, Richard L. Bennett, Xiaodong Cheng, W. Stratford May. PKR cooperates with an MDS driver mutation to worsen cytopenias and promote acute leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 75. doi:10.1158/1538-7445.AM2014-75
Abstract 751: Preclinical efficacy of the novel PIM inhibitor, JP_11646, in pancreatic cancer
Authors: Ding Yi , Lim Vun-Sin , Baldino Carmen M. , Caserta Justin , Flanders Yvonne , Dumas Stephane , Fetterly Gerald , Adjei Alex A. 
Published: May 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is often first diagnosed at an advanced stage with a poor prognosis. Current systemic treatment approaches have limited efficacy, pointing to an urgent need to develop novel therapies. Recent studies have shown that inhibition of Pim-2 activity via JP_11646, a novel pan-PIM inhibitor, resulted in decreased anchorage-independent growth of PDAC. The aim of this work is to examine the ability of JP_11646 alone and in combination with gemcitabine to inhibit the growth of pancreatic cancer cells in vitro and in vivo.
Cell viability was assessed using the MTS assay in two pancreatic cancer cell lines, MiaPaCa2 and PANC1. Cells were seeded at an average of 5x103 per well on 96-well plates and exposed to JP_11646 in a range of concentrations (0.01 - 5 µM) for 72 hours. Exposure to JP_11646 inhibited PANC1 and MiaPaCa2 cell growth in a dose-dependent manner, with IC50 values of 0.15 µM and 0.054 µM, respectively.
For in vivo experiments, SCID mice were implanted subcutaneously with 3x 106 MiaPaCa2 cells. Upon successful establishment of tumors (approximately 100 mm3), animals were randomly divided into groups for drug and control treatments. JP_11646 was given at 5 or 10 mg/kg by intraperitoneal injection (i.p. injection) once a day for 5 consecutive days from Monday to Friday for a total of six weeks. Gemcitabine i.p. was given at 45 mg/kg in combination treatment or 90 mg/kg as a single agent twice a week every Monday and Friday for a total of six weeks. In a dose-dependent manner, JP_11646 at 5 and 10 mg/kg significantly suppressed the growth of the pancreatic xenograft by 36% and 77% respectively, compare with control PBS treatment in SCID mice. Moreover, the combination of JP-11646 5 mg/kg and gemcitabine 45 mg/kg resulted in a greater tumor inhibition (83%) than either single agent alone [JP_11646 5 mg/kg (36%) or gemcitabine 90 mg/kg (69%)].
Taken together, our results suggest that JP_11646 is a potent inhibitor of pancreatic cancer growth with equivalent efficacy to the maximum tolerated dose of gemcitabine, and is synergistic in combination with gemcitabine.
Citation Format: Yi Ding, Vun-Sin Lim, Carmen M. Baldino, Justin Caserta, Yvonne Flanders, Stephane Dumas, Gerald Fetterly, Alex A. Adjei. Preclinical efficacy of the novel PIM inhibitor, JP_11646, in pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 751. doi:10.1158/1538-7445.AM2014-751
Abstract 756: First MNK degrading agents block phosphorylation of eIF4E, induce apoptosis, and inhibit cell growth, migration and invasion in triple-negative and HER2-overexpressing breast cancer cell lines
Authors: Ramalingam Senthilmurugan , Gediya Lalji , Purushottamachar Puranik , Kwegyir-Afful Andrew , Ramamurthy Vidya priyadarsini , Mbatia Hannah , Njar Vincent 
Published: May 2015

Abstract
Introduction: Retinoic acid metabolism blocking agents are known to exhibit a range of anticarcinogenic properties. This study investigated the anticancer efficacy of novel, potent retinamide retinoic acid metabolism blocking agents (RRs) in triple negative and Her 2 overexpressing breast cancer cells. Recent findings suggest that overexpression of eukaryotic translation initiation factor 4E (eIF4E) in breast cancers critically augments CAP-dependent mRNA translation and synthesis of proteins involved in cell growth, cell proliferation, invasion and apoptosis evasion. The oncogenic potential of eIF4E is strictly dependent on serine 209 phosphorylation by upstream MAPK-interacting kinases (Mnk). Targeting Mnk/eIF4E pathway for blocking Mnk function and eIF4E phosphorylation is therefore a novel approach for treating breast cancers particularly for HER-2-positive and triple negative breast cancers that have no indications for endocrine therapy or effective treatment regimes.
Methods: Triple negative and Her 2 overexprssing breast cancer cells were treated with retinamide RAMBAs and Mnk inhibitors and evaluated the effects of RRs on growth inhibition, MAPK/Mnk mediated eIF4E protein translational machinery and downstream biological effects in triple negative and Her 2 overexpressing breast cancer cells
Results: We report that the degradation of Mnk by RRs in breast cancer cells blocks eIF4E phosphorylation and subsequently inhibits cell growth, invasion and metastasis in addition to inducing apoptosis. Most importantly the anticancer efficacy of RRs was mediated via degrading Mnk rather than inhibiting its kinase activity like Mnk inhibitors (Cercosporamide and CGP 57380). RRs effect on p-eIF4E downregulation and growth inhibition were also far more potent than the clinically relevant retinoids and Mnk inhibitors, cercosporamide and CGP 57380.
Conclusion: Together our findings provide the first preclinical proof-of-concept of novel Mnk degrading agents for Mnk based therapeutic treatment of breast cancers.
Citation Format: Senthilmurugan Ramalingam, Lalji Gediya, Puranik Purushottamachar, Andrew Kwegyir-Afful, Vidya priyadarsini Ramamurthy, Hannah Mbatia, Vincent Njar. First MNK degrading agents block phosphorylation of eIF4E, induce apoptosis, and inhibit cell growth, migration and invasion in triple-negative and HER2-overexpressing breast cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 756. doi:10.1158/1538-7445.AM2014-756
Abstract 759: ATP-binding cassette (ABC) genes genotype and expression: A potential association with pancreatic cancer development and chemoresistance
Authors: Pang Li , Word Beverly , Xu Joshua , Hammons George , Huang Shiew-Mei , Lyn-Cook Beverly 
Published: May 2015

Abstract
Genetic polymorphisms in ATP-Binding Cassette (ABC) transporter genes are associated with different responses to chemotherapy in various cancers including pancreatic cancer. In this study, four single nucleotide polymorphisms (SNPs) in the ABCB1, ABCC1 and ABCG2 genes were investigated in normal and pancreatic cancer specimens. The potential association with expression of the efflux pumps was also analyzed. The TT genotypes of G2677T and C3435T in ABCB1 gene were associated with lower risk of developing pancreatic cancer in the investigated populations (p=0.013, OR=0.35 and p=0.015, OR=0.29, respectively). To our knowledge, this is the first report of the common polymorphisms in ABCB1 gene affecting the genetic risk of developing pancreatic cancer. Moreover, compared to ABCB1 G2677T and C3435T wild-type homozygotes and heterozygotes, the expression of ABCB1 in mutant-type homozygotes (2677TT and 3435TT) was lower in normal pancreatic tissue (64.3% and 68.9%, respectively, p&lt;0.05), and the same trend was also found in pancreatic cancer specimens. Interestingly, the pancreatic cancer cells MIA1, BXPC3 and CFPAC1 are ABCB1 2677TT-3435TT homozygotes. Cell viability assay revealed that these three cell lines were much more sensitive to gemcitabine than PANC1, SU86.86, PL-45, and ASPC1, which are either ABCB1 G2677T-C3435T wild type homozygotes or heterozygotes. These results are consistent with the clinical observation that for patients receiving post-operative gemcitabine chemotherapy, the overall survival is tended to be longer in the ABCB1 2677TT and 3435TT carriers. Conclusion: Polymorphisms in ABCB1 G2677T and G3435T were associated with different susceptibility to pancreatic cancer and may predict responses to chemotherapy.
Citation Format: Li Pang, Beverly Word, Joshua Xu, George Hammons, Shiew-Mei Huang, Beverly Lyn-Cook. ATP-binding cassette (ABC) genes genotype and expression: A potential association with pancreatic cancer development and chemoresistance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 759. doi:10.1158/1538-7445.AM2014-759
Abstract 763: Resistance to cabazitaxel is associated with ABCB1/P-glycoprotein activation, alterations in β-tubulin content and dynamics, reduced BRCA1, and a mesenchymal phenotype in MCF-7 human breast cancer variants
Authors: Duran George E. , Wang Yan C. , Francisco E Brian , Martinez Francisco J. , Sikic Branimir I. 
Published: May 2015

Abstract
In order to identify determinants of cellular response to this new taxane, we derived a resistant variant from the MCF-7 human breast cancer cell line by stepwise selection in cabazitaxel. The 33-fold resistance to cabazitaxel in this variant, MCF-7/CTAX, was associated with ABCB1/P-glycoprotein (P-gp) activation, but also 3-fold residual resistance to taxanes after modulation with the P-gp inhibitor PSC-833, 2 μM. Another variant was established by co-selecting in the presence of PSC-833 (MCF-7/CTAX-P). This variant was negative for ABCB1 transcripts and accumulated parental levels of rhodamine-123, BODIPY-labeled paclitaxel and [3H]-docetaxel, indicating that the taxane resistance (9-fold) observed in this cell line is not mediated by transporters. However, we observed a 34% reduction in bound fluorescent-labeled paclitaxel in MCF-7/CTAX-P relative to parental controls by flow cytometry. These cells are hypersensitive to depolymerizing agents (vincas and colchicine) indicating a change in tubulin dynamic instability, and we observed reduced baseline tubulin polymer in untreated MCF-7/CTAX-P cells, and impaired tubulin polymerization in response to taxane exposure (cabazitaxel or docetaxel) relative to MCF-7 parental cells. Quantitative PCR and immunoblotting confirmed elevated levels of the class III (TUBB3) β-tubulin isotype in both MCF-7/CTAX and MCF-7/CTAX-P. Reduced BRCA1 content was observed in both MCF-7 variants, which could affect taxane response via the regulation of the mitotic spindle checkpoint. Gene silencing with specific siRNAs confirmed that reduced TUBB3 sensitizes cells to cabazitaxel, and reduced BRCA1 results in taxane resistance. In addition, altered epithelial-mesenchymal transition markers (elevated Vimentin, reduced E-cadherin) are associated with cabazitaxel resistance in these MCF-7 variants. In summary, cabazitaxel resistance mechanisms include MDR (although at a lower level than paclitaxel and docetaxel), and alterations in microtubule dynamicity, as manifested by higher expression of TUBB3, decreased BRCA1, and by the induction of EMT.
Citation Format: George E. Duran, Yan C. Wang, E Brian Francisco, Francisco J. Martinez, Branimir I. Sikic. Resistance to cabazitaxel is associated with ABCB1/P-glycoprotein activation, alterations in β-tubulin content and dynamics, reduced BRCA1, and a mesenchymal phenotype in MCF-7 human breast cancer variants. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 763. doi:10.1158/1538-7445.AM2014-763
Abstract 765: Short- and long-term TNF-alpha mediated NF-κB signaling exerts diverging effects on ABCB1/PgP expression
Authors: Walther Wolfgang , Bauer Lisa , Aumann Jutta , Kobelt Dennis , Stein Ulrike S. 
Published: May 2015

Abstract
Multidrug resistance (MDR) still represents one major obstacle for cancer chemotherapy. The ABC transporter ABCB1/PgP is an important factor mediating resistance of tumor cells towards cytostatic drug treatment. Among numerous overcoming strategies, persistent treatment of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) leads to down-regulation of MDR-associated genes, such as ABCB1. The transcription factor NF-κB/p65 is a known key regulator of ABCB1 expression. We analyzed short- and long-term effects of TNF-alpha regarding modulation of NF-κB/p65 signaling and ABCB1/PgP expression in colon carcinoma cells. Highly resistant ABCB1 endogenously overexpressing HCT15 human colon carcinoma cells were subjected to short- (30-120 min) or long-term (24-96 h) TNF-alpha treatment. TNF-alpha-mediated modulation of ABCB1/PgP expression was analyzed by real-time RT-PCR and Western-blot. The effect of TNF-receptor triggered NF-κB/p65 signaling on ABCB1/PgP expression was analyzed by Western blot, ABCB1 promoter reporter assays and by EMSA. The effects of TNF-alpha on drug accumulation and cytotoxicity were determined by FACScan analysis and MTT cytotoxicity assays.
The studies revealed that long-term, but not short-term action of TNF-alpha leads to TNF-receptor 1-mediated down-regulation of ABCB1/PgP expression. It furthermore dampens NF-κB/p65 activation as well as IκBα resynthesis. This is associated with reduced nuclear accumulation of NF-κB/p65 and lack of its binding to the NF-κB/p65 consensus sequence in the ABCB1 promoter. In consequence long-term TNF-alpha treatment mediates significant increase in drug accumulation and sensitization of HCT15 cells towards drug treatment. The study reveals the diverging effects of short- or long-term TNF-alpha action and provides novel insights into mechanism of ABCB1 regulation by this pro-inflammatory cytokine.
Citation Format: Wolfgang Walther, Lisa Bauer, Jutta Aumann, Dennis Kobelt, Ulrike S. Stein. Short- and long-term TNF-alpha mediated NF-κB signaling exerts diverging effects on ABCB1/PgP expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 765. doi:10.1158/1538-7445.AM2014-765
Abstract 766: Human ABCB1 and ABCG2 confer acquired resistance to Polo-like kinase 1 inhibitors, BI 2536, volasertib and GSK641364
Authors: Wu Chung-Pu , Sim Hong-May , Ambudkar Suresh V. 
Published: May 2015

Abstract
The overexpression of the serine/threonine specific polo-like kinase 1 (Plk1) has been detected in various types of cancer, and thus has fast become an attractive therapeutic target for cancer therapy. Plk1 inhibitors BI 2536, volasertib and GSK461364, were designed to selectively inhibit cancer cell proliferation by promoting G2/M cell cycle arrest at nanomolar concentrations. Unfortunately, alike most chemotherapeutic agents, the development of acquired resistance to Plk1 inhibitors is prone to present a significant therapeutic challenge. One of the most common mechanisms for acquired resistance in cancer chemotherapy is associated with the overexpression of ATP-binding cassette (ABC) transporters ABCB1, ABCC1 and ABCG2. Here, we discovered that in human cancer cells, the overexpression of ABCB1 and/or ABCG2 can lead to acquired resistance to three selective Plk1 inhibitors, BI 2536, volasertib and GSK461364. Moreover, these Plk1 inhibitors stimulate the ATPase activity of ABCB1 and ABCG2, as well as competitively inhibit the drug substrate transport mediated by ABCB1 and ABCG2. More significantly, the reduced chemosensitivity and Plk1 inhibitors-mediated G2/M cell cycle arrest in cancer cells overexpressing either ABCB1 or ABCG2 can be significantly restored in the presence of selective inhibitor of ABCB1 and ABCG2. Taken together, our findings indicate that in order to circumvent ABCB1 or ABCG2-mediated acquired resistance to Plk1 inhibitors, a combined regimen of Plk1 inhibitors and modulators or clinically active drugs that potently inhibit the function of ABC drug transporters, should be considered as a potential treatment strategy in the clinic.
Citation Format: Chung-Pu Wu, Hong-May Sim, Suresh V. Ambudkar. Human ABCB1 and ABCG2 confer acquired resistance to Polo-like kinase 1 inhibitors, BI 2536, volasertib and GSK641364. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 766. doi:10.1158/1538-7445.AM2014-766