bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1720: MSK1 mediates PI3K inhibition resistance by induction of β-catenin phosphorylation in glioblastoma
Authors: Wu Shaofang , Fu Jun , Zheng Siyuan , Verhaak Roel G. , Yung W. K , Koul Dimpy 
Published: May 2015

Abstract
Glioblastoma (GBM), the most common malignant brain tumor in adults, represents a compelling disease for kinase inhibitor therapy because majority of these tumors harbor genetic alterations that result in aberrant activation of growth factor signaling pathways. PI3K/mTOR-pathway is dysregulated in over 50% of human glioblastomas (GBM) and represents an attractive target for therapy. One major challenge for single pathway PI3K inhibition targeting therapy is intrinsic resistance. To study the mechanism of intrinsic resistance to PI3K inhibition, we analyzed the pre- and post-treatment reverse phase protein arrays (RPPA) data of both giloma cells and giloma initiating cells (GIC). Mitogen- and stress-activated protein kinase 1 (MSK1) was markedly induced after PI3K inhibitor treatment and it was linked with increase expression of β-catenin. We further found that MSK1 directly interacts with β-catenin and stabilizes β-catenin protein level. MSK1 also regulates β-catenin nuclear translocation and β-catenin transcriptional activity. More interestingly, using in vitro kinase assay, we identified MSK1 is a kinase that phosphorylates β-catenin. Finally, we showed that depletion of β-catenin potentiates PI3K inhibitors induced cytotoxity in a series of GICs. Taken together, our results suggest that MSK1/β-catenin signaling may serve as an escape survival signaling upon PI3K inhibition, and combination of PI3K inhibition and MSK1/β-catenin inhibition is required to induce lethal growth inhibition in human glioblastoma cells.
Citation Format: Shaofang Wu, Jun Fu, Siyuan Zheng, Roel G. Verhaak, W. K Yung, Dimpy Koul. MSK1 mediates PI3K inhibition resistance by induction of β-catenin phosphorylation in glioblastoma. [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 1720. doi:10.1158/1538-7445.AM2014-1720
Abstract 1733: EGF816, a novel covalent inhibitor of mutant-selective epidermal growth factor receptor, overcomes T790M-mediated resistance in NSCLC
Authors: Kasibhatla Shailaja , Li Jie , Tompkins Celin , Vaillancourt Mei-Ting , Anderson Jennifer , Pferdekamper AnneMarie Culazzo , Li Chun , Long Oliver , McNeill Mathew , Epple Robert , Liao Debbie , Murphy Eric , Bender Steve , Jia Yong , Lelais Gerald 
Published: May 2015

Abstract
Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond to EGFR tyrosine kinase inhibitors (TKI) but ultimately develop resistance to these therapies. The most common mechanism of resistance is a second site gate-keeper mutation within exon 20 of EGFR (T790M), followed by MET and other receptor tyrosine kinase amplification/activation. We developed a covalent mutant-selective EGFR inhibitor, EGF816 that potently inhibits both activating EGFR mutations as well as the T790M resistance mutation while sparing wild-type EGFR. EGF816 demonstrated strong tumor regressions in several EGFR activating and resistant tumor models in vivo. These include H1975 (L858R; T790M), HCC827 (exon 19 del) and H3255 (L858R) that are representative of the relevant clinical settings. In all of the models EGF816 inhibited tumor growth in a dose dependent manner and achieved regressions of established tumors at well tolerated doses. In single dose studies, EGF816 showed sustained inhibition of pEGFR, consistent with the irreversible binding mechanism of EGF816. EGF816 also performs exceptionally well in long term dosing studies providing durable responses in the preclinical models. Together, this data indicates that EGF816 exhibits excellent anti-tumor activity in the relevant patient derived tumor cell lines at well tolerated doses and is expected to provide long term duration of responses compared to current EGFR TKI therapy in the clinic.
Citation Format: Shailaja Kasibhatla, Jie Li, Celin Tompkins, Mei-Ting Vaillancourt, Jennifer Anderson, AnneMarie Culazzo Pferdekamper, Chun Li, Oliver Long, Mathew McNeill, Robert Epple, Debbie Liao, Eric Murphy, Steve Bender, Yong Jia, Gerald Lelais. EGF816, a novel covalent inhibitor of mutant-selective epidermal growth factor receptor, overcomes T790M-mediated resistance in NSCLC. [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 1733. doi:10.1158/1538-7445.AM2014-1733
Abstract 1735: Discovery of novel and selective reversible inhibitors of EGFR containing the T790M drug resistance mutation with activity in vitro and in vivo
Authors: Schaefer Gabriele , Hanan Emily J. , Chan Emily , Shao Lily , Chen Yuan , Knight Jamie , Yauch Robert L. , Schmidt Stephen , Sideris Steven , Malek Shiva , Heffron Timothy P. 
Published: May 2015

Abstract
Activating mutations in the epidermal growth factor receptor (EGFR) characterize a subset of non-small cell lung cancers (NSCLC) with exquisite sensitivity to tyrosine kinase inhibitors like erlotinib or gefitinib. However, after an initial dramatic response, patients harboring these mutations progress within 8-14 months on therapy. In approximately 60% of patients, the resistance to TKIs is associated with the acquisition of a secondary mutation within the EGFR kinase domain. The mutation in the kinase domain leads to the substitution of a bulky methionine for threonine at position 790 (T790M) also referred to as the gatekeeper residue.
Using structure based-design we identified and optimized a series of non-covalent, and highly selective pyridinyl-aminopyrimidine inhibitors of EGFR containing the T790M drug resistant mutation that spared the wild-type EGFR enzyme. These pyridinyl-aminopyrimidine compounds potently inhibited phosphorylation of T790M containing EGFR in enzymatic assays and cell based assays. Strong inhibition of enzyme activity resulted in anti-proliferative activity in H1975 and PC9 erlotinib resistant cells but treatment with these molecules did not affect cell lines containing wild-type EGFR. Moreover, oral dosing of mice bearing either H1975 or PC9_erlotinib resistant xenograft tumors resulted in robust inhibition of tumor growth that was accompanied by profound and dose-dependent inhibition of EGFR activity as well as downstream signaling molecules such as ERK1/2 and AKT.
These results suggest that these pyridinyl-aminopyrimidine inhibitors have the potential to benefit NSCLC patients who have developed resistance to first-generation EGFR inhibitors due to the acquisition of the T790M mutation, without the skin rash and gastrointestinal toxicity associated with wild-type EGFR inhibition.
*EJH and GS contributed equally to this work.
Citation Format: Gabriele Schaefer, Emily J. Hanan, Emily Chan, Lily Shao, Yuan Chen, Jamie Knight, Robert L. Yauch, Stephen Schmidt, Steven Sideris, Shiva Malek, Timothy P. Heffron. Discovery of novel and selective reversible inhibitors of EGFR containing the T790M drug resistance mutation with activity in vitro and in vivo. [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 1735. doi:10.1158/1538-7445.AM2014-1735
Abstract 1737: Allosteric FGFR2 inhibitor RPT835 impacts on tumor growth and neovascularization
Authors: Tsimafeyeu Ilya , Stepanova Evgenia , Solomko Eliso , Kochenkov Dmitry , Peretolchina Nina , Ryabaya Oxana , Byakhov Mikhail , Tjulandin Sergey 
Published: May 2015

Abstract
Encouraged by the clinical validation of fibroblast growth factor receptor 2 (FGFR2) as the target for the treatment of several tumors, we sought to identify pharmacological agents that could target this receptor by an allosteric mechanism. We report the efficacy of RPT835, novel highly potent inhibitor of the FGFR2 extracellular domain (RusPharmTech, LLC), in vitro and in vivo.
Concordant with this activity, in human umbilical vein endothelial cells (HUVEC) and mouse endothelial cells (SVEC-4-10), RPT835 inhibited FGF-stimulated proliferation with IC50 values of 11 and 10 nmol/L, respectively. Inhibition of HUVEC cells proliferation by brivanib as positive control was significantly lower (IC50=289 nmol/L, P&lt;0.001). Once-daily oral administration of RPT835 significantly ablated experimental FGF-induced angiogenesis in vivo and reduced endothelial cell migration, capillary-like tubular structure and mature vessel formation in comparison with bevacizumab (P&lt;0.001). The growth of established human tumor xenograft of breast cancer (HS578T) in athymic mice was inhibited by RPT835 with chronic administration of 30 mg per kg per day. Differences with control group were significant on 34 day of study. There was no significant impact of RPT835 on colon (HCT-116, 10 mg/kg) and lung (NCI-H226, 30 mg/kg) cancer growth.
Collectively, the data obtained with RPT835 are consistent with potent inhibition of FGF signaling, angiogenesis, and breast cancer growth.
Citation Format: Ilya Tsimafeyeu, Evgenia Stepanova, Eliso Solomko, Dmitry Kochenkov, Nina Peretolchina, Oxana Ryabaya, Mikhail Byakhov, Sergey Tjulandin. Allosteric FGFR2 inhibitor RPT835 impacts on tumor growth and neovascularization. [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 1737. doi:10.1158/1538-7445.AM2014-1737
Abstract 1748: Novel Ig1 inhibitors of the Axl tyrosine kinase that block Gas6-inducible receptor activation
Authors: Welsh William J. , Kholodovych Vladyslav , Birge Raymond , Comollo Tom , Kimani Stanley , Singh Kamal 
Published: May 2015

Abstract
Tyro-3, Axl, and Mer (abbreviated TAMs) are a family of three homologous receptor tyrosine kinases (RTKs) expressed predominantly on myeloid-derived hematopoietic cells and epithelial cells that function as inhibitory receptors that dampen inflammatory responses and maintain tissue tolerance. Both TAMs and their ligands (vitamin K activated proteins that consist of Gas6 and Protein S) are overexpressed in many human malignancies and expression is associated with more aggressive cancer staging, drug resistance, and poorer patient survival. Based on their clinical importance, there has been considerable effort to generate anti-TAM cancer therapeutics in the form of small molecule tyrosine kinase inhibitors, monoclonal antibodies, and soluble receptor traps that capture TAM ligands and prevent receptor activation. However, whereas several tyrosine kinase inhibitors have been reported, the high degree of sequence conservation in the TAM kinase domain is associated with lack of specificity and off target effects. To generate more selective inhibitors of TAMs, we have targeted the Ig1 domain of Axl, a ligand-binding region in the extracellular domain that gives TAMs their unique structural features. From the X-ray crystallographic structure of Gas6 in complex with the human Axl ectodomain (PDB 2c5d), two unique sites were targeted that include (i) the major binding pocket around Glu59 in Axl that interacts with Arg310 and Lys312 in Gas6, and (ii) the main hydrophobic interface between the Ig1 and the Lg1 that is required for Gas6-inducible dimerization. Virtual screening of the ZINC molecular data base was performed, and several drug-like compounds were selected based on ligand-Gas6 docking. We report on the characterization of two novel types of Axl inhibitors that include a triazolo pyridazine compound that targets the Ig1 binding pocket, and a 3-cyanocoumarin compound that targets the Ig1-Lg1 interface. Both compounds show activity on human Axl reporter lines, and therefore may represent a new class of Axl inhibitors with potential applications for anticancer therapy.
Citation Format: William J. Welsh, Vladyslav Kholodovych, Raymond Birge, Tom Comollo, Stanley Kimani, Kamal Singh. Novel Ig1 inhibitors of the Axl tyrosine kinase that block Gas6-inducible receptor activation. [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 1748. doi:10.1158/1538-7445.AM2014-1748
Abstract 1751: Preclinical development of a novel multi-targeted kinase inhibitor, MG516, for the treatment of sarcoma
Authors: Ivy Kathryn S. , Patwardhan Parag P. , Schwartz Gary K. 
Published: May 2015

Abstract
Receptor tyrosine kinases (RTKs) are key regulators of tumor development as well as metastasis, aiding in the epithelial-mesenchymal transition, migration and angiogenesis. RTK signaling pathways such as VEGFR, PDGFR, and c-Met have been shown to be critical for cell survival, proliferation and metastasis in sarcomas. RTK inhibitors have been used with moderate success to block tumor cell survival and proliferation, however, internal compensatory signaling pathways give rise to drug resistance in a majority of cases. MG516, is a novel multi-targeted tyrosine kinase inhibitor that blocks RTK signaling pathways including c-Met, Ephrin receptors (Eph), and VEGFR with low nanomolar IC50 values. We evaluated the RTK inhibition profile and anti-proliferative effect of MG516 in a diverse panel of sarcoma cell lines including malignant peripheral nerve sheath tumor (MPNST), Ewing's sarcoma (A673) and leiomyosarcoma (SKLMS). MG516 inhibits tumor cell proliferation in vitro in a dose dependent manner with IC50s ranging from 500 to 2500 nM. We used a human phopho-RTK array kit, which allows the screening of 49 different phosphorylated human RTKs, in a panel of sarcoma cell lines. Our data indicates that MG516 provides robust blockade of a wide panel of RTKs including c-Met, EphB3, EphA10, PDGFR-β, Axl and IGF1-R at nanomolar to low micromolar concentrations. Western blot analysis showed a significant blockade of downstream effectors including p-AKT, p-FAK and p-STAT3. These results demonstrate the efficacy of MG516 in blocking RTKs and their downstream signaling pathways. Since PDGFR-β, c-Met and IGF1-R have been shown to be involved in tumor initiation, development and metastasis in a variety of sarcoma subtypes, our data would strongly support further development of MG516 as a novel agent in the treatment of sarcomas.
Citation Format: Kathryn S. Ivy, Parag P. Patwardhan, Gary K. Schwartz. Preclinical development of a novel multi-targeted kinase inhibitor, MG516, for the treatment of sarcoma. [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 1751. doi:10.1158/1538-7445.AM2014-1751
Abstract 1754: Cycloartane anticancer activity
Authors: Lowe Henry Isaac Cloore , Toyang Ngeh J. , Watson Charah , Bryant Joseph 
Published: May 2015

Abstract
New cancer diagnoses remain on the rise despite significant improvements in early detection and treatment. The role of Kinases in cancer onset and progression has made kinases a target for the control of some cancers. The MRCKα/β kinases have recently been implicated in cancer onset and progression and as such could serve as a potential drug target. The discovery that kinases are most effectively inhibited by small molecules has also resulted in an increased search for small molecule kinase inhibitors. Cycloartanes are small molecules found in many medicinal plants including the Jamaican Ball Moss (Tillandsia recurvata). Recent studies on T. recurvata have demonstrated that it possesses significant anticancer activity. Cycloartane-3,24,25-triol, an analog of a cycloartane identified in Ball moss was also shown to have inhibitory activity against MRCKα kinase. This study was as such set up to determine the MRCKα/β kinase inhibition activity of other cycloartanes in Ball Moss and their analogs. The kinase inhibitory activity of 6 cycloartanes was investigated using the ligand-kinase binding assay while the WST-1 reagent assay was used to determine the antiproliferative activity of the cycloartanes against some prostate and breast cancer cell lines. Cycloart-23-ene-3,25-diol (1), Cycloartane-3,24,25-triol (2), Cycloart-25-ene-3,24-diol (3), 3,23-Dioxo-9,19-cyclolanost-24-en-26-oic acid (4), 24,25-Dihydroxycycloartan-3-one (5) inhibited the MRCKα kinase with Kd of 0.21 μM, 0.25µM, 0.36 µM, 3.0 µM, and 2.1 µM respectively. Hydroxycycloart-23-en-3-one,25, (6) showed no inhibition against the MRCKα kinase. Compounds 1, 3, 4, 5 inhibited the MRCKβ kinase with Kd of 4.7 μM, 1.10 µM, 3.2 µM, and 9.8 µM, respectively. Three of the six cycloartanes exhibited antiproliferation activity against two prostate and breast cancer cell lines each.
In conclusion, cycloart-23-ene-3,25-diol (1) showed the most promising activity against the MRCKα/β kinase out of the 6 cycloartanes screened demonstrating an interesting structure activity relationship profile when compared with the other molecules. Cycloart-23-ene-3,25-diol (1) deserves further studies to determine its in vivo efficacy and safety.
Citation Format: Henry Isaac Cloore Lowe, Ngeh J. Toyang, Charah Watson, Joseph Bryant. Cycloartane anticancer activity. [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 1754. doi:10.1158/1538-7445.AM2014-1754
Abstract 1761: PDE10, a novel therapeutic target for lung cancer
Authors: Zhu Bing , Li Nan , Ramirez-Alcantara Veronica , Canzoneri Joshua , Gurpinar Evrim , Fajardo Alexandra , Lee Kevin , Sigler Sara , Gary Bernard , Thomas Meagan , Keeton Adam , Chen Xi , Grizzle William , Piazza Gary 
Published: May 2015

Abstract
Phosphodiesterase 10A (PDE10) is a relatively new PDE isozyme that has been mostly studied in the brain as a therapeutic target for certain psychiatric and neurological conditions, but has not been associated with tumorigenesis. While other investigators have reported low levels of PDE10 in most adult peripheral tissues, we found a large percentage of human lung tumors express high levels of PDE10 compared with normal lung tissue as determined by real-time PCR analysis of cDNA arrays. Statistical analysis revealed that 68% of lung tumors (n=19) displayed more than two-fold increase compared with normal lung tissue, while 26% showed greater than a 10-fold difference. High levels of PDE10 mRNA and protein were also found in human non-small cell lung cancer (NSCLC) cell lines compared with normal airway epithelial cells. PDE10 knockdown by small interference RNA significantly suppressed lung tumor cell growth, as did PDE10 selective inhibitors, papaverine, PQ-10 and Pf-2545920. A novel PDE10 inhibitor, MCI-020 also inhibited the growth of NSCLC cells with a high degree of selectivity for tumor cells. Consistent with a mechanism involving PDE10 inhibition, PQ-10 and MCI-020 increased cGMP levels in a concentration-dependent manner as determined using a cGMP biosensor assay. MCI-020 also activated cGMP-dependent protein kinase (PKG) in NSCLCs as evident by increased phosphorylation of VASP-Serine239. With attractive pharmacokinetic properties, MCI-020 was studied further and found to display an unusual characteristic of achieving high concentrations in lung tissue compared with other tissues and plasma following oral administration. MCI-020 was well tolerated in mice at a dose of 250 mg/kg bid and strongly inhibited tumor formation in an orthotopic model of lung cancer at a dose of 150 mg/kg bid. These observations suggest that PDE10 is essential for lung tumor cell growth and represents a novel therapeutic target for lung cancer.
Citation Format: Bing Zhu, Nan Li, Veronica Ramirez-Alcantara, Joshua Canzoneri, Evrim Gurpinar, Alexandra Fajardo, Kevin Lee, Sara Sigler, Bernard Gary, Meagan Thomas, Adam Keeton, Xi Chen, William Grizzle, Gary Piazza. PDE10, a novel therapeutic target for lung 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 1761. doi:10.1158/1538-7445.AM2014-1761
Abstract 1765: Ras and EF-hand domain containing as a novel tissue biomarker and a therapeutic target for lung cancer
Authors: Daigo Yataro , Takano Atsushi , Nakamura Yusuke 
Published: May 2015

Abstract
Lung cancer is the most common cause of cancer-related death in the world and its incidence has been increasing. The number of patients responding well to current standard therapies is still small, therefore further development of new agents targeting cancer-specific molecules with no or minimum risk of adverse effect is urgently awaited. To screen molecules, particularly oncoantigens which could be useful for the development of diagnostic biomarkers and new drugs, we have established an effective screening strategy as follows; i) To identify up-regulated genes in 120 lung cancers by genome-wide screening using the cDNA microarray representing 27,648 genes and pure populations of tumor cells taken from cancer tissues by laser microdissection, ii) To verify the candidate genes for their very low or absent expression in normal tissues by northern-blot analyses, iii) To validate the clinicopathological significance of their expression with tissue microarray containing hundreds of archived lung cancers, iv) To verify whether the target genes are essential for the growth or survival of cancer cells by RNAi and cell growth assays. As a result of this process, we identified 40 druggable oncoproteins. We further identified the Ras and EF-hand domain containing (RASEF), which contains a Rab GTPase domain and is considered as a member of Rab GTPase protein family. Immunohistochemical staining using tumor tissue microarrays consisting of 341 archived non-small cell lung cancers revealed the association of strong RASEF positivity with poor prognosis (P = 0.0034 by multivariate analysis). Reduction in RASEF expression by siRNA suppressed lung cancer cell proliferation, while induction of RASEF conferred growth-promoting activity of mammalian cells. RASEF could bind to extracellular signal-regulated kinase (ERK) 1/2 and appeared to enhance the ERK1/2 signaling. In addition, inhibition of interaction between RASEF and ERK1/2 using cell-permeable peptide that corresponded to the ERK1/2-interacting site of RASEF protein, suppressed growth of lung cancer cells. RASEF may play important roles in lung carcinogenesis, and could be useful as a prognostic biomarker and a target for the development of new molecular therapies.
Citation Format: Yataro Daigo, Atsushi Takano, Yusuke Nakamura. Ras and EF-hand domain containing as a novel tissue biomarker and a therapeutic target for lung 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 1765. doi:10.1158/1538-7445.AM2014-1765