bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-181: The impact of Ras/MAPK/S6K signaling pathway on prediction of clinical outcome in metastatic Her-2 positive breast cancer patients treated with trastuzumab
Authors: Svoboda Marek , Khoylou Marta , Grell Peter , Navratil Jiri , Fabian Pavel , Juracek Jaroslav , Palacova Marketa , Vyzula Rostislav , Hajduch Marian 
Published: May 2015

Abstract
Background: The overexpression of Her-2 (c-erbB2/Neu) in breast cancer is associated with poor prognosis, tumor recurrence and shortened survival. The administration of the trastuzumab significantly improves patients prognosis. However, in spite of these successful results, trastuzumab is effective only in 30-50% of cases. PI3K/Akt and Ras/MAPK signaling pathways are activated through Her-2 receptor and other growth factors’ receptors and both play important role in tumor behavior.
Methods: The study included 76 women with verified Her-2+ metastatic breast cancer (MBC) who were treated with trastuzumab based palliative chemotherapy. Immunohistochemistry was performed on formalin fixed, paraffin embedded tissue sections with antibodies against S6K, p-S6K-Ser235/236, MAPK, p-MAPK-Thr202/Tyr204, GSK3β, p-GSK3β-Ser9, mTOR, p-mTOR-Ser2448. The cytoplasmatic and nuclear fractions of the staining were assessed separately.
Results: Patients whose tumors showed cytoplasmic (c) and nuclear (n) expression of p- GSK3β-Ser9 exhibited worse PFS compared to tumors with negative p-GSK3β-Ser9 (PFS 5,1 vs 9,1 months; P=0,006). Similar results were also found in p-S6K kinase activity, with the difference that it was possible to observe the dependence on the p-S6K kinase compartmentalization. Patients whose tumors showed p-S6K-Ser235/236 expression accompanied with only cytoplasmatic (c) or nuclear and cytoplasmatic (n+c) staining exhibited worse PFS compared to tumors with negative p-S6K-Ser235/236 expression (negat) (c vs negat: 6,3 vs 16,1 months, P=0,006; n+c vs negat: 7,8 vs 16,1 months, P=0,025).
Of the remaining kinases, we showed no effect of their expression on treatment outcome.
Conclusions: This study confirms that prediction of the response or resistance to trastuzumab treatment depends on the S6K and GSK3β kinase activity. Patients, whose tumors had high level of p-S6K or p-GSK3β, had poorer benefit from trastuzumab based therapy. These patients are candidates for targeted blockade of PI3K/Akt and/or RAS/MAPK signaling pathways. Supported by the Internal Grant Agency of Ministry of Health, Czech Republic, No.NT/14599 and Biomedreg CZ.1.05/2.1.00/01.0030.
Citation Format: Marek Svoboda, Marta Khoylou, Peter Grell, Jiri Navratil, Pavel Fabian, Jaroslav Juracek, Marketa Palacova, Rostislav Vyzula, Marian Hajduch. The impact of Ras/MAPK/S6K signaling pathway on prediction of clinical outcome in metastatic Her-2 positive breast cancer patients treated with trastuzumab. [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 LB-181. doi:10.1158/1538-7445.AM2014-LB-181
Abstract LB-188: Co-evolution of primary and metastatic colorectal cancer
Authors: Yeatman Timothy J. , Teer Jamie , Grenawalt Danielle , Kim Richard , Schell Michael J. 
Published: May 2015

Abstract
Introduction: Metastasis is thought to be a clonal event whereby a single cell initiates the development of a new tumor that reproduces the primary tumor at a distant site. We hypothesized that primary tumors and their derivative metastases might be genetically identical. To test this hypothesis, we used deep nextgen sequencing to assess the molecular composition of primary:metastatic tumor pairs. Methods: Nearly 20,000 tumors were molecularly profiled as part of a large personalized medicine initiative. Of these, 468 colorectal tumor samples were further assessed by targeted exome sequencing of 1321 individual genes. 16 patients produced genomic profiles paired primary:metastatic specimens; 2 patients produced paired metastases. Non-synonymous, deleterious, single nucleotide variants were identified as potential driver or passenger mutations using the BWA/GATK pipeline.
Results: An average of 33.3 mutations/tumor was concordant (shared), with common drivers identified (APC, KRAS, TP53). An average of 2.3 mutations/tumor was discordant (unshared) in the paired primary and metastatic sites. Thus, the overall concordance rate for mutations was 93.5%; however, nearly all (17/18 (94.4%)) paired tumors showed at least one mutational discordance: TTN, the largest gene (5 discordant pairs); ADAMTS20, APC, MACF1, RASA1, TP53, and WNT2 (2 discordant pairs); SMAD2, SMAD3, SMAD4, FBXW7, and ∼66 others (1 discordant pair).
Conclusions: Primary and metastatic tumors displayed little variance overall supporting clonality; however, in ∼50% of cases, co-evolution produced incremental, potential driver mutations in both. These results suggest analysis of the primary lesion alone may be insufficient to precisely tailor therapy.
Citation Format: Timothy J. Yeatman, Jamie Teer, Danielle Grenawalt, Richard Kim, Michael J. Schell. Co-evolution of primary and metastatic colorectal 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 LB-188. doi:10.1158/1538-7445.AM2014-LB-188
Abstract LB-189: GRK3 is essential for metastatic cells and promotes prostate cancer progression
Authors: Ai Nanping , Hulsurkar Mohit , Akslen Lars , Watnick Randolph , Harlow Ed , Li Wenliang 
Published: May 2015

Abstract
Metastasis is responsible for over 90% of cancer deaths. However, biochemical and molecular mechanisms that regulate tumor progression to metastatic phenotype are still poorly understood, especially the control of survival and proliferation of metastatic cells. Kinases play key roles in regulation of many cellular processes. Here we employed an unbiased RNAi in vitro screen against human kinases and a focused cDNA in vivo screen to identify kinases that have novel roles in metastasis. Beta adrenergic receptor kinase 2 (BARK2, ADRBK2, GRK3) was one of the kinases we discovered to have a novel role in cancer progression through this work. It was essential for survival and proliferation of metastatic cells in vitro and in vivo. Moreover, it was also sufficient to promote primary prostate tumor growth and metastasis upon exogenous expression in poorly metastatic cells in mouse xenograft models. Mechanistically, we found that GRK3 functions at least in part through regulating several angiogenic factors and stimulating angiogenesis. Furthermore, GRK3 was found to be overexpressed in human prostate cancers, especially in metastasis. Taken together, these data suggest that GRK3 plays an important role in prostate cancer progression and metastasis.
Citation Format: Nanping Ai, Mohit Hulsurkar, Lars Akslen, Randolph Watnick, Ed Harlow, Wenliang Li. GRK3 is essential for metastatic cells and promotes prostate cancer progression. [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 LB-189. doi:10.1158/1538-7445.AM2014-LB-189
Abstract LB-190: Soluble E-Cadherin promotes cell invasion but not proliferation in prostate cancer
Authors: Fang Xiaolan , Balaji K. C. , NickKholgh Bita , Gyabaah Kenneth 
Published: May 2015

Abstract
Metastasis is responsible for the majority of prostate cancer-related deaths. Despite progress in early detection and management, there remains no effective, long-term cure for metastatic prostate cancer, partially due to the unclear molecular mechanism of cancer cell invasion and metastasis. Clinical reports discovered that soluble E-cadherin (sE-Cad, the cleaved ectodomain of human E-Cadherin protein) was elevated in body fluids and serum of patients with a variety of cancers, and its serum levels have been shown to correlate positively with metastatic cancers and disease invasiveness. However, little is known about the role of sE-Cad in metastasis, or the molecular mechanism of its abnormal accumulation in cancerous microenvironment. Our lab generated C4-2 prostate cancer cell lines which would secret synthetic sE-Cad by Doxycycline induction. We found that increased sE-Cad in the conditioned medium promotes cell invasion, but not cell proliferation. We analyzed the protein subcellular localizations in different cell compartments (membrane, cytoskeleton, nucleus and cytoplasm) and observed increased binding of synthetic sE-Cad to membrane E-Cadherin, indicating that sE-Cad could promote cell motility by interacting with membrane proteins and possibly disrupting the cell-cell adhesion. This work is supported by Wake Forest University institutional funds to KC Balaji and by NIH grant CA079448 to X Fang.
Citation Format: Xiaolan Fang, K. C. Balaji, Bita NickKholgh, Kenneth Gyabaah. Soluble E-Cadherin promotes cell invasion but not proliferation in prostate 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 LB-190. doi:10.1158/1538-7445.AM2014-LB-190
Abstract LB-193: Separable bilayer microfiltration device for viable label-free enrichment of circulating tumor cells
Authors: Zhou Ming-Da , Hao Sijie , Williams Anthony J. , Lv Bo , Zhu Jiyue , Cote Richard J. , Datar Ram H. , Tai Yu-Chong , Zheng Siyang 
Published: May 2015

Abstract
We designed a new separable bilayer (SB) microfiltration device for the viable enrichment of circulating tumor cells (CTCs) independent of antigen expression. Bilayer pore structures at the micro scale decrease cell damage to preserve viability, while maintaining throughput to allow rapid enrichment. The large pore size (40 um) of the upper layer facilitates the CTCs proliferation on chip. The separability enables the efficient release of the CTCs after successful on chip culture of captured CTCs.
We characterized the device performances including capture efficiency, enrichment against leukocytes, viability and proliferability. The SB device can enrich tumor cells with 80% capture efficiency, higher than 103 enrichment, and better than 70% viability from 1 mL whole blood samples on a 1 cm2 device. Multiple cell lines were shown to be able to proliferate after captured on SB device. Furthermore, using CTCs derived from an in vivo model system, cell cultures were established by releasing the captured CTCs from the chip. The cultured CTCs and their corresponding parental cell lines were injected into mice. Tumors were established with no discernable differences in volume and rate of growth, demonstrating similar tumorigenicity of viable CTCs recovered by the SB device. In a feasibility study, we successfully detected CTCs from 1 mL of clinical whole blood sample enriched via SB device.
Citation Format: Ming-Da Zhou, Sijie Hao, Anthony J. Williams, Bo Lv, Jiyue Zhu, Richard J. Cote, Ram H. Datar, Yu-Chong Tai, Siyang Zheng. Separable bilayer microfiltration device for viable label-free enrichment of circulating tumor cells. [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 LB-193. doi:10.1158/1538-7445.AM2014-LB-193
Abstract LB-203: Structural variants shuffle chromatin to activate GFI1 family oncogenes in medulloblastoma
Authors: Lee Catherine , Northcott Paul A. , Zichner Thomas , Lichter Peter , Korbel Jan O. , Pfister Stefan M. , Wechsler-Reya Robert J. 
Published: May 2015

Abstract
Medulloblastoma is a highly malignant pediatric brain tumor currently treated with a combination of surgery, radiation, and non-specific chemotherapy, posing a significant threat to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma and identified four distinct molecular subgroups. Group 3 and Group 4 subgroup medulloblastomas account for the majority of pediatric cases, yet, oncogenic drivers for these subtypes remain poorly understood. Here we report a series of prevalent, highly disparate genomic structural rearrangements, restricted to Groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto- oncogenes, GFI1 & GFI1B. Diverse mechanisms of structural variation activate GFI1/GFI1B expression through relocation of their coding sequences to genomic regions of transcriptionally active chromatin. Moreover, Gfi1 and Gfi1b each cooperate with Myc, an important oncogene in Group 3 medulloblastomas, to drive tumor initiation in mice. These data reveal GFI1 and GFI1B as novel medulloblastoma oncogenes, warranting their prioritization for molecularly targeted therapy of a marked proportion of Group 3 and Group 4 patients.
Citation Format: Catherine Lee, Paul A. Northcott, Thomas Zichner, Peter Lichter, Jan O. Korbel, Stefan M. Pfister, Robert J. Wechsler-Reya. Structural variants shuffle chromatin to activate GFI1 family oncogenes in medulloblastoma. [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 LB-203. doi:10.1158/1538-7445.AM2014-LB-203
Abstract LB-204: Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis in Wilms tumors
Authors: Rakheja Dinesh , Chen Kenneth S. , Liu Yangjian , Chang Tsung-Cheng , Shukla Abhay A. , Malter James , Mendell Joshua T. , Amatruda James F. 
Published: May 2015

Abstract
Wilms tumor is the most common pediatric kidney cancer and the fourth most common childhood cancer overall. It is treated with a combination of surgery, chemotherapy, and radiation, and, while most children are cured, survival remains poor in those with advanced-stage disease. Known driver mutations (in WT1, WTX, and CTNNB1) account for only one-third of Wilms tumor cases. To better define the genomic landscape of Wilms tumor, we performed whole-exome sequencing of 44 Wilms tumors. We also sequenced matched germline DNA by whole-exome sequencing (15 cases) or targeted Sanger sequencing of candidate mutations (29 cases) to identify somatic mutations. Through this approach, we identified recurrent somatic mutations in MYCN, DROSHA, and DICER1 which were mutually exclusive with known Wilms tumor mutations in WT1 and CTNNB1. The ribonucleases DROSHA and DICER1 perform two key steps in the biogenesis of microRNAs (miRNAs), which are ∼22-nt non-coding RNAs that regulate the stability and translation of target mRNAs. DROSHA and DICER1 mutations occurred at or near conserved metal-binding residues in their ribonuclease (RNase) IIIB domains. In vitro processing assays modeling these mutations showed that they partially or completely disrupt the ribonuclease activity of DROSHA and DICER1. In addition, next-generation sequencing of small RNAs in these tumors revealed that the DICER1 mutations preferentially impaired processing of miRNAs derived from the 5′ arm of pre-miRNA hairpins, including the let-7 tumor suppressor miRNA family. Although DROSHA-mutant tumors did not exhibit skewed expression of 5′ vs. 3′-derived miRNAs, expression of let-7 and other putative tumor suppressor miRNAs was reduced in these tumors as well. While germline and somatic mutations in DICER1 have been reported in some cancers, this is the first report of recurrent DROSHA mutations in any human tumor type. Moreover, these results suggest that impairment of miRNA processing by somatic mutation of DROSHA and DICER1 defines a novel subclass of Wilms tumor.
Citation Format: Dinesh Rakheja, Kenneth S. Chen, Yangjian Liu, Tsung-Cheng Chang, Abhay A. Shukla, James Malter, Joshua T. Mendell, James F. Amatruda. Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis in Wilms tumors. [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 LB-204. doi:10.1158/1538-7445.AM2014-LB-204
Abstract LB-216: Integrated analysis of differential pathway resiliency in response to MAPK inhibition in BRAF-mutant cancer
Authors: Sos Martin L. , Levin Rebecca , Gordan John , Oses-Prieto Juan , Webber James , Salt Megan , Hann Byron , Burlingame Alma , Mccormick Frank , Bandyopadhyay Sourav , Shokat Kevan 
Published: May 2015

Abstract
Despite the development of potent RAF-MAPK pathway inhibitors, only a fraction of BRAF-mutant patients responds to the treatment with these drugs. Here, we applied a combined chemo-genomics and chemo-proteomics approach to gain insights into the dynamics of primary resistance signaling and to define novel cancer vulnerabilities in these tumors. These analyses uncovered differential pathway resiliency in response to MAPK inhibition in BRAF-mutant cancer cells. Using forward- and reverse-genetics we identify the assembly of RAS/RAF/MEK complexes as a critical force to override RAF-MAPK pathway inhibitor efficacy. Mapping of global phosphorylation dynamics using orthogonal mass-spectrometry based methods revealed multi-layered MAPK pathway feedback-loop release that feeds into MAPK-pathway hyperactivation. The phosphoprotein nuclear interacting partner of ALK (NIPA) identified in the phosphoproteome screen is critical for maintenance of the primary resistance phenotype. Overall, our data provide a kinome- and phosphoproteome-wide view of the adaptive process of primary resistance to MAPK inhibitors in BRAF-mutant tumors and reveals translatable strategies toward improvement of the efficacy of individualized therapies in these patients.
Citation Format: Martin L. Sos, Rebecca Levin, John Gordan, Juan Oses-Prieto, James Webber, Megan Salt, Byron Hann, Alma Burlingame, Frank Mccormick, Sourav Bandyopadhyay, Kevan Shokat. Integrated analysis of differential pathway resiliency in response to MAPK inhibition in BRAF-mutant 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 LB-216. doi:10.1158/1538-7445.AM2014-LB-216
Abstract LB-219: Synthetic lethal screening reveals FGFR as one of combinatorial targets to overcome resistance to Met-targeted therapy
Authors: Kim Bogyou 
Published: May 2015

Abstract
Met is a receptor tyrosine kinase that promotes cancer progression. In addition, Met has been implicated in resistance of tumors to various targeted therapies such as EGFR inhibitors in lung cancers, and has been prioritized as a key molecular target for cancer therapy. However, the underlying mechanism of resistance to Met targeting drugs is poorly understood. Here, we describe screening of 1310 genes to search for key regulators related to drug resistance to an anti-Met therapeutic antibody (SAIT301) by employing a siRNA-based synthetic lethal screening method. We found that knockdown of 69 genes in Met-amplified MKN45 cells sensitized the anti-tumor activity of SAIT301. Pathway analysis of these 69 genes implicated FGFR as a key regulator for anti-proliferative effects of Met targeting drugs. Inhibition of FGFR3 increased target cell apoptosis through the suppression of Bcl-xL expression, followed by reduced cancer cell growth in the presence of Met targeting drugs. Treatment of cells with the FGFR inhibitors substantially restored the efficacy of SAIT301 in SAIT301-resistant cells and enhanced the efficacy in SAIT301-sensitive cells. In addition to FGFR3, integrin β3 is another potential target for combination treatment with SAIT301. Suppression of integrin β3 decreased AKT phosphorylation in SAIT301-resistant cells and restores SAIT301 responsiveness in HCC1954 cells, which are resistant to SAIT301. Gene expression analysis from using CCLE DB shows cancer cells with high levels of FGFR and integrin β3 are resistant to crizotinib treatment, suggesting FGFR and integrin β3 could be used as predictive markers for Met targeted therapy and provide a potential therapeutic option to overcome acquired and innate resistance for the Met targeting drugs.
Citation Format: Bogyou Kim. Synthetic lethal screening reveals FGFR as one of combinatorial targets to overcome resistance to Met-targeted therapy. [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 LB-219. doi:10.1158/1538-7445.AM2014-LB-219
Abstract LB-234: Suppression of Bruton tyrosine kinase with X-022, a highly selective next-generation irreversible inhibitor
Authors: Mulvihill Mark J. , Chen Xiangyang , Shaw JP , Liu Richard , Ni Haihong , Babiss Lee , Renzetti Louis 
Published: May 2015

Abstract
BTK is a member of the TEC family of kinases and is a critical component of B cell receptor (BCR) signaling, promoting B cell maturation, survival and proliferation. BCR signaling is requisite in all B cell-mediated malignancies where clinical trials with BTK inhibitors have proven efficacious. X-Rx utilized its drug discovery platform and knowhow to advance multiple novel series of BTK inhibitors. X-022 was then identified as a next generation, oral small molecule BTK inhibitor. X-022 irreversibly inhibits BTK with an IC50 of 2.3 nM. In primary human B cell and HWB assays, X-022 inhibited B cell activity with IC50 values of 49 and 93 nM, respectively. X-022 showed superior selectivity against a panel of 456 kinases, only inhibiting at &gt;90% BTK at a concentration of 1000 nM. Oral bioavailability of &gt;20% is observed in mice, rats and dogs. In a mouse PK/PD model, X-022 showed a dose dependent decrease in B cell activation measured over an 8 hour time interval with &gt;98% inhibition observed at 10 mg/kg po. In an established model of collagen induced arthritis in mice, X-022 caused a dose dependent decrease in disease severity consistent with mechanism of action. No safety issues were identified in a pilot study in rodents at doses up to 300 mg/kg po. X-022 is a promising next generation irreversible oral BTK inhibitor for the treatment of B cell malignancies and chronic autoimmune diseases. In addition, the high degree of selectivity combined with favorable molecular properties make X-022 an excellent candidate for co-formulation with other targeted therapeutics.
Citation Format: Mark J. Mulvihill, Xiangyang Chen, JP Shaw, Richard Liu, Haihong Ni, Lee Babiss, Louis Renzetti. Suppression of Bruton tyrosine kinase with X-022, a highly selective next-generation irreversible inhibitor. [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 LB-234. doi:10.1158/1538-7445.AM2014-LB-234