bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B134: Stathmin is involved in the maternal embryonic leucine zipper kinase pathway in human astrocytomas.
Authors: Uno Miyuki , Oba-Shinjo Sueli Mieko , Silva Roseli , Gimenez Marcela , Reis Gisele , Rosa Jose C. , Marie Suely K. N. 
Published: August 2014

Abstract
Introduction: Maternal Embryonic Leucine Zipper Kinase (MELK) is a serine/threonine kinase involved in several cell processes, including the cell cycle, proliferation, apoptosis and mRNA processing. MELK has shown multiple features consistent with the potential utility of this gene as an anticancer target, including in astrocytomas, the most common brain tumor in adults. Nevertheless the pathway of MELK in tumorigenesis is not well known yet.
Purpose: This study aim to analyze genes and proteins involved in the MELK pathway in the tumorigenesis of gliomas, enabling the discovery of new therapeutic targets.
Material and Methods: Analysis of the expression profile of a panel of protein relevant to the process of tumorigenesis that MELK is involved was performed by Proteomic analysis by two dimensional electrophoresis and mass spectrometry for human glioma cell line U87MG transfected with siRNA for the MELK compared to U87MG transfected with non-target control (NTC) cells. Analysis and validation of gene expression was performed by Quantitative real time PCR (qRT-PCR) using SYBR Green method in a series of 154 astrocytomas of different malignant grade (23 AGI, 26 AGII, 18 AGIII and 87 GBM) relative to 22 non neoplastic (NN) brain samples.
Results: Differentially expressed proteins in U87MG cell line transfected with siRNA for the MELK compared to NTC control cells were identified by proteomic analysis. One of the proteins with lower expression when MELK was silenced was Stathmin (STMN1). The analysis in astrocytoma samples showed lower significant STMN1 relative expression of astrocytoma samples when compared to NN. Spearman correlation for gene expression levels of MELK and STMN1 for GBM samples were statistically significant (r=0.66, p&lt;0.003). We found significant differences of median survival times of two GBM groups: 39 with hypoexpression of both STMN1 and MELK (8 months), versus 9 with hypoexpression of STMN1 and hiperexpression of MELK (5 months), log rank=0.016.
Conclusions: STMN1 plays a role in regulation of the cell cycle and is defined as an oncoprotein. Thus, our results showed that STMN1 is involved in the MELK pathway suggesting that this protein plays an important role in glioma tumorigenesis.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B134.
Citation Format: Miyuki Uno, Sueli Mieko Oba-Shinjo, Roseli Silva, Marcela Gimenez, Gisele Reis, Jose C. Rosa, Suely K. N. Marie. Stathmin is involved in the maternal embryonic leucine zipper kinase pathway in human astrocytomas. [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 B134.
Abstract B137: Oncogenic chromosomal blocks in cancer genomes.
Authors: Wagner Joel P. , Liu Edison T. 
Published: August 2014

Abstract
Our preliminary observations suggest that chromosome structure rearrangements in cancer genomes are a parsimonious strategy to activate or suppress the expression of blocks of genes that contribute to cancer sustenance. We hypothesize that these rearrangements exploit the natural organization of the human genome to promote tumor development and drug resistance. We believe that in the process of cancer evolution, genes are brought together by chromosome rearrangement and then subsequently co-selected for providing a survival advantage to the cancer. In this manner, chromosome structure represents a novel means for encoding information in cancer cells, beyond the enzymatic and protein-protein interactions defining biochemical pathways. Using public data from a large collection of human cancer cell lines, we uncovered blocks of genes on each chromosome that undergo copy number alterations as a unit, which we term Cancer Syntenic Blocks (CSBs). Similar to syntenic blocks in comparative evolution, these CSBs appear to engage in rearrangements as chromosomal blocks, suggesting they may function as systems modules in cancer biology. We developed quantitative measures to identify CSBs in individual cancer types using a multi-gene network clustering approach, and showed that CSBs are enriched for cancer relevant functions. We further demonstrated that some CSBs are conserved across multiple cancer types, suggesting they may function in pan-cancer modules. We hypothesize that the component genes within a CSB do not necessarily act in one biochemical pathway, but instead may represent the coordination of pathways that contribute to a common cellular physiologic function. We also identified co-occurring sets of intra- and inter-chromosomal CSBs (both undergoing copy number gain, loss, or gain paired with loss), suggesting that multiple CSBs can act coordinately. The CSB framework can be exploited to assess systems activation of oncogenic blocks of genes in cancer, which can be used in cancer classification and in genome-based diagnostics.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B137.
Citation Format: Joel P. Wagner, Edison T. Liu. Oncogenic chromosomal blocks in cancer genomes. [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 B137.
Abstract B146: Mid-therapy FDG PET as an outcome biomarker in sarcoma patients.
Authors: Eary Janet F. , O'Sullivan Janet , O'Sullivan Finbarr , Conrad Ernest U. 
Published: August 2014

Abstract
Objective: To determine the prognostic biomarker capability of neo-adjuvant mid-therapy FDG PET for sarcoma monitoring.
Methods: Patients with a sampling of sarcoma subtypes presenting to clinic and treated with neo-adjuvant chemotherapy according to standard clinical practice had baseline, mid-therapy (after 2 cycles of chemotherapy) and pre-resection FDG PET studies. Tumor FDG SUV maximum at each timepoint, tumor type, location, size, gender, and histopathologic grade along with patient age were recorded. Months from baseline FDG PET to events of tumor local recurrence, metastasis, or death were determined from clinical records for comparison with imaging data. Baseline tumor uptake data, with the addition of the variable for percent difference between the baseline and mid-therapy FDG tumor maximum to describe change mid-therapy were analyzed for association with outcome in a model that included all other available covariates. Data was analyzed using univariate and multivariate Cox regression analyses to evaluate the contribution of the PET FDG response for predicting death, metastases, or tumor local recurrence.
Results: Data from 65 patient studies were analyzed. Univariate and multivariate analyses showed that the difference in FDG PET tumor maximum uptake added significantly to the prognostic ability of the model using baseline tumor uptake alone with the other clinical covariates. The median value for this difference for the group was 35.7% with a difference below that value implying a significantly higher risk for poor outcome. Additionally, Cox regression analysis showed that there is a continuous dose effect for FDG PET tumor uptake values and FDG PET percent change. Local recurrence was predicted independently from metastases.
Conclusion: Mid-neo-adjuvant therapy FDG PET tumor uptake in sarcoma patients can be used as an imaging biomarker for prediction of local recurrence, metastases, and overall survival.
Supported by NIH/NCI CA 65537 and SFI 11/PI/1027
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B146.
Citation Format: Janet F. Eary, Janet O'Sullivan, Finbarr O'Sullivan, Ernest U. Conrad. Mid-therapy FDG PET as an outcome biomarker in sarcoma patients. [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 B146.
Abstract B156: Regulation of tumor metabolism by the investigational proteasome inhibitor ixazomib in KRAS wild-type and KRAS mutant xenograft tumors.
Authors: Chattopadhyay Nibedita , Berger Allison , Garnsey James , Bernard Hugues , Koenig Erik , Lightcap Eric , Amidon Ben 
Published: August 2014

Abstract
The investigational proteasome inhibitor ixazomib (MLN2238) inhibits cell growth in a broad panel of solid tumor and hematological cell lines when tested in vitro. In contrast, antitumor activity in xenograft-bearing mice is model-dependent, with some solid tumor models showing no response to ixazomib treatment. A survey of 15 NSCLC and 6 colon xenograft models showed a striking relationship between the degree of antitumor activity of ixazomib and KRAS genotype. Tumors with wild-type (WT) KRAS showed higher sensitivity to ixazomib compared to the tumors harboring a KRAS activating mutation. These xenografts included cell-line-derived subcutaneous xenografts as well as patient derived primary tumors. To confirm that KRAS mutation impacts response to ixazomib, we used SW48 isogenic colon cancer cell lines, in which a KRAS-G13D mutation was introduced into KRAS-WT SW48 cells to generate stable SW48-KRAS-G13D cells. Although in vitro sensitivity to ixazomib was similar between the paired cell lines, in vivo antitumor activity was observed in only SW48 KRAS WT tumors, but not SW48-KRAS-G13D tumors. These data confirm the association of KRAS status and response to ixazomib. Since KRAS activating mutations are known to be associated with metabolic reprogramming, we performed metabolite profiling using in vivo SW48 isogenic tumor pairs treated with or without ixazomib. As expected, prior to treatment there were significant baseline differences between SW48 WT and SW48-KRAS-G13D tumor metabolite profiles in categories such as glutathione levels and glycogen breakdown intermediates, reflecting higher oxidative stress and glucose utilization in the KRAS-G13D tumors. After a single dose of ixazomib, significant metabolic regulation was noted in categories including free amino acid pools, and polyamine levels, and some of these changes were more pronounced in the SW48 KRAS WT tumors as compared to the KRAS-G13D tumors. Our data also showed activation of GCN2 mediated signaling following ixazomib treatment, possibly as a result of amino acid deprivation in the tumors. The results suggest additional non-clinical avenues to explore mechanisms of sensitivity and resistance to proteasome inhibitors in solid tumors.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B156.
Citation Format: Nibedita Chattopadhyay, Allison Berger, James Garnsey, Hugues Bernard, Erik Koenig, Eric Lightcap, Ben Amidon. Regulation of tumor metabolism by the investigational proteasome inhibitor ixazomib in KRAS wild-type and KRAS mutant xenograft tumors. [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 B156.
Abstract B163: Over-expression of STAT-3 induces anoikis resistance, promotes cell migration and metastatic potential in cancer cells.
Authors: Fofaria Neel Manoj , Srivastava Sanjay K. 
Published: August 2014

Abstract
Anoikis is an anchorage independent cell death. Resistance to anoikis is one of the key features of the metastatic cells. In the current study, we have shown the role of STAT-3 in anoikis resistance in various melanoma and pancreatic cancer cells. Marked anoikis was induced as such in the cells that were grown in anchorage-independent conditions. The melanoma and pancreatic cancer cells that resisted anoikis were observed to have higher rate of migration as compared to the cells that were exposed to anchorage dependent growth, as observed in cell migration and invasion assays. These anoikis resistant cells also had significantly higher expression and phosphorylation of STAT-3 at Tyr 705, than the cells that were attached to the basement membrane. Treatment of these cells with IL-6, a cytokine which phosphorylates STAT-3, prevented the induction of anoikis. STAT-3 inhibitors AG490 and piplartine induced anoikis in a concentration-dependent manner, whereas IL-6 blocked anoikis. Over-expression of STAT-3 by transfection, not only increased the anoikis resistance but also protected cancer cells from piplartine-induced anoikis, confirming the role of STAT-3 in anoikis resistance. On the other hand, silencing STAT-3 decreased the potential of cancer cells to resist anoikis. Furthermore, STAT-3 (-/-) cancer cells were more sensitive to anoikis as well as to the effect of piplartine as compared to STAT-3 (+/+) cells. The STAT-3 (+/+) cells also had enhanced migration potential as compared to STAT-3 (-/-) cells. STAT-3 (-/-) cells and the cells that were treated with PL completely failed to develop tumors when injected subcutaneously in immune-compromised mice. Moreover, these cells also failed to metastasize when injected intravenously. On the other hand, STAT-3 (+/+) cells not only formed aggressive tumors subcutaneously but also highly metastasized when injected intravenously. In summary, our results establish STAT-3 as a critical player that renders anoikis resistance to the cancer cells and enhance their metastasis potential.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B163.
Citation Format: Neel Manoj Fofaria, Sanjay K. Srivastava. Over-expression of STAT-3 induces anoikis resistance, promotes cell migration and metastatic potential in cancer 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 B163.
Abstract B167: Targeting glioblastoma invasion with GSK-3 inhibitors: Rapid effects on vimentin dynamics.
Authors: Lawler Sean E. , Nowicki Michal O. , Chiocca E. Antonio 
Published: August 2014

Abstract
Tumor cell invasion of surrounding normal brain remains a formidable obstacle to the effective treatment of the lethal brain tumor glioblastoma. Moreover, invasion may be enhanced by radiation and bevacizumab, which are important clinical agents in glioblastoma treatment. At present there are no agents available clinically that specifically target the invading tumor cell population. We previously identified that small molecule inhibitors of the protein kinase GSK-3 (glycogen synthase kinase-3), are able to specifically block glioblastoma invasion in vitro and in vivo, where they also prolong survival in animal models bearing intracranial invasive orthotopic glioblastoma xenografts.
GSK-3 is a ubiquitous multifunctional serine/threonine protein kinase involved in many signaling pathways. To better understand the functions of GSK-3 in glioblastoma we used proteomics and gene/microRNA expression profiling to determine the molecular effects of GSK-3 inhibition in glioblastoma cells with the inhibitors Lithium chloride and 6-bromoindirubin-3’-oxime (BIO). This revealed distinct and overlapping effects of each compound, including the expected upregulation of β-catenin targets such as Axin2. Proteomics revealed major changes in the cytoskeleton, with downregulation of the EMT marker vimentin as the most significant alteration. Vimentin is an intermediate filament protein that functions as an organizer of a number of critical proteins involved in attachment, migration, and cell signaling. The downregulation of vimentin was rapid and due to alterations in its dynamics in response to GSK-3 inhibition. GSK-3 and vimentin were shown to associate with each other in glioblastoma cells, and reduction in phosphorylation of vimentin serine 38 was observed in response to treatment with inhibitors. We showed that vimentin is highly expressed in patient glioblastoma samples and higher levels of vimentin are associated with poorer prognosis in glioblastoma patients. Vimentin knockdown also reduced glioblastoma cell migration. The mechanism of action of GSK-3 inhibition in the context of glioblastoma invasion and the potential of developing a therapeutic strategy based on these observations will be discussed.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B167.
Citation Format: Sean E. Lawler, Michal O. Nowicki, E. Antonio Chiocca. Targeting glioblastoma invasion with GSK-3 inhibitors: Rapid effects on vimentin dynamics. [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 B167.
Abstract B171: Traditional Chinese medicine (TCM) herbal mixture LQ targets lung cancer metastasis.
Authors: Zhang Lei , Wu Chengyu , Zhang Yong , Liu Fang , Wang Xiaoen , Zhao Ming , Hoffman Robert M. 
Published: August 2014

Abstract
Traditional Chinese Medicine (TCM) compositions usually comprise multiple herbs and components that interact. In the present report, the TCM mixture LQ (gavage, 600 mg/kg/day) significantly inhibited lung cancer primary tumor growth and metastasis suggesting selective targets. LQ was efficacious against primary and metastatic cancer without weight loss in contrast to cyclophosphamide and doxorubicin, which caused significant weight loss. Survival of tumor-bearing mice was also prolonged by LQ comparable to doxorubicin. Cancer cell apoptosis was selectively induced by LQ. The results indicate that LQ can have non-toxic efficacy against metastatic lung cancer in clinically relevant orthotopic mouse and experimental metastasis models of cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B171.
Citation Format: Lei Zhang, Chengyu Wu, Yong Zhang, Fang Liu, Xiaoen Wang, Ming Zhao, Robert M. Hoffman. Traditional Chinese medicine (TCM) herbal mixture LQ targets lung cancer metastasis. [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 B171.
Abstract B186: The unexpected role of p110β in HER2 amplified and PIK3CA mutant breast cancers.
Authors: Costa Carlotta , Ebi Hiromichi , Faber Anthony C. , Nishtala Madhuri , Chul Song Young , Engelman Jeffrey A. 
Published: August 2014

Abstract
The PI3K pathway is alterated in up to 70% of breast cancers. Although both isoform-specific and pan-PI3K inhibitors are available, it is still unclear which compounds are more effective among the different subtypes of breast cancer. We performed time course experiments using the selective p110α inhibitor, BYL-719, in PIK3CA mutant and HER2 amplified cell lines in order to test whether p110α inhibition alone was sufficient to abrogate PI3K-AKT signaling. We observed a rebound of PIP3, the PI3K product, 24 hours after treatment in all cell lines. Notably, both PIP3 and p-AKT levels increased after 24 hours in HER2 amplified cells, while the rebound of p-AKT in PIK3CA mutant was minimal and did not correlate with PIP3 levels. Both p110β inhibitor and siRNA againt p110β were effective in blocking the PIP3 rebound observed after 24 hours of treatment with BYL-719 alone. Consistent with this, the combination of p110α and p110β inhibitors reduce cell growth in long term viability assays and induced a greater apoptotic response in comparison to BYL-719 alone. Importantly, p110α and p110β inhibitors in combination induced tumor regression in vivo, while with single agent BYL-719 we observed only tumor stasis. Finally, we demonstrated, both in vitro and in vivo, that PIP3 levels correlate with inhibitor efficacy more accurately than p-AKT in PIK3CA model. Thus, PIP3 may serve as a more effective biomarker than p-AKT levels to predict response to PI3K inhibitors in PIK3CA mutant and HER2 amplified breast cancers.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B186.
Citation Format: Carlotta Costa, Hiromichi Ebi, Anthony C. Faber, Madhuri Nishtala, Young Chul Song, Jeffrey A. Engelman. The unexpected role of p110β in HER2 amplified and PIK3CA mutant breast cancers. [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 B186.
Abstract B187: Pharmacodynamics of OSI-027, a dual mTORC1/mTORC2 inhibitor, in tumor and surrogate tissues: Results from the expansion phase of a first-in-man study.
Authors: Mateo Joaquin , Schoffski Patrick , Olmos David , Dumez Herlinde , Moreno Victor , Jie Fei , Poondru Srinivasu , Samberg Nancy L. , Van Tornout Jan M. , Kaye Stanley B. , LoRusso Patricia M. 
Published: August 2014

Abstract
Background: The kinase activity of the mammalian target of rapamycin (mTOR) involves 2 multiprotein complexes, mTORC1 and mTORC2, regulating distinct signaling pathways. We conducted a first-in-human study of OSI-027, an orally bio-available inhibitor of both mTORC1 and mTORC2, with the aim of evaluating its safety, pharmacokinetics (PK), maximum tolerated dose (MTD) and pharmacodynamics (PD). We present final results, focusing on expansion cohorts for biomarker assessments at different dose levels.
Material and Methods: Three dose-escalation arms evaluated different schedules (S) of administration; S1: once daily for 3 of every 7 days (qd 3/7d), S2: once weekly (qwk) or S3: continuous qd, in 21-day cycles. Dose limiting toxicities (DLT) were assessed in cycle 1 (CTCAE v3). Safety and PK were studied after single and multiple dosing. Expansion cohorts for biomarker assessment were initiated at different dose levels based on safety data, collecting PBMC samples and paired pre/post-treatment tumor and skin biopsies.
Results: 123 patients (pts) were treated. Overall, DLTs (n=11) were fatigue (4), elevated serum creatinine (2), cardiomyopathy (1), decreased left ventricular ejection fraction (1), hyperglycemia (1), rash (1) and bone pain (1). S3 was discontinued (MTD 35mg qd) due to renal toxicity. Based on safety data, expansion cohorts were initiated to assess PD at 90mg qd 3/7d, 120mg qd 3/7d (MTD for S1) and 240mg qwk (maximum administered dose on S2 due to high number of capsules required; MTD for S2 not reached). Cmax and AUC were dose-linear. PD inhibition in PBMC was associated with OSI-027 exposure; results of tumor and skin biopsies are presented in table 1. Stable disease (RECIST 1.0) after 24 weeks was observed in 5 pts.
Conclusions: OSI-027 modulates mTORC1/mTORC2 in a dose-dependent manner. PD in skin samples did not predict PD in tumor. While 90mg qd 3/7d inhibited target in PBMC and skin, 120mg qd 3/7d was required to achieve substantial effect in tumor but this dose was not well tolerated: 1/3 of pts required dose-reductions due to adverse events.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B187.
Citation Format: Joaquin Mateo, Patrick Schoffski, David Olmos, Herlinde Dumez, Victor Moreno, Fei Jie, Srinivasu Poondru, Nancy L. Samberg, Jan M. Van Tornout, Stanley B. Kaye, Patricia M. LoRusso. Pharmacodynamics of OSI-027, a dual mTORC1/mTORC2 inhibitor, in tumor and surrogate tissues: Results from the expansion phase of a first-in-man study. [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 B187.