bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 63: TKTL1 is activated by promoter hypomethylation and contributes to head and neck squamous cell carcinoma carcinogenesis via increased aerobic glycolysis and HIF1-alpha stabilization
Authors: Sun Wenyue , Liu Yan , Glazer Chad A. , Shao Chunbo , Bhan Sheetal , Demokan Semra , Zhao Ming , Rudek Michelle A. , Ha Patrick K. , Califano Joseph A. 
Published: February 2011

Abstract
Described decades ago, the “Warburg effect”, an elevation in aerobic glycolysis, is a fundamental property of cancer cells. Lactate and pyruvate, the end products of glycolysis, are highly produced by cancer cells even in the presence of oxygen. Previously, we observed promoter hypomethylation and overexpression of TKTL1 (Transkelolase-like 1) in Head and Neck Squamous Cell Carcinoma (HNSCC). This study aimed to investigate whether aberrant expression of TKTL1 contributes to HNSCC tumorigenesis and whether this is associated with aerobic glycolytic metabolism. We found that TKTL1 exhibits high frequency of promoter hypomethylation in HNSCC tumors compared with the normal oral epithelial mucosa, correlating with its overexpression in HNSCC. Overexpression of TKTL1 in HNSCC cells promoted cellular proliferation and enhanced tumor growth in vitro and in vivo. Further, in a murine xoenograft and human model of HNSCC, we found that overexpression of TKTL1 increased the production of fructose-6-phosphate and glyceraldehyde-3-phosphate, in turn elevating the production of pyruvate and lactate production accompanied by the elevated glucose uptake and ATP production. Importantly, overexpression of TKTL1 is associated with the normoxic stabilization of the malignancy-promoting transcription factor HIF1α by aerobic glycolytic metabolites including pyruvate and lactate. Notably, reduction of TKTL1 expression decreased HIF1α accumulation, and inhibition of HIF1α could abrogate the growth effects mediated by TKTL1 overexpression. These findings suggest that TKTL1 is a novel protooncogene that is epigenetically activated by aberrant hypomethylation and contributes to a malignant phenotype via altered glycolytic metabolism and HIF1α accumulation, providing opportunities for therapeutic targeting of metabolic pathways in cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 63.
Abstract 633: Tumor cell resistance mechanisms to aurora kinase inhibitors
Authors: Kollareddy Madhusudhan , Zheleva Daniella , Dzubak Petr , Hajduch Marian 
Published: February 2011

Abstract
Aurora kinase inhibitors are being developed as anti-cancer drugs and more than 10 small molecules are currently undergoing clinical trials. CYC116, an Aurora kinase inhibitor, discovered and developed by Cyclacel Ltd. is currently in phase I clinical trial in patients with advanced solid tumors. CYC116 showed significant anti-proliferative activity in preclinical studies. However tumor cell resistance mechanisms towards this Aurora kinase inhibitor have not been yet established. We developed several HCT116 p53 wild-type and HCT116 p53 null resistant clones towards CYC116 by exposing the cells to high drug concentrations. In order to compare resistance mechanisms, another Aurora kinase inhibitor, ZM447439, was used as a reference compound. Here we present the preliminary data characterizing CYC116-resistant clones. In MTT cytotoxicity assays all the clones showed CYC116 resistance and cross resistance to other Aurora kinase inhibitors, and to some anticancer drugs, which suggest a multidrug resistance phenotype. However the degree of resistance is variable between the clones. All CYC116-resistant clones irrespective of their p53 background became tetraploid. This was not observed for the ZM447439-resistant clones. PH3 (ser10), an Aurora kinase B phosphorylation site, was not inhibited in all resistant clones, suggesting that this kinase is still active. DNA and RNA synthesis were also not inhibited in these clones. Flow cytometry based studies revealed no up regulation of PgP drug transporter in all CYC116-resistant clones, whereas two HCT116 p53 null ZM447439-resistant clones displayed an increase in PgP levels. Up regulation of MRP was only detected in one HCT116 p53 null CYC116-resistant clone, which expressed high levels of this drug transporter. From the initial data it is obvious that there were no common resistance mechanisms towards the studied Aurora kinase inhibitors. We are continuing the characterization of these resistant clones, which include microarray gene expression studies, 2-D electrophoresis and mass spectrometry studies, Aurora A and B sequencing (target mutations), and other drug transporter (e.g. BCRP & LRP) expression studies. These will further help the understanding of the molecular basis of acquired tumor resistance to CYC116 and will aid us in predicting the clinical response as well as in designing combination treatment regimens for overcoming resistance hence furthering clinical development. This work was kindly supported by the Czech ministry of education. Grant number: MSM6198959216 and LC07017.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 633.
Abstract 649: Dynamic magnetic resonance imaging of the effects of vascular targeting agents on intracerebral metastases
Authors: Muldoon Leslie L. , Gahramanov Seymur , Marshall Deborah J. , Neuwelt Edward A. 
Published: February 2011

Abstract
Objective: Agents that target tumor vasculature are gaining use as therapeutics for brain tumors. We used dynamic magnetic resonance imaging (MRI) to evaluate the vascular effects of the monoclonal antibodies bevacizumab, targeting vascular endothelial growth factor (VEGF), and intetumumab (CNTO 95), targeting αV integrins, in a rat model of lung cancer brain metastasis.
Methods: Female nude rats received intracerebral implantation of human LX-1 small cell lung carcinoma cells. At 10 days after tumor implantation, rats were untreated or treated with intetumumab (30 mg/kg IV) or bevacizumab (45 mg/kg IV) (n = 4-5 per group). MRI at 12T was performed prior to treatment and at 1, 3, and 7 days after treatment, using dynamic contrast enhanced (DCE) MRI with gadolinium-based contrast agent (GBCA), and dynamic susceptibility contrast (DSC) MRI with the blood pool iron oxide nanoparticle ferumoxytol. Tumor relative cerebral blood volume (rCBV) and permeability markers were assessed.
Results: Intetumumab increased brain tumor vascular permeability at 3 and 7 days after treatment on DCE-MRI, as determined by the ratio of maximum GBCA signal intensity to normal brain, a measure of the interstitial space volume fraction (ve), and time to peak enhancement, a surrogate for Ktrans, the rate constant for passive leakage across the blood-brain barrier. Intetumumab also increased tumor rCBV on DSC-MRI as compared to untreated controls. Tumors uniformly grew during the week assessment period. In contrast, bevacizumab decreased tumor permeability and rCBV, and slowed the increase in the volume of enhancing tumor on both T1-weighted and T2-weighted images, compared with controls.
Conclusions: The vascular targeting agents intetumumab and bevacizumab had diametrically opposite effects on dynamic MRI of tumor vasculature in a rat brain metastasis model. The αV integrin inhibitory antibody intetumumab appeared to increase tumor vascular permeability and blood volume, suggesting it may enhance chemotherapy efficacy by improving chemotherapy delivery to intracerebral tumors. Conversely, the effects of bevacizumab on tumor vasculature suggest it would actually decrease chemotherapy delivery, thereby minimizing chemotherapy efficacy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 649.
Abstract 653: Stat3 as a molecular signature and therapeutic target for inflammatory breast cancer
Authors: Thudi Nanda K. , Mandal Pijus K. , McMurray John S. , Robertson Fredika M. 
Published: February 2011

Abstract
Inflammatory breast cancer (IBC) is the most aggressive and lethal of all breast cancers. There is little known about the molecular signatures of IBC with the exception that these breast cancers commonly over-express E-cadherin and Rho C GTPase and exist as tumor emboli within dermal lymphatics. In addition, IBC tumor emboli exhibit characteristics of tumor initiating cells, i.e., cancer stem cells. Another interesting characteristic of IBC tumors is their ability to undergo vasculogenic mimicry, forming tube-like structures that abrogate the need of this very aggressive tumor type to induce the development of angiogenic endothelium. In vitro under low adherence culture conditions, IBC cells readily form tumor spheroids that contain ”label retaining” cells and exhibit self-renewal. In addition, when cultured as tumor spheroids in 3 dimensions, they express high levels of the phosphorylated form of the signal transducer and activator of transcription 3 (phospho-stat3), recently shown to regulate survival of embryonic stem cells. From a panel of newly developed novel stat3-targeted peptidomimetics, we found that the lead compound, designated as PM-73G, inhibited phospho-stat3, which was associated with blockade of the robust invasion, anchorage independent growth in soft agar and vasculogenic mimicry exhibited by IBC tumor cells without a significant anti-proliferative effect. Using array-based PCR and protein analysis, we found a specific pattern of inhibition of genes/proteins within the Jak/Stat pathway by PM-73G. Results of comparative studies using both PM-73G and stat3 shRNA demonstrate a role for stat3 in maintenance of the cancer stem cell phenotype exhibited by IBC tumor spheroids. Taken together, these studies suggest that stat3 may serve both as a molecular signature of IBC and as a target for development of effective therapeutics for this lethal form of breast cancer that contain tumor cells exhibiting a cancer stem cell phenotype. (Funded by The Susan G. Komen For The Cure Promise Grant KGO 81287 (FMR), The State of Texas Rare and Aggressive Breast Cancer Fund (FMR), NIH NCI CA096652 (JSM) and Center for Targeted Therapy at The University of Texas M.D. Anderson Cancer Center and the Texas Institute for Drug and Diagnostic Development at The University of Texas, Austin. (FMR & JSM).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 653.
Abstract 665: Targeting the pro-apoptotic protein BIM by dexamethasone combined with a MEK inhibitor PD184352 enhances the lethality in acute lymphoblastic leukemia
Authors: Heidari Nastaran , Richardson Amanda , Hicks Mark , Turner Keneshia , Harada Hisashi 
Published: February 2011

Abstract
Glucocorticoids (GC) represent common components of many chemotherapeutic regimens for lymphoid malignancies including acute lymphoblastic leukemia (ALL). Although the effects of GC on lymphocytes have been scrutinized for many years, the molecular mechanisms of sensitivity and resistance need to be elucidated. Since GC-resistant leukemia and myeloma are often associated with GC receptor defects, bypassing the receptor by targeting downstream molecules may develop new therapeutic strategies. We and others have previously shown that BIM (BCL-2 Interacting Mediator of cell death), a pro-apoptotic BCL-2 family protein, is up-regulated by dexamethasone (Dex) treatment in ALL cells and plays an essential role in Dex-induced apoptosis. Furthermore, BIM is inactivated by extracellular signal-regulated kinase (ERK)-mediated phosphorylation by survival/growth factors. We therefore hypothesized that co-treatment with Dex and MEK/ERK inhibitors promote apoptosis in ALL cells through BIM up-regulation and activation, resulting in cell death. We have recently demonstrated that MEK inhibitors synergistically promote Dex lethality in a variety of ALL cell lines, in which BIM is a critical molecule in cell death (Rambal et al., Leukemia 23, 1744-1754, 2009).
In the present study, we examined the therapeutic potential of co-treatment of Dex and MEK inhibitor PD184352 in vivo by severe combined immunodeficiency (SCID) mouse xenograft models of ALL. Minimum doses of Dex (8 mg/kg/day) and PD184352 (50 mg/kg/day) treatment caused BIM up-regulation and ERK dephosphorylation in xenograft tumor samples, respectively. Co-treatment of Dex and PD184352 resulted in an increase of apoptosis determined by caspase-3 cleavage and a significant decrease in size of the tumors. These data show that MEK/ERK inhibition enhances the anti-tumor activity of Dex in vivo. Our study provides a rational foundation for future attempts to improve the effect of GC with clinically relevant pharmacologic MEK inhibitors in the treatment of ALL and possibly other hematological malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 665.
Abstract 672: TumoraseTM: In vivo efficacy data for novel localized proteinase treatment applicable to solid tumors of varied tissue origins
Authors: Qian Yong , Drewe John A. , Shi Jin , McClurg Michael , Li Weidong , Campbell Thomas N. 
Published: February 2011

Abstract
To facilitate the development of noninvasive solid tumor cancer treatments, BioMedicure reports here the development of a specific proteinase treatment that when injected locally into solid tumors elicits a substantial tumor remission. Reported here is data indicating that intratumoral injection of TumoraseTM (T101, BioMedicure, San Diego, CA), a novel proteinase formulation, into solid tumors of various tissue origin destroys the tumor by digesting the solid-structure, killing cancer cells, including cancer stem cells, locally while not effecting normal tissues. The best route of TumoraseTM biochemical delivery to the tumor is intratumoral injection by a needle with a gauge 20-27. Before TumoraseTM intratumoral delivery, the tumor volume is estimated by 3-dimensional measurement and calculation: L x W X H in mm3, where “L” is the solid-tumor length, “W” solid-tumor width and “H” solid-tumor height. Tumorase works best when intratumorally injected at about 50-80% of solid-tumor volume delivered not by bolus but at about 200 uL per minute. The success rate of eliminating sparsely vascularized solid-tumors 50-400 mm3 in volume is high (over 70%). However, since inhibitory factors in serum diminish the activity of TumoraseTM, the success rate of eliminating a highly vascularized soft or liquid tumor is low (below 30%), though partial tumor mass decrease responses are observed. Multiple treatments can be applied to further diminish tumor mass. Data will be presented for the following tumor models, the human melanoma (CRL-1676 and WM-266-4), the human prostates (CRl-2505 and 22Rv1), human breast ductal carcinomas (HTB-129 and MDA-MB-435S), the human bronchioalveolar carcinomas (HTB-177 and NCI-H460) and the human colon adenocarcinomas (CCL-231 and SW48) xenografts. When a cancerous growth is found early and is accessible by a surgical knife, surgery is still the recommended treatment. However, if not accessible or there are multiple tumors, then, TumoraseTM would be a viable option, a local therapy that can be utilized for multiple tumors elimination. TumoraseTM contains proteases that cleave the extracellular matrix, including vital proteins required for cell survival, leading to cancer cell death. Presented here is in vivo data indicating the efficacy of this novel proteinase preparation for the elimination of solid tumors of multiple tumor classes by destroying tumors’ solid structure and killing cancer cells by cleaving the extracellular domains of vital cell membrane proteins. The wide range of solid cancerous tumors eliminated suggests a potential wide clinical applicability.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 672.
Abstract 707: Anti-SSTR antibodies can reverse neuroendocrine tumor cellular dedifferentiation induced by neutralizing EMT regulator miR-200c in pancreatic neuroendocrine tumor BON cells while increase cell death
Authors: Leu Frank , Nandi Minesh , Wong Chung 
Published: February 2011

Abstract
Somatostatin receptors (SSTR) are antiproliferative and antisecretory receptors that belong to the Class A of the seven-transmembrane G-protein coupled receptors. SSTR is comprised of five major subtypes namely subtype 1, 2 (A and B), 3, 4 and 5. Recently, we reported that SST signaling serves as a determinant in neuroendocrine-mesenchymal transition (NMT), a process that is dependent on the TGF-beta - SST signaling axis. NMT is similar to the epithelial-mesenchymal transition (EMT), but it has the opposite cellular differentiation outcome in response to the TGF-beta treatment. For instance, TGF-beta promotes cell dedifferentiation in EMT but promotes cell differentiation in NMT. In epithelial cancers, the micro RNA 200c (miR-200c) has been shown to negatively regulate the zinc finger homeodomain enhancer-binding protein (ZEB1) (an E-cadherin's transcriptional repressor) and thus able to keep EMT invasiveness in check. In this study, we found that upon transient transfection of the miR-200c repressor (X-miR-200c made by Oligoengine Inc., designed by Todd Hauser) into BON cells, the X-miR-200c was able to drive NMT forward. In general, the X-miR-200c triggers the expression of tumor metastasis markers to change, such as ZEB1 protein increase coupled with E-cadherin protein decrease, these changes altogether lead to both Vimentin and Twist protein increase. Interestingly, our anti-SSTR 2, 3, and 5 antibodies derived from the extracellular loop 2 ectodomain region were able to reverse BON cells from the mesenchymal state back to the neuroendocrine state. Additionally, the wound gap healing assay demonstrated that the gap closes at a much slower rate (∼2.5x slower) in the presence of either anti-SSTR2 antibody or anti-SSTR5 antibody treatment than the isotype IgG treatment. Our results suggest that similar to EMT, the miR-200c is also involved in controlling the process of NMT and it is reversible in the presence of anti-SSTR2, 3 and 5 antibodies. Furthermore, we also found that these anti-SSTR antibodies examined can increase neuroendocrine tumor cell death that may or may not be dependent on the NMT reversal.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 707.
Abstract 709: The fully human IGF-1 receptor antibody, CP-751,871, targets putative colon cancer stem cell populations
Authors: Hart Lori S. , Dicker David T. , Grimberg Adda , Christensen James , El-Deiry Wafik S. 
Published: February 2011

Abstract
The identification of cancer stem cells (CSCs) has the potential to provide answers to questions of tumor pathogenesis, metastasis, and therapeutic resistance. We have previously shown that insulin-like growth factor 1 (IGF-1) enriches putative colon CSC populations, an important finding with the potential to explain the association of colon cancer risk and chemoresistance with the levels of circulating IGF-1 and obesity. Here, we have employed three established methods (side population (SP) analysis, aldehyde dehydrogenase activity (ALDH+), and CD133 expression) to analyze a panel of 8 human colon cancer cell lines for putative cancer stem cell properties. We have found enrichment of SP and/or ALDH+ populations across the panel of 8 colon cancer cell lines, as well as many lines originating from other tissues. The enrichment of SP cells by IGF-1 is independent of altered ABC transporter activity as measured by mitoxantrone efflux. Enrichment of CSCs by IGF-1 does not appear to depend on the activity of MAP kinases (based on inhibition with PD098059 and U0126); therefore, we are currently exploring dependence on alternative IGF signaling pathways downstream of Akt, including NF-κB and mTOR. While we continue our efforts to unravel the mechanism by which IGF-1 enriches CSCs we are also interested in the more immediate clinical implications of our findings. CP-751,871 is a fully human antibody with specificity to the IGF-1 receptor and is currently being tested in clinical trials for a variety of solid malignancies. We have found that CP-751,871 reduces both SP and ALDH+ CSC populations in multiple colon cancer cell lines in vitro, and has promising activity against these populations in pilot experiments in vivo. We are currently repeating these studies to yield conclusions supported by statistics. Interestingly, CP-751,871 blocks IGF-1 enrichment of the side population in DLD1 cells, but not in SW480 cells suggesting a potential role of alternative receptors, such as the insulin receptor in some cell lines, a possibility we are currently analyzing. These studies have the potential to affect clinical oncology treatment strategies as the role of CSCs in tumor growth is delineated. Our results suggest that CP-751,871 has preferential activity against putative CSC populations, and therefore, may benefit current standard chemotherapeutic regimens that target cycling cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 709.