bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1266: Oncogenic stress induced by Bcr-Abl over-activation leads to cell death mediated by a massively enhanced aerobic glycolysis
Authors: Dengler Michael A. , Staiger Annette , Gutekunst Matthias , Hofmann Ute , Aulitzky Walter E. , van der Kuip Heiko 
Published: June 2012

Abstract
It is well established that normal cells respond to over-activation of oncogenes by induction of genetically encoded programs such as apoptosis or senescence. Therefore, too much activity of a growth promoting oncogene seems to disturb the cellular homeostasis, a phenomenon which is known as oncogenic stress. To investigate the molecular mechanisms behind this phenomenon we used cell clones overexpressing the oncogene Bcr-Abl and cultivated them continuously in the presence of the Bcr-Abl inhibitor Imatinib. Removal of Imatinib led to a robust induction of Bcr-Abl autophosphorylation and concomitant overstimulation of the Bcr-Abl downstream pathways PI3K/AKT-, RAS/MAPK-, and JAK/STAT. Importantly, this acute over-activation of Bcr-Abl resulted in a delayed non-apoptotic cell death starting not before 48 hours after Imatinib withdrawal. This cell death was preceded by a massively enhanced aerobic glycolysis and glutaminolysis (Warburg effect) and amino acid metabolism leading to an elevated cellular ATP and protein content. During the first 30 hours after Imatinib deprivation the enhanced metabolism had no effect on proliferation but resulted in cellular swelling, cytoplasmic vacuolization, and massive induction of ER stress markers indicating that Bcr-Abl over-activation induces ER stress response. However, cell death upon Bcr-Abl over-activation was not dependent on this severe ER stress since siRNA mediated knockdown of CHOP and BIM had no effect on cell viability. In contrast, both inhibition of aerobic glycolysis by 2-deoxy-glucose as well as reduction of glutamine concentration in the medium were sufficient to block Imatinib deprivation induced cell death. These data demonstrate that the Bcr-Abl over-activation mediated enhanced metabolism is responsible for oncogenic stress induced cell death. Interestingly, screening of 1200 marketed small molecule inhibitors (Prestwick chemical library) for their potential effects on oncogenic stress response uncovered selectively steroids to effectively antagonize both ER stress and cell death upon Bcr-Abl over-activation. These agents were also able to normalize cellular metabolism upon Imatinib withdrawal, supporting the view that “overshooting” metabolism upon oncogenic over-activation leads to cell death.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1266. doi:10.1158/1538-7445.AM2011-1266
Abstract 1267: Metabolic sensor O-GlcNAc Transferase is a novel regulator of prostate cancer invasion and angiogenesis via regulation of FoxM1
Authors: Lynch Thomas P. , RaElle Jackson S. , Shahriari Kristina S. , Ferrer Christina M. , Lazarus Michael , Walker Suzzane , Vosseller Keith , Reginato Mauricio J. 
Published: June 2012

Abstract
Cancer cells universally increase glucose and glutamine consumption, leading to the altered metabolic state known as the Warburg effect. One metabolic pathway highly dependent on glucose and glutamine is the Hexosamine Biosynthetic Pathway (HBP). Increased flux through the HBP leads to increases in the post-translational addition of O-linked-β-N-acetylglucosamine (O-GlcNAc) on a diverse population of nuclear and cytosolic proteins. A number of these target proteins are implicated in cancer, yet the role of O-GlcNAc modifications in cancer remains poorly defined. Here, we show that OGT is overexpressed in prostate cancer tissue compared to normal prostate epithelium and, that OGT protein and O-GlcNAc levels are elevated in prostate carcinoma cell lines compared to non-transformed prostate cells. Decreasing O-GlcNAc levels using OGT-targeted RNAi in the metastatic prostate cancer cell line PC3-ML inhibited growth in three-dimensional (3D) culture, as well as decreased colony formation in soft agar assays. Furthermore, decreasing O-GlcNAc levels was also associated with cell cycle arrest at G1 and increased expression of the CDK inhibitors p27 and p21. However, reducing O-GlcNAc levels in the non-tumorigenic prostate epithelial cell line RWPE-1 had minimal effects on growth in 3D culture. In addition to growth inhibition, reducing O-GlcNAcation in PC3-ML cells was associated with reduced expression of matrix metalloproteinase-2 (MMP-2), MMP-9 and vascular endothelial growth factor (VEGF), resulting in the inhibition of invasion and angiogenesis. OGT regulation of invasion and angiogenesis was dependent upon regulation of the oncogenic transcription factor FoxM1, as reducing OGT expression led to increased FoxM1 proteasomal degradation. Moreover, overexpression of a FoxM1 degradation-resistant mutant abrogated OGT RNAi inhibition of invasion, MMP levels, as well as angiogenesis and VEGF expression. Finally, the use of novel second-generation small molecule inhibitor of OGT led to the similar reduction in growth, invasion and inhibition of MMPs and VEGF levels. Current experiments are underway to test whether targeting OGT blocks prostate cancer metastasis. Altogether, these data suggest that as prostate cancer cells alter glucose and glutamine levels, O-GlcNAcation serves as nutrient sensitive modification contributing to oncogenesis and suggest that OGT is positioned as a novel target for therapeutic intervention for the treatment of human prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1267. doi:10.1158/1538-7445.AM2011-1267
Abstract 1269: Identifying Pten-sensitive drug therapy through metabolic phenotype-arrays
Authors: Naguib Adam , Nowak Dawid G. , Chen Muhan , Trotman Lloyd C. 
Published: June 2012

Abstract
The loss or mutation of tumor suppressor genes is a predominant event in the initiation, progression and metastatic development of cancer. PTEN and p53 are frequently inactivated in lethal metastatic prostate cancer, as they provide a critical growth, proliferation and anti-apoptotic advantage to cells in which their activity is diminished. In mouse prostate cancer models, loss of p53 alone in the prostate does not result in noticeable neoplasia. However, subsequent additional deletion of Pten causes lethal prostatic adenocarcinoma within 6 months, illustrating the need to combat the cooperative power of these two genetic lesions. Although inactivation of these tumor suppressor genes has been widely described at the level of their cancer phenotype, it has recently emerged that one understudied route to combat lesions harboring these alterations is to understand and exploit critical underlying changes in their metabolic makeup.
In the present study, we used an array platform to determine the growth phenotype of p53 null Mouse Embryonic Fibroblast (MEFs) under close to 1200 conditions involving different sources of energy, amino acids, hormones, growth factors, chemical ions and responses to chemotherapy agents. with subsequent comparison to the response in p53/Pten double-null MEFs. Our analysis showed that loss of Pten critically altered response, utilization and sensitivity especially to specific hormones, ions and chemotherapy agents. Since this approach revealed Pten-status specific cell sensitivities, we are utilizing this information to establish selective targeting of cells as a precursor to therapeutic intervention in our genetically engineered mouse models of prostate cancer, which harbor the identical tumor suppressor lesions. Collectively, our results establish a rapid screening platform for identification of genotype-specific anti-cancer agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1269. doi:10.1158/1538-7445.AM2011-1269
Abstract 1294: Metabolism and excretion of eribulin in patients with advanced solid tumors
Authors: Dubbelman Anne-Charlotte , Mergui-Roelvink Marja , Koetz Barbara , Lymboura Margarita , Reyderman Larisa , Lopez-Anaya Arturo , Rosing Hilde , Marchetti Serena , Beijnen Jos H. , Schellens Jan HM 
Published: June 2012

Abstract
This Phase I, open-label, mass-balance study investigated the metabolism and excretion of eribulin, a non-taxane microtubule dynamics inhibitor with a novel mechanism of action, in patients with advanced solid tumors.
A single 14C-eribulin acetate (∼85 μCi) 2 mg dose was given on Day 1 (cycle 1) as a 2-5-min IV bolus injection to 6 patients ≥18 years with advanced solid tumors that progressed after standard therapy or for which no standard therapy existed. Patients received 1.4 mg/m2 unlabeled eribulin mesylate (E7389) on Day 8 (cycle 1), and Days 1 and 8 of each subsequent 21-day cycle. Blood, urine, and fecal samples were collected from Days 1-8 (cycle 1) at specified time points or until sample radioactivity was &lt;1% of the administered dose. Pharmacokinetic parameters were determined from plasma, urine, and fecal concentrations of unmetabolized eribulin and 14C-eribulin- derived material from Day 1 dosing.
Mean plasma eribulin exposure (627 ng.hr/mL) was comparable to that of total radioactivity (568 ng equivalent.hr/mL). Time-matched concentration ratios of eribulin to total radioactivity approached unity in blood and plasma: unchanged parent compound constituted almost all eribulin-derived radioactivity. Few metabolites of eribulin were detected in plasma. Each metabolite represented &lt;0.6% of eribulin indicating there were no major metabolites of eribulin in plasma. Elimination half-lives for eribulin (45.6 hr) and total radioactivity (42.3 hr) were comparable. Eribulin-derived radioactivity excreted in feces was slightly higher (mean 81.5%, range 60.2-101.2%) than that of unchanged eribulin (mean 61.9%, range 42.8-78.5%) indicating that unchanged eribulin was primarily excreted in feces. Renal clearance (0.301 L/hr) was a minor component of total eribulin clearance (3.93 L/hr). Eribulin-derived radioactivity excreted in urine was comparable (mean 8.9%, range 5.4-16.4%) to that of unchanged eribulin (mean 8.1%, range 5.0-15.3%), indicating minimal excretion of metabolite(s) in urine. Total recovery of the radioactive dose was 90.4% in urine and feces.
Overall, no major metabolites of eribulin were detected in plasma. Eribulin is primarily eliminated unchanged in feces, while urine constitutes a minor route of elimination.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1294. doi:10.1158/1538-7445.AM2011-1294
Abstract 1298: Effects of carfilzomib (CFZ) on pharmacokinetics of midazolam (MDZ) in subjects with solid tumors
Authors: Jones Suzanne F. , Bendell Johanna C. , Burris Howard A. , Vallone Marcy K. , Wong Alvin F. , Infante Jeffrey R. 
Published: June 2012

Abstract
Introduction: CFZ is a novel, highly selective epoxyketone proteasome inhibitor that has demonstrated durable single-agent antitumor activity in patients (pts) with relapsed or refractory myeloma and solid tumors. PX-171-008 was an open-label, Phase 1b, non-randomized, fixed sequence study to determine the effect of CFZ on the PK of MDZ, a sensitive substrate of human cytochrome P450 3A4.
Methods: During Period 1, pts received a single, 2 mg oral dose of MDZ. In Period 2 the same pts received 27 mg/m2 CFZ IV push on Days 1, 2, 8, 9, 15, and 16 of a single 28-day cycle. Oral MDZ was given immediately following CFZ on Days 1 and 16. The primary endpoint was to evaluate the PK of MDZ in the presence or absence of CFZ. The extent of CYP 3A4/5 interaction was evaluated based on fold-change in AUC for MDZ. ICH Guideline for extent of interaction: Strong = &gt; 5-fold change, Moderate 2-5-fold, Weak = 1.25-2. Safety was evaluated by assessment of adverse events (AEs), clinical laboratory tests, physical exams, vital signs, and an ECG.
Results: 18 pts (12 female, 6 male) were enrolled. Of these, 12 completed and were eligible for full PK analysis, 5 terminated prior to receiving all 6 doses of CFZ and were included only in the day 1 PK analysis, and 1 discontinued prior to receiving any doses of CFZ and was excluded from all PK and safety analysis. All 17 pts included in the PK analysis had significant exposure to CFZ on Day 1. The results suggest that CFZ does not clinically interact with oral MDZ (not even qualifying as a weak inhibitor of CYP3A4). PK parameters are summarized below.

All pts experienced at least 1 AE. The most common were fatigue (52.9%), nausea (52.9%), dyspnea (35.3%), anxiety (23.5%), headache (23.5%), and vomiting (23.5%). AEs were primarily Grade 1/2 in severity and were similar to the safety profile in other CFZ studies.
Conclusions: Administration of CFZ did not result in a clinically significant impact on the PK of MDZ. The observed safety profiles were similar to those previously reported for each drug.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1298. doi:10.1158/1538-7445.AM2011-1298
Abstract 13: Chemical genomics identifies MCL1 repressors and resistance mechanism
Authors: Wei Guo , Margolin Adam , Brown Emily , Cucolo Lisa , Stransky Nicolas , Barretina Jordi , Garraway Levi , Beroukhim Rameen 
Published: June 2012

Abstract
Dysregulated apoptotic mechanisms are central to the pathogenesis and maintenance of cancer, and are major barriers to effective treatment. The BCL2 gene family, comprised of both pro- and anti-apoptotic members, controls the intrinsic activation of apoptosis. Amplification of one of the anti-apoptotic members of this pathway, MCL1, constitutes one of the most frequent somatic genetic events in cancer. However, the design of small molecules targeting MCL1 has proven difficult, and the genomic determinants of MCL1 dependence are not well-understood. Furthermore, the contribution of MCL1 regulation in current chemotherapy drug action remains undefined. We therefore developed a chemical genomic approach to identify repressors of MCL1. We measured gene expression levels of all BCL2 family members upon treatment with 2,922 small molecules, including the majority of FDA-approved drugs. We indentified several small molecules inhibiting MCL1 expression, including a few widely used chemotherapy drugs and a natural product triptolide. Those compounds all share similar apoptotic profile when they were tested in panels of cell lines. Genomic profiling indicated that those compounds were global transcriptional repressors (TR). Nevertheless, MCL1 was among the most repressed genes. To further define the contribution of MCL1 repression by those TR compounds, we compared the sensitivity to TRs and MCL1 knockdown. Sensitivity to all TRs correlated with sensitivity to MCL1 knockdown by shRNA; and there is no additive effect of TRs and MCL1 shRNAs. Furthermore, ectopic expression of physiological levels of MCL1 rescued cells from TRs. Triptolide was able to inhibit tumor growth and promote survival in a mouse xenograft model that is sensitive to TR in vitro. Whole genome expression analysis revealed genomic features that correlated with sensitivity to these compounds and to MCL1 shRNAs, and may shed light on biomarker selection when targeting MCL1.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 13. doi:10.1158/1538-7445.AM2011-13
Abstract 131: Biological effect of miR-210 overexpression on renal carcinoma cells
Authors: Nakada Chisato , Tsukamoto Yoshiyuki , Matsuura Keiko , Nguyen Tung Lam , Hijiya Naoki , Uchida Tomohisa , Sato Fuminori , Mimata Hiromitsu , Seto Masao , Moriyama Masatsugu 
Published: June 2012

Abstract
MiR-210 is significantly upregulated in clear cell renal cell carcinoma (CCC), but the mechanism and biological consequences of miR-210 upregulation are poorly understood. Here, we show that miR-210 is highly expressed in renal carcinoma cell lines and that its expression is clearly correlated with accumulation of hypoxia inducible factor 1α (HIF1α) under normoxia as well as hypoxia, suggesting that miR-210 upregulation in renal carcinoma cells is most likely due to accumulation of HIF1α. To reveal the effects of miR-210 upregulation, the miR-210 precursor was transfected into renal carcinoma cells. After transfection, the cells accumulated at G2/M phase of the cell cycle and their viability was decreased, suggesting that miR-210 overexpression may trigger an event that hinders normal cell division. Immunocytochemistry demonstrated a multipolar spindle accompanied by centrosome amplification in cells overexpressing miR-210. It has been reported that centrosome amplification induces chromosome mis-segregation, finally leading to chromosome instability and aneuploidy. Indeed, the proportion of aneuploid cells (&gt;4n) was increased in miR-210 overexpressed cells. By using the TargetScan and PicTar algorithms, E2F3 was identified as one of the possible targets of miR-210, and was suppressed at the protein level by miR-210. Moreover, the proportion of aneuploid cells was increased in E2F3 siRNA transfected cells. On the basis of these results, we propose that miR-210 upregulation due to HIF1α accumulation may induce aneuploidy via E2F3 downregulation at least in part, and may play a role in tumorigenesis and/or progression of CCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 131. doi:10.1158/1538-7445.AM2011-131
Abstract 1312: Comparative pharmacokinetics of diethylstilbestrol from oral suspension and oral dissolving film (ODF)
Authors: Ako Roland , Tu Shi-Ming , Chow Diana 
Published: June 2012

Abstract
Purpose: To determine the comparative pharmacokinetics of diethylstilbestrol (DES) from oral suspension and oral dissolving film (ODF). DES is a non-steroidal estrogen that has been used in the treatment of both androgen dependent and androgen-independent prostatic cancinoma. However the use of DES to treat advanced prostate cancer was severely limited in the 1980s, because of its thrombogenic side effects common to all estrogens, which are thought to be due to their metabolism in the liver. This metabolism or first pass effect induces the production of proteins associated with the coagulation and fibrinolysis processes, which results in thrombosis and other side effects depending on a patients baseline coagulation-to-fibrinolysis balance. ODF-DES has a potential of bypassing the first pass metabolism minimizing the induction of the coagulation and fibrinolysis proteins.
Methods: The study was performed using 7-week-old male Sprague- Dawyley rats. Under light ketamine and xylazine anesthesia, rats were orally given 1 mg of DES suspension in a 1 ml volume, or topically applied 1 mg of ODF-DES to the buccal cavity. The film was cut into two pieces of 1 cm × 2 cm each and applied to the inner cheeks on each side. Blood samples (250 µl) were collected from the jugular vein up to 30 hr in both cases. DES was extracted from the blood samples using ethyl acetate and analyzed by a validated LC-MS/MS assay.
Results: The pharmacokinetic parameters of DES from oral suspension and ODF-DES were derived using the WinNonlin software. The peak time (tmax) was significantly longer (6.67 ± 2.31 vs 2.16 ± 1.42 hr), and peak concentration (Cmax, 25.82 ± 8.73 vs 6.84 ± 2.45 ng/ml) and systemic exposure (AUC, 213.76 ± 73.09 vs 55.98 ± 3.99 ng h/ml) of ODF-DES were significantly higher with p-values of 0.05, 0.02, and 0.020, respectively than those from oral suspension.
Conclusion: ODF delivery of DES has been demonstrated to improve the bioavailability of DES, by yielding a significantly higher systemic exposure and peak concentration. Further evaluations of ODF-DES are in order to establish the potential merit of the delivery system to reduce the induction of thrombogenic proteins.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1312. doi:10.1158/1538-7445.AM2011-1312
Abstract 1320: Estrogen as a modulator of thyroid proliferative disease: Implications for disease etiology and therapy
Authors: Rajoria Shilpi , George Andrea , Shanmugam Arulkumaran , Kamat Ameet , Schantz Stimson P. , Geliebter Jan , Suriano Robert , Tiwari Raj K. 
Published: June 2012

Abstract
Metastasis of cancer is a multifactorial disease and is responsible for over 90% of all cancer related deaths. Thyroid cancer is the most common endocrine related cancer with well differentiated thyroid cancer metastasizing to the nearby lymph nodes in upto 50% of the cases. Interestingly, according to American Thyroid Association (ATA), the incidences of thyroid cancer are four to five times more in women than in men with one in eight women developing thyroid disorder at least once in her lifetime. In this study, we explored the possible etiological contribution of estrogen in thyroid proliferative disease using an in vitro experimental model system. We observed that thyroid cancer cells express functionally active estrogen receptors (ER), ER-α and ER-β. Furthermore, estrogen enhances the metastatic propensity of thyroid cells as evidenced by increased migration, adhesion and invasion, which is reversed by anti-estrogens. These observations were further supported by ER-α down-regulation (siRNA) studies. Western blot and zymography analyses provide direct evidence for this estrogen mediated enhancement of metastasis associated events by enhanced secretion of the proteolytic enzymes, matrix metalloproteinases (MMP), MMP-2 and MMP-9. We also observed that conditioned medium from estrogen treated thyroid cells contains enhanced levels of vascular endothelial growth factor (VEGF) and modulates angiogenesis associated events, such as migration, proliferation and tubulogenesis of endothelial cells. Our studies provide evidence that the higher incidence of thyroid cancer in females is potentially attributed to the presence of a functional ER that participates in cellular processes contributing to enhanced mitogenic, migratory, invasive and angiogenic properties of thyroid cells, which is responsive to anti-estrogens. Our findings formed the basis of an ongoing clinical trial in patients with thyroid proliferative diseases using dietary anti- estrogenic compound, 3, 3’-diindolylmethane (DIM).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1320. doi:10.1158/1538-7445.AM2011-1320