bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 446: Cross-talking of hypoxia stress with IGF-1R signaling in cancer stem cell formation (germline lineage)
Authors: Huang Yen-Hua , Chen Yi-Chun , Chiang Shu-Liang , Ling Thai-Yen , Chang Te-Sheng 
Published: February 2011

Abstract
Recent advances in cancer research suggest that there exist cancer stem cells (CSCs) in tumors. The resources of CSCs are still controversial; but the CSCs were originated from its stem cells have been hypothesized (like glioma CSCs and intestine CSCs). The niche stress such as hypoxia effect may provide external signals in stem cell transformation. However, mechanism in regulation of hypoxia-induced stem cell transformation still remains unclear. Our preliminary observations in human pluripotent testicular tumors (seminomas and embryonal carcinomas) showed a high expression level of hypoxia-inducible protein HIF-1α/HIF-2α as well as IGF protein in tissues. This observation strongly highlights the cross-talking of niche hypoxic stress and IGF-1 signaling in transformation of germline stem cells into pluripotent cancers. To address this point, we have successfully established a serum-free stem-niche cell co-culture system to generate pluripotent germline stem cells from neonatal mouse testis (AP+GSCs), and uncovered the role of IGF-1/IGF-1R signaling in germ cell pluripotency. Interestingly, while comparing with the normoxia (21 % O2), the AP+GSCs cells showed in a dramatically increase of alkaline phosphatase activity (AP), cell proliferation, HIF-1α, HIF-2α, Oct-4 protein expression, and pluripotent gene expression (such as Oct-4, Sox2, Nanog, Klf-4, and c-Myc) under hypoxia condition (5 % O2). Moreover, the IGF-1 and IGF-1R expression were also significantly increased under hypoxia. Further analysis by using PPP (a specific inhibitor of IGF-1R phosphorylation) and/or LY294002 (a specific PI3K inhibitor) treatment dramatically reduced the Oct-4 expression as well as HIF-1α/HIF-2α protein of AP+GSCs. These observations suggested the regulation of Oct-4/HIF-2α expression by IGF-1/IGF-1R signaling. In summary, our results demonstrated an up-stream regulation of stemness (Oct-4, Sox2, Nanog, and Klf-4) and tumor factor (c-Myc) by hypoxia which was cross-talking with IGF-1/IGF-1R signaling in stem cell transformation under hypoxia condition.
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 446.
Abstract 4473: PF-04691502, a potent and selective mTOR/PI3K dual inhibitor, demonstrates in vitro and in vivo antitumor activity in non-small cell lung carcinoma cells
Authors: Mehta Pramod P. , Walls Marlena , Baxi Sangita M. , Li Chunze , Batugo Minerva , Bagrodia Shubha , Cheng Hengmiao , Marx Mattew A. , Yin Min-Jean 
Published: February 2011

Abstract
The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway plays a critical role in the regulation of cell growth, proliferation and survival in cancer. In non-small cell lung carcinomas cells (NSCLCs), the PI3K/AKT/mTOR pathway is frequently activated through either the amplification/mutation of PIK3CA (which encodes the p110α subunit of PI3K), or the functional loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). In addition, the PI3K/AKT/mTOR pathway plays a critical role downstream of epidermal growth factor receptor (EGFR) in a defined NSCLC population; in particular, those harboring the EGFR mutations. Dual inhibition of PI3K and mTOR therefore represents a high therapeutic value for NSCLC patients. PF-04691502 is a dual-specificity inhibitor of PI3K and mTOR which shows potent and selective activity in biochemical, cell, and animal studies. In this study, we show PF-04691502 inhibits phosphorylation of AKT (at both S473 and T308) and S6 ribosomal protein (S6RP) in a variety of NSCLC lines harboring a PIK3CA mutation or EGFR mutation, subsequently resulting in anti-proliferative activity in the NSCLC lines. Furthermore, we demonstrate that PF-04691502 is capable of inducing tumor growth inhibition in four NSCLC xenograft models including an Erlotinib resistant line, NCI-H1975. In these murine xenograft models, decreased phosphorylation of AKT, p70S6K, and S6RP was observed in treated tumors in a manner consistent with the drug levels achieved. Therefore, PF-04691502 exhibits potent inhibition in the PI3K/mTOR axis and leads to both in vitro and in vivo anti-tumor activity in NSCLCs. Moreover, our data suggests that PF-04691502 may have clinical benefit to NSCLC patients including those found to be resistant to Erlotinib treatment.
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 4473.
Abstract 4478: BAY 80-6946, a highly potent and efficacious class I PI3K inhibitor, induces complete tumor regression or tumor stasis in rat xenograft tumor models with PIK3CA mutant or PTEN deletion
Authors: Liu Ningshu , Haegebarth Andrea , Bull Cathy , Schatz Christoph , Wiehr Stefan , Hauff Peter , Pichler Bernd J. , Mumberg Dominik , Jenkins Susan , Schwarz Thomas , Ziegelbauer Karl 
Published: February 2011

Abstract
We report on BAY 80-6946, a highly selective and potent pan class I PI3K inhibitor currently in Phase I clinical trials. The PI3K pathway is aberrantly activated in many tumors either by growth factor receptor tyrosine kinases, or by the genetic mutation and amplification of key pathway components. BAY 80-6946 was evaluated in a panel of human xenograft tumor models. This compound was administered every second (Q2D) day or once weekly using intravenous (i.v.) bolus dosing. BAY 80-6946 was well tolerated with a MTD of 10 mg/kg (Q2D) in athymic rats. In the rat KPL-4 breast tumor model (PIK3CAH1047R and HER2O/E (protein levels)), BAY 80-6946 showed robust and dose-dependent tumor growth inhibition with complete tumor regressions (10/10 CRs) observed at the 3.0 and 6.0 mg/kg doses. The animals remained tumor-free until termination of the study on day 65. BAY 80-6946 also demonstrated complete tumor stasis in the human H460 large cell lung carcinoma and HCT116 colorectal carcinoma models (bearing PIK3CA (E545K and H1047R respectively) along with mutations in KRAS), In U87MG human glioma tumor model (PTEN-deletion) dosed Q2D schedule partial regressions (PRs) were observed. The robust in vivo anti-tumor activities for this class I pan PI3K inhibitor correlated very well with the potent and sustained pharmacodynamic inhibition of p-Akt in tumors, which allowed several i.v. dosing schedules including a once weekly schedule. Thus, BAY 80-6946 given at 6mg/kg, BID once weekly demonstrated similar efficacy as given every other day (Q2D) at 6 mg/kg. Further investigation of pharmacodynamic biomakers revealed that i.v. bolus injection of BAY 80-6946 1 and 6 mg/kg produced a significant dose-dependent reduction in [18F]FDG uptake measured by decrease in SUV in rat H460 tumors supporting the clinical exploration of [18F]FDG imaging to monitor pharmacodynamic drug activity in patients.
In conclusion, BAY 80-6946 is a highly efficacious and well tolerated PI3K inhibitor in preclinical rat tumor models expressing HER2, PIK3CA mutant and PTEN-deletion. BAY 80-6946 is currently in phase I clinical trials.
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 4478.
Abstract 4558: 6-Nitroquinoline as a metabolically-activated probe for direct fluorescence detection of hypoxia
Authors: Rajapakse Anuruddha , Sarkar Ujjal , Linder Collette , Daniels J Scott , Gates Kent S. 
Published: February 2011

Abstract
Hypoxic (oxygen poor) cells in tumors play an important role in cancer biology. For example, the hypoxic environment may select for cells that are incapable of undergoing apoptosis. In addition, there is recent speculation that cancer stem cells that may be responsible for metastases are harbored in the hypoxic niche of tumors. Indeed, tumor hypoxia correlates with poor patient prognosis. Accordingly, detection of tumor hypoxia may soon become an important part of the clinical characterization of human cancers. Fluorescent probes for the direct detection of hypoxia in biological systems could provide a useful complement to the radiochemical imaging and immunohistochemical staining methods that are commonly used in this field. Building on our longstanding interest in metabolically-activated, hypoxia-selective antitumor agents, we set out to develop a probe that would be metabolized under hypoxic conditions into a product with known utility as a fluorescent reporter. We selected the molecule 6-nitroquinoline as a forum to explore the fundament chemistry, biochemistry and biology underlying the development of hypoxia-selective, bioreductively-activated fluorophores. We expected that hypoxia-selective reduction of the nitro group in this probe would generate the fluorophore 6-aminoquinoline. First, we confirmed that 6-nitroquinoline is not fluorescent. We next examined whether enzymatic metabolism converted this probe to a fluorescent product. The xanthine/xanthine oxidase enzyme system was employed for the one-electron reductive activation of the probe. We find that incubation of the probe with xanthine oxidase in the presence of a stoichiometric excess (5 equiv) of the substrate xanthine generates a substantial (approximately 30 fold) increase in fluorescence at 530 nm, as expected for generation of the 6-aminoquinoline product. Mass spectrometric analysis confirms that 6-aminoquinoline is generated under these conditions. In contrast, only a small increase in fluorescence at 530 nm is observed under aerobic conditions. Experiments that varied the amount of xanthine substrate used to “fuel” the reduction reaction revealed the presence of intermediate fluorescent products that generate an emission maximum at about 430 nm. This is likely due to 6-hydroxylamino and dimerized azoxy metabolites. The enzyme NADPH: cytochrome P450 reductase similarly converts 6-nitroquinoline to fluorescent products in a hypoxia-selective manner. In conclusion, we have established that 6-nitroquinoline can serve as a direct-light-up fluorescent probe for the detection of hypoxia and we have characterized the mechanisms by which this agent is converted to fluorescent products.
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 4558.
Abstract 4599: The RING E3 ligase BCA2 is regulated by estrogen and co-expressed with estrogen receptor in breast cancer cells
Authors: Kona Fathima R. , Bacopulos Stephanie , Amemiya Yutaka , Seth Arun K. , Burger Angelika M. 
Published: February 2011

Abstract
The Breast Cancer Associated gene 2 (BCA2) protein contains a RING H2 finger and a zinc finger near the N-terminus. The presence of the RING domain allows BCA2 to function as an E3 ligase. RING finger proteins play critical roles in mediating the transfer of ubiquitin and ubiquitin-like modifiers to substrates; such modifications are pivotal in regulating protein homeostasis and basic cellular processes such as gene-transcriptional regulation. The RING domain in BCA2 is known to act as an E3 ligase in its auto-regulation, and is suspected to play a role in the modification of other proteins. In a cohort of 945 primary invasive breast cancers examined for estrogen receptor-alpha (ER) and BCA2 expression, 67% were found to be ER-positive, 74% of which also exhibited strong nuclear BCA2 protein expression (p = 0.004). In this study, we examined potential mechanism(s) underlying BCA2 and ER co-expression at transcriptional and protein levels. Estrogen-responsive and non-responsive breast cancer cell lines were used as model systems. To investigate whether BCA2 is an estrogen responsive gene, BCA2 and ER-positive T47D breast cancer cells were cultured in medium containing charcoal-stripped fetal calf serum supplemented with 10 nM and 100 nM 17β-estradiol respectively over a 72-hour time course. Northern and Western blots showed a 17β-estradiol-associated induction of BCA2 mRNA and protein within 72 hrs. Moreover, when ER is ectopically or stably expressed in ER and BCA2-negative MDA-MB-231 cells, prominent BCA2 expression is detected, suggesting that ER is responsible for induction of BCA2 transcription. To investigate a possible interaction of BCA2 and ER at a transcriptional level, bioinformatic analysis of the BCA2 promoter region revealed ER and PR binding sites as well as possible sites of general transcription factors.
Together our data indicates that BCA2 is upregulated in response to estrogen and that BCA2 expression can be rescued by the introduction of ER, suggesting that ER and BCA2 may be participating in crosstalk at the transcriptional level. Further investigations into this phenomenon are necessary to determine the possibility of the development of drugs targeting BCA2 in order to manipulate ER.
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 4599.
Abstract 4626: The mechanism and structure localization relationship studies of a small organic molecule as a fluorescent tumor marker
Authors: Kang Chi-Chih , Chang Ta-Chau 
Published: February 2011

Abstract
BMVC, 3,6-bis(1-methyl-4-vinylpyridinium)carbazole diiodide, is a novel organic molecule with special tumor recognition characteristic. BMVC appears bright fluorescence in the nucleus of cancer cells while only weak fluorescence in the cytoplasm of normal cells. The strong fluorescence of BMVC in the nucleus is mainly due to significant enhancement of BMVC fluorescence upon binding to DNA. Therefore, these distinct properties of BMVC in cells allow us to differentiate cancer cells from normal cells. It appears that BMVC is a potential fluorescent tumor marker.
It is of interest to elucidate the reason why BMVC can act as a potential fluorescence tumor marker. Confocal microscopic images by merging with organelle trackers suggested that BMVC mainly localizes in the nucleus and mitochondria of cancer cells, but in the lysosome of normal cells. Several leading experiments suggested that the major pathway for BMVC uptake is endocytosis. In addition, the carbonyl-cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) and microinjection experiments showed that the destination of endocytosed BMVC is trapped in the lysosome of normal cells. However, it is not clear why BMVC is not trapped in the lysosome of cancer cells. Since the lysosomal membrane permeabilization (LMP) could sensitize cancer cell to death, we performed the cathepsin immunofluorescence and vacuolization experiments to elucidate whether there is LMP difference between cancer and normal cells. Our results showed that the LMP indeed plays an important role for trapping BMVC in the lysosome of normal cells, but releasing BMVC to the nucleus and mitochondria of cancer cells.
Furthermore, the structure localization relationship (SLR) studies show that BMVC derivatives with large hydrogen bonding capacity (HBC) are less lysosomal membrane permeable in normal cells. In addition, we found the more lipophilic of BMVC derivatives the more mitochondria localization in cancer cells. It is likely that the HBC and the lipophilicity are two important characters in determining intracellular localization of BMVC derivatives in cells.
In summary, the LMP and SLR studies of BMVC and its derivatives demonstrated a new direction for further design and synthesis of better fluorescent tumor markers and also provided a new platform for cancer selective drug through the combination of a cancer targeting molecule and anticancer drug.
Reference:
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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 4626.
Abstract 4652: Identification and validation of a novel nine-gene signature predicting clinical outcome in malignant melanoma
Authors: Brunner Georg , Heinecke Achim , Reitz Martina , Lippold Andrea , Berking Carola , Suter Ludwig , Atzpodien Jens 
Published: February 2011

Abstract
Incidence of malignant melanoma is rapidly increasing - with a doubling rate of 10-20 years. Conventional histopathological and clinical staging (based on Breslow tumor thickness, lymph node status, and ulceration) is largely inadequate for predicting clinical outcome of malignant melanoma. On the other hand, molecular prognostic markers are not yet available. Here, we identified a nine-gene signature which is closely associated with overall survival of melanoma patients.
To identify prognostic genes we correlated gene expression profiles of 136 primary melanomas with patient overall survival using Cox regression analysis: Initially, a comparative analysis of 20 high-risk vs. 20 low-risk primary melanomas with a clinical follow-up of more than 20 years (training cohort) was performed using whole-genome DNA microarray analysis and yielded 92 prognostically relevant candidate genes. Technical and statistical validation using TaqMan Array real-time RT-PCR and correlation of gene expression with patient overall survival reduced candidate gene number to 11. Expression of these 11 genes was further analyzed in an extended group of 91 primary melanomas (study cohort), yielding a nine-gene signature with prognostic significance. This novel prognostic melanoma gene signature was successfully validated using an independent set of 45 primary melanomas (validation cohort).
A risk score, based on the expression of the nine genes of the signature (KRT9, SPINK7/ECG2, KBTBD10, DCD, HES6, COL6A6, PIP, SCGB1D2, SCGB2A2), or any subgroup thereof, predicted patient overall survival in the study cohort (p = 0.0004, hazard ratio 3.83), independently of conventional AJCC 2002 staging. When combining gene expression score and AJCC staging, approximately two thirds (29/45, 64%) of patients with AJCC intermediate prognosis (i.e. stages IIA, IIB, and IIIA) were reclassified into good prognosis, exhibiting a long-term overall survival probability of 95%. Misclassification rate of all patients classified into good prognosis (low-risk gene score combined with AJCC stages I IIA/B, or IIIA) was very low at 4.6% and 6.25% in the training and validation cohorts, respectively.
The prognostic value of this novel signature-based risk score is its ability to identify patients at low risk, not identified by AJCC staging. This re-classification may allow these patients to stay treatment-free while experiencing excellent long-term survival. The remaining patients are risk patients and are in need of adjuvant therapies.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
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 4652.
Abstract 4703: Lack of expression of argininosuccinate synthetase in human cancer tissue: A biomarker for sensitivity to arginine depletion with pegylated arginine deiminase
Authors: He Wei , Chen Jianhe , Zheng Yuhui , Dai Zaoming , He Yan , Prestayko Archie , Thomson James , Wu Bor-Wen , Bomalaski John 
Published: February 2011

Abstract
There is increasing awareness of metabolic abnormalities in cancer that can be exploited with new forms of treatment. In addition, there is a need for biomarkers that would help select such tumors for targeted therapies. One such metabolic abnormality is the requirement of arginine for growth by certain cancers. These cancers lack expression of argininosuccinate synthetase (ASS), the rate limiting step in the metabolism of citrulline to arginine in the Krebs urea cycle, and must obtain arginine from the circulation. It has previously been shown that hepatocellular carcinoma and metastatic melanoma have a high frequency of lack of expression of ASS. As a result, these cancers are susceptible to arginine deprivation with pegylated arginine deiminase (ADI-PEG 20) both in pre-clinical models and in phase 2 clinical trials. Similar lack of ASS expression in human tissue samples and sensitivity to arginine depletion with ADI-PEG 20 in pre-clinical models have been found in a high percentage of pancreatic, prostate, and platinum-resistant ovarian cancers. In order to explore potential other cancers that may lack ASS expression we have examined breast, lung and gastric cancer microarray samples for ASS expression by immunohistochemistry. Our results indicated that 46/111 (41.4%) breast carcinoma, 28/90 (31.1%) lung carcinoma and 68/121 (56.2%) gastric cancer were ASS negative. To explore this further, a panel of 40 ATCC tumor cell lines representing 12 different human cancer types were screened for ADI-PEG 20 induced growth inhibition using the MTS assay. Significant inhibition of proliferation in a dose dependent manner after 48 hours of ADI-PEG 20 treatment was found in 19 out of 40 tumor cell lines screened, including breast, lung, gastric, sarcoma, ovarian, prostate and pancreatic carcinomas and chronic myelogenous leukemia. Lack of ASS expression in those responding cell lines were confirmed by Western blot. These findings suggest that ASS may serve as a biomarker for targeted therapy with ADI-PEG 20. Since a high percentage of patients with breast, lung or gastric cancer lack expression of ASS, these tumors may be sensitive to arginine depletion therapy. Clinical trials of ADI-PEG 20 in these cancers are being planned.
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 4703.