bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4513: IND-enabling studies for CEQ508 targeting β-catenin of GI polyps: First oral RNAi drug
Authors: Bodyak Natalya , Borrelli Alex , Fruehauf Johannes H. , Harborth Jens , Laroux F. Stephen , Vaze Moru , Grillot-Courvalin Catherine , Silva Alison D. 
Published: February 2011

Abstract
Targeted delivery remains one of the biggest challenges in the development of RNAi-based therapeutics. Cequent has developed a proprietary delivery technique for RNA interference, transkingdom RNAi (tkRNAi), in which non-pathogenic bacteria are engineered to invade specific target cells, produce and release short hairpin RNA (shRNA). We have previously shown tkRNAi to be successful in cell culture assays, in a mouse model for human colon cancer (APCmin), and in non-human primates (cynomolgus monkeys), by suppressing the oncogene, β-catenin. β-catenin is the key oncogene implicated in Colorectal Cancer (CRC) and Familial Adenomatous Polyposis (FAP); the latter being an orphan hereditary disease resulting in the formation of hundreds of polyps in the gastrointestinal tract and ultimately leads to the development of colon cancer without surgical intervention. No pharmaceutical treatment is available for patients with FAP. The non-human primate studies designed to evaluate on-target toxicities were conducted with a precursor (CEQ501) to our clinical candidate, CEQ508. Following optimization, which most importantly included platform engineering to improve hairpin production and processing, we conducted a large GLP mouse bridging toxicity study comparing off-target effects of CEQ508 and CEQ501. No CEQ508 or CEQ501-related adverse responses were identified in the following study parameters analyzed: clinical observations, body weights, serum chemistry, hematology, cytokines, gross or histopathology. As no test article-related changes were identified under the conditions of this study at the highest dose evaluated, the No Observed Effect Level (NOEL) for daily oral administration of either CEQ508 or CEQ501 was 5×109 cfu/day, or 2×1011 cfu/kg/day. (CEQ501 in non-human primates showed a similar safety profile with the No Observed Adverse Effect Level (NOAEL) determined to be 1×1012 cfu/day, or 2×1011 cfu/kg/day). Together with multiple internally conducted pharmacology and pharmacokinetic experiments, Cequent used this data in the nonclinical section of an IND filed in late 2009. In addition to presenting detailed in vivo data from our filing, an update on further development will be presented on CEQ508 for the proposed daily dosing of FAP patients with this oral tkRNAi therapeutic targeting β-catenin.
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 4513.
Abstract 4528: Small molecules inhibitory for MDMX expression activate p53 and induce apoptosis
Authors: Wang Hongbo , Ma Xujun , Ren Shumei , Yan Chunhong 
Published: February 2011

Abstract
P53 inactivation caused by aberrant expression of its major regulators(e.g, MDM2 and MDMX) contributes to 50% of human cancers. Recent studies have demonstrated that restoration of p53 activity by counteracting p53 repression is a promising anti-cancer strategy. Although agents(e.g., Nutlin-3a) disrupting the MDM2-p53 interaction can inhibit tumor growth, they are less effective in cancer cells with high MDMX expression levels. MDMX binds to p53 and serves as a major p53 antagonist by mainly repressing its transcriptional activity. Here we reported the identification of two samll molecules inhibitory for MDMX expression through high-throughput screening. Treatments of MCF-7 cells with these MDMX inhibitors dramatically increased the stability of p53, leading to elevated expression of proapoptotic genes(e.g., PUMA, Bax, and PIG3). These results argue for a recent notion that MDMX is a major regulator of the p53 stability. While they exerted limited effects on cell cycle progression, this new class of small-molecule p53 activitors induced MCF7 cells to undergo apoptosis. However, the MDMX inhibitors only modestly enhanced p53 activition induced by Nutlin-3a. We conclue that small molecules targeting MDMX expression would be of therapeutic benefits and be useful in dissecting the p53 network through chemical biological approaches.
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 4528.
Abstract 4539: Anti-leukemic activity of mitochondria-targeted asymmetrical 2,2′-binaphthoquinones
Authors: Ricklis Rebecca M. , Vuica-Ross Milena , Brodsky Robert A. , Sausville Edward , Dang Chi V. , Karp Judith E. , Emadi Ashkan 
Published: February 2011

Abstract
Introduction: Binaphthoquinones are unique molecules consisting of two linked naphthoquinone units. By definition biquinones cause more effective oxidative stress than their monoquinone counterparts. Previously, we regiospecifically synthesized a series of asymmetrical binaphthoquinones, which possess HIV integrase inhibitory activity. Potent activity against HIV-uninfected CEM-T4 cells prompted us to investigate other cytotoxic mechanisms. A genome-wide yeast screen uncovered that mitochondria-related genes are required for sensitivity and resistance to these agents. Since mitochondria membrane permeabilization occurs early in the apoptotic program and is located downstream of most identified chemotherapy resistance mechanisms in hematological malignancies, we hypothesized that binaphthoquinones would be able to interfere with mitochondria function in leukemia cells and induce apoptosis by abrogating or bypassing other mechanisms of drug resistance.
Materials and Methods: Seventeen of our biquinones were incubated with four leukemia cell lines (MV411, MOLM14, HL-60, U937) grown under standard conditions. A standard MTT cell proliferation assay was used to identify IC50 values. Two of the most potent compounds, biquinones #7 and #10 (BiQ7 & BiQ10), were assayed against MV411 cells and analyzed by flow cytometry for loss of mitochondria membrane potential (via rhodamine 123 staining), as well as a variety of apoptosis markers, such as phosphatidylserine, activated caspases, and sub-2n DNA increases by using Annexin V-PE (with 7AAD), a fluorescent caspase inhibitor reagent, and propidium iodide (PI), respectively.
Results: The IC50 values for both compounds were less than 5 μM against all cell lines. A loss of mitochondria membrane potential was observed in 98-100% of the treated cells (control 5%). Loss of plasma membrane phosphatidylserine asymmetry was observed in 94-95% of the treated cells (control 18%). The cells showed increases in staining for activated caspases 3 & 7 (control 10%; BiQ7 98%; and BiQ10 96%). Finally, the cell cycle analyses showed increases in sub-2n DNA in the treated cells compared to the control (control 12%; BiQ7 34%; and BiQ10 54%). These assays were subsequently repeated to obtain triplicate results.
Conclusion: Our study shows that this new class of compounds possesses promising in vitro anti-leukemic effects by targeting mitochondria membrane potential. In vivo experiments in a xenograft model and ex vivo experiments on primary human cells are in progress. The cytotoxicities of binaphthoquinones could vary widely as a result of the array of structural configurations available.
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 4539.
Abstract 4543: Targeting the NADPH binding site of dihydrofolate reductase for cancer therapy
Authors: Hsieh Yi-Ching , Lawal Rialnat AdeBisi , Scotto Kathleen , Banerjee Debabrata , Abali Emine Ercikan , Bertino Joseph R. 
Published: February 2011

Abstract
Dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate into tetrahydrofolate using NADPH as the cofactor. Folate-dependent one carbon metabolism is essential for the de novo synthesis of purines, pyrimidines and certain amino acids. Thus, DHFR plays an essential role in production and maintaining reduced folates for cellular proliferation, and consequently it has been a critical target for chemotherapy. Methotrexate (MTX), an antifolate that targets DHFR, has been used for decades in the clinic. However, both intrinsic and acquired resistance occurs due to decreased uptake, gene amplification and protein mutation. We have initiated studies to find an inhibitor that targets the cofactor NADPH binding site that would bypass these resistance mechanisms to MTX in contrast to analogs that target the dihydrofolate binding site.
Fourteen NAD/NADP analogues were screened by the MTT assay in Chinese hamster ovary (CHO) cells which lack endogenous DHFR expression but were stably transfected with a DHFR-EGFP fusion construct driven by a CMV promoter (DG44 DHFR-EGFP). Two compounds, thionicotinamide adenine dinucleotide (NAD-S) and thionicotinamide adenine dinucleotide phosphate (NADP-S), had IC50 values of 1 μM. NAD-S and NADP-S were also found to be potent inhibitors of two other cancer cell lines, C85 (metastatic human colon cancer cell line) and CCRF-CEM (human T-cell lymphoblastic leukemia cell line).
Surprisingly, both NAD-S and NADP-S decreased the levels of DHFR in CEM-CCRF cells. Pulse-chase experiments showed that the half life of DHFR is significantly reduced upon treatment of cells with 10 μM NADP-S. Furthermore, this NADP analog caused an increase in cells at the G1 phase (11% at 10 μM and 44% at 40 μM NADP-S treatment) that was reversible by removing NADP-S from the cell culture. Because NADP-S decreased DHFR levels, the combination of NADP-S with MTX was tested and found to significantly reduce colony formation, and was synergetic in vitro (Chou-Talalay analysis). We conclude that NADPS has a novel mechanism of action, i.e., it causes degradation of DHFR, likely by competing with NADPH binding, known to stabilize DHFR.
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 4543.
Abstract 4548: Erythrose kill cancer cell in vitro and inhibit tumor growth in vivo
Authors: Wang Xingnong , Wei Youcheng 
Published: February 2011

Abstract
In general, mutations in oncogenes and tumor suppressor genes are believed to represent the fundamental cause of carcinogenesis. Mitochondrial deficiency (Warburg effect) may be a direct or indirect consequence of these mutations. Accordingly, tumor cells depend on glycolysis rather than mitochondrial oxidative metabolism as energy source for their survival and proliferation. Targeting this kind of metabolism could offer a possibility for cancer treatment. Erythrose was used as an alternative energy source to test its inhibitory effect on several tumor cell lines in vitro and in vivo.
Cancer cell lines (breast BT474 and MCF-7, brain U87mg, pancreas Panc-1, HEL, LL-2 Lewis lung, and colorectal CT26 and SW480 lines) were grown in DMEM + 10% FBS media with different concentrations of D-erythrose and cell growth was tested with the Trypan blue assay. In general, 70% of cancer cells did not survive after 24 hrs of culture with 500mg/L D-erythrose. Addition of ZnCl2 (40µM) doubled the cancer killing effect at 400mg/L D-erythrose. In addition, LL-2 Lewis lung cells were subcutaneously introduced into the immunocompetent C57BL/6 mice. After allowing tumor growth to 2.7±0.4mm wide diameters, a daily subcutaneous injection beside the tumor with D-erythrose (∼1g/kg bw) was administered for 25 days; controls received a PBS injection instead. Tumor growth in erythrose-treated mice was inhibited more than 90% by weight.
We hypothesize that the administration of erythrose leads to CO2 production from oxidation in cytosol or mitochondria. Carbonic acid is formed from CO2 and water, accelerated by carbonic anhydrase (a zinc enzyme), which can convert lactate to lactic acid, and cause intracellular acidosis and cancer death since cancer cells have increased lactate production.
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 4548.
Abstract 4561: Quantitative phosphoproteomics of an AKT inhibitor in a PTEN-LOF breast model by label free phospho-dMS demonstrates modulation of protein transcription, protein translation, and motility
Authors: Chi An , Keilhack Heike , Guo Hongbo , Nagashima Kumiko , Andersen Jannik , Paweletz Cloud , Hendrickson Ronald 
Published: February 2011

Abstract
Among the many types of molecular mechanisms that are currently understood, none is more important for the control of cellular faith than the network of protein kinases and phosphatases. The importance of understanding these signaling networks is furthermore highlighted by the fact that virtually all major pharmaceutical companies have significant projects focused on targeted interference against oncogenic kinases as potential anti-tumor therapies. Yet, a system's wide analysis of signaling phosphorylations by these inhibitors in in vivo (i.e. tissue or xenograft models) is cost prohibitive and rarely performed.
The use of mass spectrometry is a powerful approach to study complex mixtures, and some techniques have used either chemical or metabolical isotopic labeling strategies to quantify protein differences between cohorts. While these techniques have been shown to be useful and are routinely applied for cell culture systems, they do not extend readily to in vivo studies as these require either combining of samples or are dependent on the duty cycle of the mass spectrometer. Here we report a generally applicable proteomic approach to identify global protein phosphorylation changes in in-vivo systems. This label-free discovery platform, named phospho-differential mass spectrometry (phospho-dMS) does not require complex mixing or pooling strategies or isotope labeling, and instead identifies statistically significant changes in full scan mass spectrometry data. Hence, in-vivo samples can be analyzed individually, allowing the use of longitudinal designs and within-subject data analysis.
We demonstrate phospho-dMS on 27 breast tumor tissues samples (3 concentrations, 3 time points, 3 mice each) excised from a PTEN-LOF mouse model. We quantified in excess of 2000 high confidence phosphorylation events. The most prominent protein modules inhibited by compound treatment (P&lt;0.0001) relate to cytoskeletal machinery such as cell polarity and cytoskeletal reorganization, transcription factors, co-activators, and protein translation with known relevance to cancer. For the first time, using quantitative MS, the topology and significance of phosphorylation networks may be investigated in xenograft, GEM models, and tumor tissue samples marking a new era of cancer signaling research
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 4561.
Abstract 4567: Urine biomarkers outperform serum biomarkers in the diagnosis of various human cancers
Authors: Nolen Brian M. , Lomakin Aleksey , Bast Robert , Lu Karen , Grizzle William E. , Jhala Nirag C. , Eloubeidi Mohamad A. , Christein John D. , Arnoletti Juan P. , Oelschlager Denise K. , Vickers Selwyn M. , Marrangoni Adele , Lokshin Anna 
Published: February 2011

Abstract
Background: The measurement of biomarkers present in the bodily fluids of cancer patients represents an important avenue for the development of minimally invasive tests to predict tumorigenesis, disease recurrence, or treatment response. A great deal of work along these lines has already been devoted to blood, given its systemic exposure and extensive availability through tissue banks. However, blood is a dynamic biofluid with a proteome under continuous metabolic and homeostatic regulation. Alternatively, urine represents a biofluid that is inherently quiescent in that all molecular and proteolytic activity is largely complete upon sampling. Additional characteristics of urine including its high level of temperature stability and low-complexity matrix resulting from renal filtration have led many to propose urine as an alternative or companion to blood for biomarker studies.
Methods: We performed an analysis of biomarkers present in the urine and serum of patients diagnosed with ovarian, pancreatic, and breast cancer utilizing multiplexed bead-based immunoassays developed for the Luminex® xMAP® platform. Ovarian and breast cancer patients were compared to matched healthy controls while the pancreatic cancer patients were compared to a group of patients diagnosed with benign pancreatic conditions. Each case/control group was tested for 10-15 biomarkers identified as informative for each cancer type through previous population-based analyses of serum biomarkers.
Results: In our analysis, nearly all of the tested biomarkers were detectable in urine and many of the biomarkers exhibited mean relative differences of greater magnitude in urine versus serum. Our multivariate analysis identified several urine multimarker panels capable of discriminating the cancer from the control groups with high sensitivity and specificity. The use of a 4-biomarker panel comprised of 3 urine biomarkers and one serum biomarker resulted in the discrimination of ovarian cancer patients from healthy controls with a sensitivity of 100% at 95% specificity. For the ovarian and pancreatic cancer comparisons, urine/serum multimarker panels outperformed the best serum biomarker panels identified. A urine 5-biomarker panel was identified in the breast cancer comparison that demonstrated a high discriminatory power in both training and validation sample sets.
Conclusions: Our results support the use of urine biomarkers as alternatives and/or companions to serum biomarkers for the diagnosis of selected human cancers.
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 4567.
Abstract 4570: Using laser capture microdissection functionally coupled with mass spectrometry for an enhanced study of solid tumor heterogeneity via tissue proteomics
Authors: Johann Donald J. , Mukherjee Sumana , Rodriquez-Canales Jaime , Hanson Jeffrey , Prieto DaRue , Veenstra Timothy D. , Emmert-Buck Michael , Blonder Josip 
Published: February 2011

Abstract
Introduction
Examining solid tumor heterogeneity using a tissue proteomics approach, which relies on a functional coupling between Laser Capture Microdissection (LCM) and biological mass spectrometry (MS), is the purpose of this research study. A common characteristic of solid tumors is a heterogeneous architecture, which enables distinct cellular morphologies and molecular behaviors. This diverse composition of cells, specifically cancer cells proper along with both modified and unmodified stromal elements, collectively forms a microenvironment that serves to nurture the malignant process.
Methods
Using LCM, homogeneous regions of cells exhibiting uniform histology were isolated and captured from fresh frozen tissue specimens, which were obtained from a human lesion of breast carcinoma metastasis. All slides were reviewed by a pathologist and the LCM session planned. Multiple specimens each containing ∼ 50,000 cells were collected by LCM. Specimens were processed directly on LCM caps, using sonication in buffered methanol to lyse captured cells, solubilize, and digest extracted proteins.
Preliminary results
Prepared samples were analyzed by LC-MS/MS resulting in more than 500 unique protein identifications. High confidence measures were employed by including only proteins identified by ≥ 2 unique peptides. Decoy database searching revealed a false-positive rate between 5 and 10%. Machine learning methods assisted with molecular profiling activities to better discern the concurrent expression of multiple cellular phenotypes due to the heterogeneity of the solid tumor. Cross validation via Western Blot analysis confirmed specific linkage of 12 validated proteins to underlying pathology and their potential role in solid tumor heterogeneity.
Summary and conclusion
Solid tumors are composed of an assortment of cell types, which have diverse morphologies, as well as distinct molecular phenotypes. Tumor heterogeneity may be viewed as a memory of the malignant process and thus a novel proteomic study may yield insights regarding cancer development and more effective treatment. The biological background of such heterogeneity is not well understood. With continued research and optimization of this method including analysis of additional clinical specimens, this approach may lead to an improved understanding of tumor heterogeneity, and serve as a platform for solid tumor biomarker discovery.
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 4570.
Abstract 458: A novel resveratrol analogue, HS-1793, down-regulates the expression levels of hypoxia-inducible factor-1α and VEGF, and inhibits hypoxia-induced cell migration of human prostate cancer cells
Authors: Kim Dong Hwan , Kim Min Young , Hossain Mohammad Akbar , Kim Jin-Ah , Kang Yong Jung , Suh Hongsuk , Choi Yung Hyun , Kim Gi Young , Kim Nam Deuk 
Published: February 2011

Abstract
Hypoxia-inducible factor-1α (HIF-1α), a transcription factor, over- expressed in many human tumors and their metastases, and is closely associated with more aggressive tumor phenotype. An important objective of anti-cancer therapy is the development of new drugs that suppress hypoxic responses in solid tumors. In many studies, resveratrol has been shown to chemopreventive effect in various cancer cells. However, resveratrol's biological activity is limited by its photosensitivity and metabolic instability. This study was investigated the effects of a novel analogue of resveratrol, HS-1793, on the expression levels of HIF-1α and vascular endothelial growth factor (VEGF) in PC-3 human prostate cancer cells. Hypoxic condition induced a time-dependent increase in the level of HIF-1α protein in PC-3 cells, and treatment with HS-1793 markedly decreased HIF-1α expression level. HS-1793 also inhibited VEGF expression level. Mechanistically, HS-1793 inhibited HIF-1α and VEGF expression through multiple mechanisms. Firstly, HS-1793 inhibited both PI3K and Erk phosphorylations in PC-3 cells. Secondly, HS-1793 substantially induced HIF-1α protein degradation through the proteasome pathway. Finally, HS-1793 inhibited hypoxia-induced cell migration. These data suggested that HS-1793 may inhibit human prostate cancer progression and angiogenesis by inhibiting HIF-1α and VEGF expression. Moreover, HS-1793 showed more potent effect than resveratrol on the cytotoxic effects on PC-3 cells. Taken together, these results implied that HS-1793, a novel analogue of resveratrol, might be a new potent chemopreventive agent against human prostate cancer cells. [This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MOST) (R01-2006-000-11117-0)].
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 458.