bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3736: The mTOR inhibitor, RAD001, displays higher cytotoxicity in leukemias with hyperactivated PI3K/AKT/mTOR pathway
Authors: Cani Alice , Simioni Carolina , Capitani Silvano , Martelli Alberto M. , Neri Luca M. 
Published: August 2012

Abstract
Acute myelogenous leukemia (AML) is a disease resulting from the clonal expansion and accumulation of hematopoietic stem cells arrested at various stages of development. B-cell Acute lymphoblastic leukemia (B-ALL) is a form of leukemia characterized by lymphoblast abnormal increase. B-ALL is the most common form of cancer in childhood with a peak of incidence at 2-5 years of age, and another peak in the elderly. The overall cure rate in children is about 80%, and about 38% to 60% of adults have long-term disease-free survival. Although the prognosis of AML and ALL has improved in the last decades, the outcome of relapsed and chemoresistant AML and ALL is still poor, especially in adults, with only a 35-40% survival at 5 years. Therefore, major efforts are being made to develop rationally targeted therapies against alterated signaling cascades that sustain AML and ALL cell proliferation, survival, and drug-resistance. A signaling pathway that is frequently upregulated in AML and ALL is the PI3K/Akt/mTOR network. To explore whether this pathway could represent a potential pharmacological target in AML and ALL, we evaluated the effects of the mTOR inhibitor, RAD001, on the HL60 AML cell line and on the SEM B-ALL cell line.RAD001decreased viability in AML and ALL cell lines, as demonstrated by MTT experiments. The values of IC50 at 24 and 48 hours in HL60 cell line was 8μM, while in SEM cell line, that displays an hyperactivation of the PI3K/Akt/mTOR pathway, the IC50 range was from 4,7 to 6,8 μM, thus showing an higher sensitivity of this cell line to this targeted therapy. As documented by Western Blotting, RAD001 showed a concentration-dependent induction of apoptosis with a relevant increment of PARP, Caspase 3, 8 and 9 cleavage in both cell lines. The ALL cell line SEM, with hyperactivated PI3K/Akt/mTOR pathway, displayed a much higher Caspase and PARP cleavage dependent apoptosis.PI3K/Akt/mTOR downstream targets were also partially dephosphorylated by RAD001, in particular GSK3β and 4E-BP1. RAD001 induced no significant changes in Akt dephosphorylation in HL60 and SEM cell lines, and this is in agreement with several reports showing no relevant changes in the phosphorylation of Akt. The cells always expressed unchanged total Akt. This indicates that PI3K/Akt/mTOR inhibition could be an attractive target to develop innovative therapeutic strategies directed towards AML and ALL leukemia cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3736. doi:1538-7445.AM2012-3736
Abstract 374: Development of tumor-targeted near infrared dyes for fluorescence guided surgery
Authors: Kelderhouse Lindsay E. , Chelvam Venkatesh , Wayua Charity , Sakkarapalayam Mahalingam M. , Poh Scott , Kularatne Sumith A. , Low Philip S. 
Published: August 2012

Abstract
Surgical resection of malignant disease is currently one of the most common and effective cancer treatments. Unfortunately, quantitative tumor resection is limited by a surgeon's ability to distinguish diseased tissue from adjacent healthy tissue. Fluorescence guided surgery has emerged as a tool to aid surgeons in the identification and removal of malignant tissue. While non-targeted fluorescent dyes injected near the primary tumor mass have been shown to passively accumulate in tumors and lymph nodes, the resulting tumor to background ratios are often poor and boundaries between malignant and normal tissue difficult to define. To circumvent these problems, our lab has developed high affinity tumor-specific ligands that can bind to either the prostate specific membrane antigen (PSMA) or the folate receptor (FR); i.e. cell surface molecules that are over-expressed on a number of cancers. In this study, we link these tumor targeting ligands to near infrared (NIR) dyes and explore their use in fluorescence guided surgery. In vitro, all FR and PSMA targeted NIR dyes were found to have binding affinities in the low nanomolar range. Binding was quantitatively blocked with 100-fold excess of free ligand. Upon injection into mice with metastatic disease, the targeted NIR dyes allowed clear distinction of tumor tissue from adjacent healthy tissue. Surgical resection could be conducted until all fluorescent tissue was removed. All resected fluorescent lesions were later confirmed by histology to be malignant. Of the NIR dyes tested, the 800 nm dyes were found to have the greatest fluorescence intensity through porcine tissue, indicating their superior ability to reveal buried tumor nodules. Collectively, these tumor-specific NIR dyes demonstrate significant potential for use in fluorescent guided surgery by aiding in the complete resection of diseased tissue.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 374. doi:1538-7445.AM2012-374
Abstract 3744: Antitumor activity of CUDC-907, a dual PI3K and HDAC inhibitor, in hematological cancer models
Authors: Rudi Bao , Wang Dagong , Qu Hui , Yin Ling , Zifcak Brian , DellaRocca Steven , Xu Guang-Xin , Borek Mylissa , Samson Maria , Atoyan Ruzanna , Poli Anne , Wang Jing , Zhai Hai-Xaio , Lai Cheng-Jung , Pepicelli Carmen , Cai Xiong , Qian Changgeng 
Published: August 2012

Abstract
Recent evidence indicates that both PI3K-Akt-mTOR signaling pathway and HDAC are validated targets in hematological cancers. In order to overcome primary resistance and prevent secondary resistance resulting from compensatory/feedback mechanisms in cancer cells, CUDC-907 was designed to inhibit all isoforms of Class I PI3K and Class I and II HDAC, based on previous observations that synergistic effects can be achieved by inhibition of both HDAC and PI3K in cancer cells. In cell proliferation assays, this compound displays potent anti-proliferation activity in hematological cancer cell lines including non-Hodgkin's lymphoma (NHL), and multiple myeloma (MM). Mechanistically, CUDC-907 is able to simultaneously suppress PI3K-Akt-mTOR as well as other essential signaling pathways due to epigenetic modifications via HDAC inhibition. CUDC-907 is orally bio-available in dogs, has a long half-life in murine tumors, induces apoptosis and inhibits cancer cell proliferation in xenograft tumors. In efficacy studies in NHL and MM models, CUDC-907 is more efficacious than either a single-agent PI3K or HDAC inhibitor reference compound or a combination of the two agents given at maximally tolerated doses (MTD). Furthermore, CUDC-907 is more efficacious than the PI3Kα-selective inhibitor CAL-101 when dosed at MTD doses. These observations are related to our findings that, all isoforms of PI3K are expressed in most hematological cancer models. Therefore, the efficacy of isoform selective PI3K inhibitors may be limited only to those cancers driven by a specific PI3K subtype. In addition, a synergistic antitumor effect can be achieved in efficacy studies when CUDC-907 is combined with standard of care agents in both NHL and MM models. In conclusion, through broad network disruption, CUDC-907 may offer a greater therapeutic benefit than isoform-specific PI3K inhibitors as a novel anti-cancer treatment of hematological malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3744. doi:1538-7445.AM2012-3744
Abstract 3757: CR8, a novel CDK inhibitor, enhances vandetanib activity in a human medullary thyroid carcinoma model
Authors: Broutin Sophie , Hervé-Bazin Morgane , Commo Frédéric , Oumata Nassima , Meijer Laurent , Dupuy Corinne , Schlumberger Martin , Bidart Jean-Michel 
Published: August 2012

Abstract
Introduction: CR8 (ManRos Therapeutics) is a novel inhibitor of cyclin-dependent kinases (CDKs) that selectively targets CDK1/2/3/5/7/9. CDK inhibitors have already shown potent antitumoral activity. Recently, vandetanib (Astra Zeneca), a tyrosine-kinase inhibitor, was approved in the U.S. for the treatment of adult patients with metastatic Medullary Thyroid Carcinoma (MTC). The absence of complete tumor responses justifies the development of new therapeutic options. The aim of this study was to investigate the preclinical activity of CR8 alone and in combination with vandetanib in a MTC model. Materials and Methods: The human MTC TT cell line, bearing a RETC634W activating mutation, was cultured in the absence or the presence of CR8 (10-10 000 nM) and/or vandetanib over 6 days. Cell proliferation was assessed by WST-1 assay. Activation of RET, PP1α and oncogenic pathways (PI3K/AKT, MEK/p44-42) was analyzed by western-immunoblotting. Calcitonin secretion in cell culture media was measured by ELISA. Results: Both CR8 and vandetanib when used alone strongly inhibit TT cell proliferation at day 3 of treatment. Addition of CR8 (10 nM) enhances the antiproliferative activity of low vandetanib concentrations. As expected, vandetanib alone inhibits RET, MAPK and AKT phosphorylation and CR8 inhibits PP1α. Interestingly, CR8 alone induces activation of RET, MAPK and AKT phosphorylation, and the addition of vandetanib (&gt;100 nM) inhibits RET signalling pathways. At day 3 of treatment, vandetanib (&gt;100 nM) and CR8 (100 nM) reduced and induced calcitonin secretion, respectively. Conclusion: CR8 displays an antiproliferative effect on TT cells and enhances the antiproliferative activity of vandetanib. CR8 acts by inhibiting PP1α and, surprisingly, induces an activation of RET and stimulates calcitonin production. These results suggest that the combination of vandetanib with CDKs inhibitors such as CR8 may be of value to improve therapeutic response.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3757. doi:1538-7445.AM2012-3757
Abstract 3768: Evaluating the effects of bortezomib (Velcade®) on the pharmacokinetics (PK) of pegylated liposomal doxorubicin (Doxil®, PLD)
Authors: La-Beck Ninh M. , Walko Christine M. , Scoggins Lakia , Dees E. Claire , Orlowski Robert Z. , Wu Huali , Amantea Michael , Fardin Mahsa , Zamboni William 
Published: August 2012

Abstract
Background: PLD is a pegylated liposomal formulation of doxorubicin approved for the treatment of ovarian cancer, Kaposi's sarcoma, and multiple myeloma. We have reported that age, gender, and monocyte count may affect the clearance (CL) of PLD. In multiple myeloma, PLD is used with bortezomib, a proteosome inhibitor which can affect monocyte count. The purpose of this cross study comparison was to assess the effects of bortezomib on the CL of PLD. Methods: This was a cross trial comparison of patients with solid tumors who received PLD alone and PLD + bortezomib. The PLD alone group (n = 34) received PLD at 10 to 60 mg/m2 IV every 28 days. The PLD + bortezomib group (n = 25) received bortezomib at 0.90 to 1.50 mg/m2 IV on days 1, 4, 8, and 11, and PLD at 30 mg/m2 IV on day 4, every 21 days. PK studies of PLD were performed for cycle 1, after administration of PLD alone and PLD + bortezomib. Serial blood samples were obtained from 0 to 96 h and from 7 to 28 days after administration of PLD. Plasma samples were processed to measure sum total (encapsulated + released) doxorubicin via HPLC and the clearance (CL) was calculated with WinNonlin using noncompartmental methods. Results: In patients &lt; 60 years old, the mean (± standard deviation) PLD CL after administration of PLD alone and in combination with bortezomib was 63.4 (± 46.1) and 23.3 (± 7.6) mL/h, respectively (P=0.017). In patients &gt;= 60 years old, the PLD CL after administration of PLD alone and in combination with bortezomib was 39.1 (± 18.5) and 38.0 (± 15.5) mL/h, respectively (P&gt;0.05). In male patients, the PLD CL after administration of PLD alone and in combination with bortezomib was 65.4 (± 33.4) and 38.4 (± 9.7) mL/h respectively (p&gt;0.05). In female patients, the PLD CL after administration of PLD alone and in combination with bortezomib was 40.1 (± 33.4) and 24.6 (± 11.2) mL/h respectively (P&gt;0.05). Conclusion: This cross study comparison suggests that bortezomib decreases PLD CL in younger patients and in male patients. Although the underlying mechanism for this effect on PLD CL is not known, it may be related to bortezomib inhibition of mononuclear phagocyte activity in certain patient populations, which is responsible for the CL of PLD. There is a need to further investigate this in a prospective drug interaction study.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3768. doi:1538-7445.AM2012-3768
Abstract 3773: Absolute bioavailability of BRAF inhibitor GSK2118436: Use of a microtracer study in patients with cancer
Authors: Denton Cathrine L. , Carson Stanley W. , Young Graeme C. , Richards-Peterson Lauren E. , Botbyl Jeffrey , Morrison Royce A. , Blackman Samuel C. , Ouellet Daniele 
Published: August 2012

Abstract
Background. Absolute bioavailability (BA) studies in oncology are logistically and technically challenging. Use of an intravenous (IV) microtracer offers an attractive alternative to conventional cross-over design studies. This method involves concomitant administration of a non-labeled oral therapeutic dose with a radiolabeled IV microtracer dose. Advantages include: 1) fewer subjects required as comparisons are within-subject and within-period, yielding reduced variability; 2) easier development of IV formulation for drugs with low solubility (microtracer doses are ≤ 100 μg); 3) radioactivity doses are low and do not require special handling (usually ≤ 270 nCi of 14C) and 4) negligible toxicity, as the contribution of the microtracer dose to overall exposure is typically &lt; 0.5% of the oral dose. The approach required development of an ultra-sensitive assay using accelerator mass spectrometry (AMS) to determine pharmacokinetic (PK) parameters from IV dosing. The purpose of this study was to determine absolute BA for the BRAF inhibitor GSK2118436 in cancer patients. Methods. Patients with BRAF-mutant solid tumors were enrolled in an open-label, non-randomized study. Patients received a single oral dose of GSK2118436 (150 mg capsule) followed by a 15-min microtracer infusion (50 μg [14C] GSK2118436), started 1.75 h after the oral dose to coincide with oral Tmax. Plasma samples were collected at timed intervals up to 72 h post-oral dose. Total radioactivity and [14C] GSK2118436 were measured by AMS. Non-labeled GSK2118436 was measured by LC-MS/MS. PK parameters were calculated using standard non-compartmental methods. Results. Preliminary PK parameters were determined in 4 subjects (Table). Absolute BA, expressed as least squares mean (90% CI), was 84.2% (72.3-98.1). Conclusions. The absolute BA of oral GSK2118436 was high. This innovative IV microtracer study was an efficient and accurate way to determine absolute BA of GSK2118436 in patients with advanced cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3773. doi:1538-7445.AM2012-3773
Abstract 3784: AME-133v, a humanized, Fc-engineered anti-CD20 monoclonal antibody, demonstrates greater B cell depletion than Rituxan in vitro
Authors: Wayne Jennifer L. , Campbell Mary-Ann , Marulappa Shashi , Jain Vinay 
Published: August 2012

Abstract
Purpose The efficacy of AME-133v in depleting B lymphocytes was compared in vitro to that of Rituxan, and the effect of FcαRIII genotype was assessed. Methods Blood samples from 37 healthy donors were collected and genotyped for FcαRIII polymorphism. Varying concentrations of AME-133v or Rituxan were applied to samples and CD19+ peripheral circulating B lymphocytes were measured using fluorescence-activated cell sorting (FACS). B cell depletion was listed as a percentage of baseline level. Results In an in vitro whole blood assay, AME-133v was more effective in depleting B lymphocytes from baseline levels than Rituxan, particularly at increasing concentrations (Table 1). Significant differences were found between treatments averaged over doses, between doses averaged over treatments, and between treatments depending on dose, all with p&lt;0.0001. AME-133v's superior effect in depleting B cells is independent of dose (p&lt;0.001), but caused greater B cell depletion at lower concentrations of antibody. In both AME-133v and Rituxan treatments, VF and FF patients demonstrated less B cell depletion, corroborating previous data citing decreased response to Rituxan among F-carriers and indicating improved pharmacodynamics of AME-133v. Conclusion AME-133v is engineered for a 6-fold more potent effector function in antibody-dependent cell-mediated cytotoxicity (ADCC) compared to Rituxan, which is elucidated through improved B cell depletion, across doses. Depletion in AME-133v-treated patients was also greater across all genotypes, suggesting superior pharmacodynamics of AME-133v in the low-responding F-carrier population. These findings indicate relevant biological activity of the antibody and suggest that AME-133v may provide additional clinical benefit for low-affinity FcαRIII patients. A randomized trial is being planned to compare clinical efficacy of AME-133v vs. Rituxan, targeting low-affinity FcαRIII patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3784. doi:1538-7445.AM2012-3784
Abstract 3809: Effects of honokiol on UACC-62 and SKMEL-2 melanoma cell lines
Authors: Guillermo Ruth F. , Stevens Jonathan M. , Kaushik Radhey S. , Young Alan , Zeman David , Dwivedi Chandradhar 
Published: August 2012

Abstract
Honokiol is a plant lignan extracted from the magnolia bark tree, previous studies from our laboratory showed its chemopreventive effects in a UVB-induced skin cancer model, as well as pro-apoptotic effects in A431 squamous cancer cell line. Studies from other groups have reported antineoplastic effects in different cancer models as well. In this study, the antineoplastic effects of honokiol were evaluated in vivo and in vitro against UACC-62 cell line that harbors mutated BRAF, CDK4i, PTEN and against SKMEL-2 cell line that presents NRAF, and TP53 mutated genes. For the in vivo studies, nude male mice were injected subcutaneously with 5x106 UACC-62 or SKMEL-2 cells. The next day animals were randomized into control and treatment groups, each group containing 20 animals. The control group received 250 αl of sesame oil intraperitoneally (IP), the treatment groups received honokiol dissolved in sesame oil; 1.25 mg (IP) in the UACC-62 group and 50 mg/kg (IP) in the SKMEL-2 injected mice. Animals were treated three times a week, for 5-7 weeks. Tumors’ incidence, multiplicity and volume were recorded every three days, mice's weights and external signs of toxicity were also closely monitored. Tumor tissues were collected for histopathology, Western blots, and PCR arrays. For the in vitro studies, both cell lines were evaluated for cell viability, proliferation, apoptosis by TUNEL assay, cell cycle arrest by propidium iodide staining, and Western blots for proteins expressions. Honokiol treatment significantly reduced (p&lt;0.05) tumor volumes in both xenograft experiments. No evident signs of toxicity were observed in the honokiol treated animals. In both cell lines, honokiol significantly decreased (p&lt;0.05) cell viability and proliferation, honokiol caused cell cycle arrest in Go/G1 phase in UACC-62 cell line, while it caused accumulation of cells in the G2/M phase in SKMEL-2 cell line; honokiol significantly increased the DNA fragmentation in both cell lines. Honokiol strongly decreased the expressions of cyclin D1, cyclin D2 and cyclin B1 while increasing the cleavage of caspase 3, caspase 8, caspase 9 and PARP in both cell lines. In UACC-62 honokiol decreased the expressions of CDK2, CDK4, cyclin E, cdc2p34 and p21. In SKMEL-2, honokiol decreased the expression of CDK4, PCNA and increased the expression of p21. These findings suggest that honokiol is a good candidate for further studies as a treatment for malignant melanoma. This work is supported by a Translational Cancer Center Research Grant, funded as 2010 Research Initiative Center by the State of South Dakota.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3809. doi:1538-7445.AM2012-3809
Abstract 3817: Nitric oxide-donating aspirin induces G2/M phase cell cycle arrest in human cancer cells by regulating phase transition proteins
Authors: Gao Li , Williams Jennie L. 
Published: August 2012

Abstract
NO-aspirin (NO-ASA), consisting of aspirin, a non-steroidal anti-inflammatory drug (NSAID), and a nitric oxide (NO)-releasing group, is reportedly safer than aspirin and effective in colon cancer chemoprevention. NO-ASA reduced the growth of several cancer cell lines much more potently than aspirin, with IC50 values at 24-h as follows: (a) colon (HT-29, SW480, HCT-15, and LoVo) 174 to 257 µM; (b) pancreas (BxPC-3), 175 µM; (c) skin (A431), 133 µM; (d) cervix (Hela), 240 µM; and (e) breast (MCF-7), 268 µM. In all instances, the IC50 values for the parent compound were &gt;1,000 µM. To assess NO-ASA's mechanism of action, we studied in vitro its effect on colonocyte kinetics. In all cell lines examined, the growth inhibitory effect of NO-ASA was accompanied by cell cycle arrest in the G2/M phase transition. This inhibition directly correlated to altered expression of G2/M transition related proteins. Specifically, NO-ASA had a time- and concentration-dependent effect on the expression of cyclin D1. Here we propose that NO-ASA-mediated G2/M arrest is probably caused by ROS generation. This conclusion is based on (a) treatment with NO-ASA generates ROS in SW480 and (b) the G2/M arrest induced by NO-ASA is abolished on pretreatment with the antioxidant NAC. Thus, NO-ASA's superior effectiveness compared to traditional aspirin is due in part to its ability to induce G2/M phase cell cycle arrest in human cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3817. doi:1538-7445.AM2012-3817