bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5390: QBI-139, a human RNase variant in a phase I trial, works in combination
Authors: Strong Laura E. , Kink John A. , Mei Baigen , Shahan Mark N. , Raines Ronald T. 
Published: February 2011

Abstract
The EVade™ Ribonucleases (RNases) are a new class of anti-cancer drugs that target the RNA in cancer cells. These EVade™ RNases are variants of native mammalian RNases that have been converted to anti-cancer agents by diminishing their binding to their natural inhibitor protein.
One of these EVade™ RNases, called QBI-139, has advanced to human clinical trials. QBI-139 shares 95% sequence identity with the wild type human RNase 1. QBI-139 has shown tumor growth inhibition against a variety of cancers, including: colon, non-small cell lung, ovarian, pancreatic and prostate cancers. QBI-139 is currently in a Phase I clinical trial in patients with solid tumors. A frog RNase called Ranpirnase (Alfacell) that shares only 20% sequence identity with human RNase 1 has been in clinical trials and responses have been seen in esophageal, non-small cell lung and breast cancers as well as unresectable mesothelioma.
The next stage of clinical development of QBI-139 will require selection of a specific indication as well as an existing treatment regimen to be used in combination with QBI-139. The Phase I trial may provide insights about sensitive tumor types. However, mouse models of cancer will be used to select the combinations for development.
QBI-139 has shown efficacy against non-small cell lung cancer (A549 cell line) in xenograft models. Cisplatin is a standard of care treatment for non-small cell lung cancer in patients. The ability of QBI-139 and cisplatin to work together to cause tumor growth inhibition was determined in a non-small cell lung cancer xenograft model (A549 cell line). Cisplatin (3 mg/kg) and QBI-139 (15 mg/kg) were used as controls. The combination of cisplatin and QBI-139 (3 and 15 mg/kg, respectively) was also tested. Cisplatin treatment resulted in tumor growth inhibition (TGI) of 60% while QBI-139 caused 76% TGI. The combination of the two drugs resulted in a TGI of 96%, strongly supporting the use of QBI-139 in combination with cisplatin for the treatment of lung cancer. Even the combination of the two drugs exhibited minimal impact on the health of the animals.
EVade™ Ribonucleases are novel agents that provide a new way to target the RNA in cancer cells and are an innovative new tool for oncologists. QBI-139 has a variety of benefits, including: a novel mechanism of action with clinical support, broad in vivo anti-tumor activity alone and in combination with standard of care therapies and a strong tolerability profile.
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 5390.
Abstract 540: Lactate as a mediator of mesenchymal stem cell interactions within the tumor microenvironment
Authors: Rattigan Yanique I. , Martin Alister F. , Glod John , Banerjee Debabrata 
Published: February 2011

Abstract
Mesenchymal stem cells (MSCs) are multipotent stromal precursor cells that have the capacity to migrate, proliferate, differentiate and contribute in vivo to the hypoxic tumor stroma. Cancer cells primarily depend on the anaerobic breakdown of glucose to generate ATP, even in the presence of oxygen. A consequence of this altered metabolic phenotype of cancer cells is the accumulation and secretion of lactate. Recent reports suggest that lactate produced by cancer cells may be taken up by stromal cells and recycled to regenerate pyruvate. Interestingly, stromal cells can efflux pyruvate to serve as a power supply to sustain the metabolic needs of cancer cells. Here we provide evidence that MDA-MB-231 and MCF-7 breast cancer cell lines secrete enhanced levels of lactate (2-fold) under hypoxia (1.5% O2) as compared to normoxia (21% O2). Analysis of MSC migration, showed that 15mM lactate enhanced MSC migration over 3-fold compared to control medium. Lactate stimulation of MSCs induced expression of a functional monocarboxylate transporter MCT-1, one of the proteins involved in lactate transport, at both mRNA and protein levels. Furthermore, activation of Stat3 signaling leading to enhanced MSC migration and NF-[[Unable to Display Character: &#312;]]B regulated survival pathways following lactate stimulation was observed suggesting that lactate plays a role in the metabolic fate of cancer cells through the recruitment of MSCs. Delineating the interaction between MSCs, lactate and the tumor microenvironment will be fundamental in understanding tumor cell metabolism and provide knowledge for the development of novel anticancer therapies.
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 540.
Abstract 5405: PPARγ-agonist can render bladder tumor sensitive to EGFR inhibition
Authors: Mansure Jose J. , Szymanski Konrad , Nassim Roland , Rocha Joice , Aldousari Saad , Chevalier Simone , Kassouf Wassim 
Published: February 2011

Abstract
Abstract
Purpose: The two signalling molecules that are extremely attractive for targeted therapy are the epidermal growth factor receptor (EGFR) and the peroxisome proliferator-activated receptor γ (PPARγ). We evaluate the integration of combined drugs against these targets in the management of bladder cancer therapy.
Methods: The effect of EGFR inhibitor (Gefitinib) and PPARγ-agonist DIM-C, on cell growth, were screened in a panel of 9 human urothelial carcinoma cell lines derived from well-differentiated superficial bladder tumors as well as from high-grade invasive tumors. Cell proliferation was determined with an MTT assay after incubation with varying concentrations of the targeted agents (10-3 to 102 mM) for 72 h. Antiproliferative effects of combined therapy (Gefitinib and DIM-C) compared to each drug alone were monitored in vitro, by MTT assays. Levels of expression of EGFR and PPARγ were evaluated by Western Blot analysis at baseline and after pre-treatment with EGFR inhibitor (Gefitinib). Immunofluorescence was then used to determine PPARγ nuclear accumulation mediated by Gefitinib. In vivo, the effect of Gefitinib, DIM-C alone and combined were determined in nude mice bearing human KU-7 subcutaneous xenografts.
Results: Several bladder cancer cell lines were demonstrated to be relatively resistant to Gefitinib. Induction of PPARγ expression was observed in response to different concentrations of Gefitinib for 24 h. Moreover, nuclear accumulation of PPARγ was observed following its upregulation. MTT assay shows that PPARγ agonist significantly sensitized bladder cancer cell lines that were resistant to EGFR inhibition in a schedule-specific manner. These findings were confirmed in vivo where combination therapy maximally inhibited tumor growth in contrast to each treatment alone when compared to control (p&lt;0.04).
Conclusions: Preliminary results suggest that PPARγ-agonist DIM-C can render bladder tumor sensitive to EGFR inhibition and combination efficacy might be achieved in a schedule-specific manner.
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 5405.
Abstract 5407: Inhibitory Raf-1 phosphorylations at Ser-43 and Ser-259 are induced in vitamin K1 enhancement of Sorafenib-mediated HCC cell growth inhibition
Authors: Wang Ziqiu , Wang Meifang , Carr Brian I. 
Published: February 2011

Abstract
Sorafenib, a multi-kinase inhibitor, is an FDA-approved agent for treatment of human hepatocellular carcinoma (HCC). However, tumor shrinkage is minor. K vitamins can activate protein kinase A (PKA), which in turn can mediate inhibitory Raf phosphorylation. We developed a new strategy to combine naturally occurring K vitamins with Sorafenib to treat HCC, and found that K vitamins were able to enhance the inhibition of HCC cell growth in vitro and in vivo by Sorafenib. To explore the mechanisms involved, we examined the role of Raf-1 kinase, because it has been reported that Sorafenib inhibits tumor cell growth as a direct inhibitor of Raf, whereas vitamin K2 can induce PKA activity, which is a Raf-1 upstream kinase. We found that while lower doses of vitamin K1 (10 μM) or Sorafenib (2.5 μM) alone slightly induced Raf-1 phosphorylation at both Ser-43 and Ser-259 in Hep3B cells, combination vitamin K1 plus Sorafenib treatment resulted in strong Raf-1 phosphorylation at these two Raf-inhibitory serine residues. Raf-1 protein kinase activity assay showed that lower concentrations of vitamin K1 or Sorafenib alone had little, if any effects on Raf-1 activity, combination vitamin K1 plus Sorafenib at the same low concentrations significantly inhibited Raf-1 activity, judged by strong inhibition of MEK, and of ERK phosphorylation, its down stream targets. Since Raf-1 phosphorylation at Ser-43 and Ser-259 can be regulated by either PKA or Akt kinase, we examined the effects of both vitamin K1 and Sorafenib on their phosphorylation. Although both vitamin K1 and Sorafenib alone induced PKA phosphorylation, no synergistic phosphorylation effects on PKA were found using the combination. However, vitamin K1 enhanced Sorafenib-induced Akt phosphorylation, which was associated with enhanced c-Met tyrosine phosphorylation at Tyr-1349, a known phospho-Akt regulator. Our data suggest that enhanced inhibitory Raf-1 phosphorylation at Ser-43 and Ser-259 may play a central role in vitamin K1 plus Sorafenib synergy in inhibiting HCC cell growth.
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 5407.
Abstract 5421: Targeting glucose and glutamine for the metabolic management of systemic metastatic cancer
Authors: Shelton Laura M. , Huysentruyt Leanne C. , Seyfried Thomas N. 
Published: February 2011

Abstract
Metastatic cancer is a major cause of morbidity and mortality. Current therapeutic options consist of chemotherapy, radiation, or targeted therapies. However, these therapies are often toxic, effective over a small range of cancer types, or result in drug resistance. Therefore, a more global, less toxic strategy for the management of metastatic cancer is required. Though most cancers display increased glucose metabolism, glutamine is also a major energy substrate for many cancers. We evaluated the anti-metastatic potential of 6-diazo-5-oxo-L-norleucine (DON), a glutamine analog, using the new VM mouse model of systemic metastasis. In addition we evaluated the combined inhibition of glucose and glutamine metabolism by treating mice with both DON, which targets glutamine, and calorie restriction (CR), which reduces circulating glucose levels. We found that primary tumor growth was about 20-fold less in DON treated mice than in untreated control mice. We also found that DON treatment administered alone or in combination with CR inhibited metastasis to liver, lung, and kidney as detected by bioluminescence imaging and histology. Although DON treatment alone did not reduce the incidence of tumor metastasis to spleen compared to the controls (68% controls, 50% DON treatment), DON administered together with CR significantly reduced the incidence of metastasis to the spleen to 27%, indicating a diet/drug synergy. Furthermore, DON toxicity was less in the DON + CR group than in the DON alone group. Less DON was needed to achieve the same level of tumor growth inhibition when administered with CR than administered alone. Finally, survival was greater in the DON + CR group than in the DON group alone further illustrating drug/diet synergy. Our findings provide proof of concept that metabolic therapies targeting both glucose and glutamine metabolism can manage systemic metastatic cancer. (Supported by Boston College REG).
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 5421.
Abstract 5423: Effects of atorvastatin, celecoxib and tipifarnib alone or in combination on the growth of pancreatic cancer in Panc-1 cells cultured in vitro or Panc-1 tumors grown in immunodeficient mice
Authors: Zheng Xi , Cui Xiao-Xing , Gao Zhi , Shi Yi , Rabson Arnold , Conney Allan H. 
Published: February 2011

Abstract
Ras mutation and overexpression of cyclooxygenase-2 (Cox-2) are present in the majority of pancreas cancer patients. An approach for inhibiting the progression and growth of pancreas cancer is the use of agents that inhibit the function of both Ras and COX-2. In the present study, we assessed the effects of atorvastatin, celecoxib and tipifarnib alone or in combination on the growth of human pancreatic cancer Panc-1 cells cultured in vitro or grown as xenograft tumors in severe combined immunodeficient (SCID) mice. In the in vitro studies, we found that treatment of Panc-1 cells with a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on proliferation and a stronger stimulatory effect on apoptosis than each drug alone or for any combination of two drugs. We also found that treatment of Panc-1 cells with a combination of the 3 drugs decreased the level of phosphorylated Erk1/2 and Atk to a much greater extent than the individual compounds alone or any combination of two compounds. In animal experiment, we found that daily i.p injections of a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on the growth of Panc-1 tumors in SCID mice than each drug alone or for any combination of two drugs. The results from our study indicate that a combination of atorvastatin, celecoxib and tipifarnib may be an effective strategy for the treatment of pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5423.
Abstract 5445: Suberoylanilide hydroxamic acid induces Epstein-Barr virus lytic cycle and enhanced apoptosis in nasopharyngeal carcinoma
Authors: Hui Kwai Fung , Tsao George Sai-Wah , Chiang Alan Kowk-Shing 
Published: February 2011

Abstract
Nasopharyngeal carcinoma (NPC) has uniquely high prevalence in Southern Chinese populations and a predilection to affect young adult males. Epstein-Barr virus (EBV) is harbored in every tumour cell of NPC but it persists in tightly latent form expressing few viral proteins and evading the immune system. Induction of EBV lytic cycle will lead to expression of a much larger number of viral proteins which may serve as potential therapeutic targets against the cancer. We reported that suberoylanilide hydroxamic acid (SAHA), a FDA-approved histone deacetylase inhibitor, could strongly induce viral lytic cycle in EBV-positive gastric carcinoma cells. Here, we demonstrated that SAHA (at 5-10 μM) could potently induce EBV lytic cycle in a panel of EBV-positive NPC cell lines, as evidenced by increased viral DNA replication, expression of immediate early (Zta and Rta), early (BMRF1) and late (VCA-p40 and gp350/220) viral lytic proteins and production of infectious viral particles. Immunofluorescent staining demonstrated expression of viral lytic proteins in more than 40% of the NPC cells. Enhanced killing of EBV-positive NPC cells when compared with that of EBV-negative counterparts was observed and cleaved form of PARP was predominantly expressed in EBV-positive than EBV-negative NPC cells, following treatment with SAHA for 24, 48 and 72 hours. The kinetics of expression of cleaved PARP correlated with that of Zta viral protein in EBV-positive NPC cells. In conclusion, SAHA is found to be a potent EBV lytic cycle inducing agent and mediates enhanced apoptosis of NPC cells. Further investigation into SAHA's development as a novel virus-targeted therapeutic drug in NPC is warranted.
This work is funded by EBV research and NPC AoE grants of AKSC.
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 5445.
Abstract 5447: A novel inhibitor of DNA methylation
Authors: Malik Mohammad T. , Rinaldo Francesca M. , Mitra Shams , Casson Lavona K. , Zacharias Wolfgang , Waigel Sabine , Arumugam Vennila , Hasan Nazarul , Hu Chuan , Bo Xu , Hammond Gerald B. , Bates Paula J. 
Published: February 2011

Abstract
We previously reported the discovery of XB05, a synthetic small molecule with antiproliferative activity. XB05 was found to be a strong inhibitor of DNMT1 activity in cell-free and cell-based assays. However, screening in the NCI 60 tumor cell lines and analysis using COMPARE indicated a novel mechanism of action for XB05, different from standard demethylating agents such as 5-azacytidine (azaC) and decitabine. Here, we report on new research to further characterize XB05 activity. We have examined the effects of XB05 on clonogenicity, promoter methylation, gene expression, and DNMT1 protein. XB05 was found to inhibit colony formation of HCT116 colon carcinoma cells in a dose-dependent manner with a sub-micromolar IC50. Western blots of nuclear extracts from HCT116 cells treated for 72 h with 100 nM XB05 or 10 µM azaC (as positive control) showed greatly decreased levels of DNMT1, suggesting that binding to XB05 can induce degradation of DNMT1 (previous research indicates direct drug-enzyme binding). Analysis of CDKN2A promoter methylation by bisulfite modification and sequencing demonstrated heavy methylation in untreated HCT116 cells. This was reversed by treatment of with 100 nM XB05 or 10 µM azaC, resulting in re-expression of the gene (which encodes tumor suppressor, p16), as shown by qRT-PCR. Experiments to assess promoter methylation using multiplex arrays and to examine gene expression changes using DNA microarrays were recently completed and data analysis is ongoing. To evaluate in vivo activity, we treated mice bearing subcutaneous HCT116 xenografts by IP injection of XB05 with multiple doses of up to 10 mg/kg. There was no evidence of toxicity as judged by body weights and gross necropsies. The tumors of mice treated with XB05, although not significantly smaller than in control animals, were characterized by extensive necrosis in the center of the tumor, leading to a “hollow” tumor in the majority (12/20) of mice. No similar necrosis was observed in vehicle-treated or azaC-treated mice, suggesting that this effect is treatment related. Because induced necrosis is seen with vascular disrupting agents, we also examined the effect of XB05 on endothelial cells in an in vitro assay, and observed reproducible inhibition of endothelial tube formation at 400 nM or higher. In summary, our new data confirm that XB05 is a potent inhibitor of DNA methylation in cultured cancer cells, and provide the first evidence of in vivo activity, which may involve effects on the tumor vasculature, as well as the tumor itself.
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 5447.
Abstract 5448: The tricyclic anti-depressant amitriptyline inhibits D-cyclin transactivation and induces myeloma cell apoptosis by inhibiting histone deacetylases
Authors: Mao Xinliang , Wang Wenjie , Cao Biyin , Li Zhihua , Hurren Rose , Trudel Suzanne , Schimmer Aaron D. 
Published: February 2011

Abstract
D-cyclins are universally dysregulated in multiple myeloma and contribute to the pathogenesis and chemoresistance of this disease. To identify novel pharmaceutical inhibitors of cyclin D transactivation, we compiled and screened a library of on-patent and off-patent drugs using NIH 3T3 cells stably expressing the Cyclin D2 promoter-driving a luciferase reporter gene. From this screen we identified the tricyclic antidepressant amitriptyline as a novel inhibitor of Cyclin D2 transactivation. In secondary assays, Amitriptyline reduced expression of cyclins D1, D2, and D3 in myeloma cell lines at low micromolar concentrations across a variety of transforming events including c-maf over-expression (JJN3, KMS11, My5 cells), FGFR3 translocation (KMS11, OPM2 cells), and cyclin D1 translocation (KMS12 cells). Consistent with its effects on D-cyclin expression, amitriptyline arrested cells in the G0/G1 phase of the cell cycle at concentrations associated with its ability to decrease D-cyclins. Decreased cyclin D expression and G1 arrest can induce apoptosis. Therefore we tested the effects of amitriptyline on cell viability. Myeloma cell lines were treated with increasing concentrations of Amit and cell viability was measured by the MTS assay. Amitriptyline reduced the viability of myeloma cells with an IC50 &lt; 20 uM within 72hr. In addition, the combination of amitriptyline and dexamethasone synergistically induced cell death. Cell death and apoptosis were confirmed by Annexin V and PI staining and were associated with activation of Caspase-3 and Poly(ADP-ribose)Polymerase (PARP) as detected by immunoblotting. To understand the mechanism by which amitryptiline inhibits D-cyclin transactivation and induces cell death, we examined the effects of this compound on HDAC levels and activity. By immunoblotting, treatment with amitriptyline increased levels of acetyl-Histone 3 in myeloma cell lines. Furthermore amitriptyline decreased levels of HDACs 3, 6, 7 and 8 in examined cell lines with a concentration consistent with the cell death and cyclin D2 inhibition.
Thus, in summary, amitriptyline inhibits D-cyclin transactivation in myeloma cells that is associated with reductions in HDAC levels. Given the preclinical activity of amitriptyline in myeloma, this work highlights a potential therapeutic strategy for this disease.
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 5448.