bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 846: Targeted inhibition of c-Met receptor by a selective c-Met inhibitor, Tivantinib, and a specific shRNA reduces breast cancer-derived bone metastases
Authors: Previdi Sara , Abbadessa Giovanni , Dalò Francesca , France Dennis S. , Broggini Massimo 
Published: August 2012

Abstract
Breast cancer exhibits a propensity to metastasize to bone, resulting in debilitating skeletal-related complications associated with significant morbidity and mortality. Because of the clinical significance of this process, many research efforts are aimed at uncovering the molecular events in bone metastases to identify novel targets and to improve clinical management of metastatic bone disease. The interactions between metastatic cells and bone are critical to the development and progression of bone metastases, and their unravelling could lead to novel preventive or therapeutic approaches. We previously demonstrated the critical role of HGF/c-Met/β-catenin/TCF system in tumor-bone interaction leading to skeletal metastases of human breast cancer cells, suggesting the potential inhibition of this pathway in vivo. In this study, we evaluated the potential therapeutic efficacy of targeting the c-Met receptor by using both an oral, selective, small-molecule c-Met inhibitor, tivantinib, and a specific shRNA against c-Met in an experimental bone metastatic model of human breast cancer. Tivantinib exhibited dose-dependent anti-metastatic activity in vivo, and the 120 mg/kg dose, while being ineffective in reducing subcutaneous tumor growth, induced significant inhibition of bone metastatic growth and a noteworthy reduction of tumor-induced osteolysis. shRNA-mediated c-Met silencing did not affect in vitro proliferation of bone metastatic cells, but strongly reduced their migration, and this effect was further enhanced by tivantinib. These data were confirmed in vivo. Indeed, dual c-Met inhibition with both tivantinib and RNA interference strategy induces pronounced tumor growth suppression with concomitant marked decreases of lytic lesions and an improvement in survival. Overall, our findings highlighted the efficacy of c-Met inhibition in delaying the onset and progression of bone metastases and strongly suggested that targeting the c-Met receptor may have promising therapeutic value in the prevention and treatment of bone metastases from breast cancer. Most importantly, the finding that tivantinib is active as an anti-metastatic agent at low, non-cytotoxic doses suggests that its efficacy may be potentiated by combining it with other therapies that target cancer cell-bone interactions.
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 846. doi:1538-7445.AM2012-846
Abstract 848: Preclinical antitumor activity of S 49076, a novel MET / AXL / FGFR kinase inhibitor and molecular stratification for tumor sensitivity
Authors: Burbridge Mike F. , Bossard Celine , Saunier Carine , Fejes Imre , Bruno Alain , Pierre Alain , Guigal-Stephan Nolwen , Rodriguez Marianne , Galizzi Jean-Pierre , Lockhart Brian P. , Jacquet-Bescond Anne , Ortuno Jean-Claude , Cruzalegui Francisco H. , Depil Stephane 
Published: August 2012

Abstract
Aberrant activity of receptor tyrosine kinases (RTKs) has been associated with tumor progression in a wide variety of human malignancies, making them promising drug targets for cancer therapy. Although, in some instances, specific inhibition of just one of these RTKs suffices for inhibition of tumor progression, in the majority of cases, targeting more than one RTK could be required for therapeutic efficacy. Moreover, increased expression or activation of RTKs is often associated with resistance to standard chemotherapy agents or signal transduction modulators. S 49076 is a novel, potent, ATP-competitive tyrosine kinase inhibitor of the RTKs MET, AXL and FGFR. S 49076 blocks autophosphorylation of these RTKs and their downstream signaling in cells with IC50 values of less than 50 nM in the case of MET and AXL, and at below 200 nM for FGFR1/2/3. In vitro, S 49076 inhibits the proliferation of MET- and FGFR2- dependent gastric cancer cells, blocks MET-driven migration of lung carcinoma cells and inhibits colony formation of hepatocarcinoma cells overexpressing FGFR2 and AXL. In vivo, oral administration of S 49076 inhibits MET autophosphorylation and tumor growth in subcutaneous GTL-16 human gastric carcinoma and U87-MG human glioblastoma at 6 mg/kg/day. In FGFR2-dependent SNU-16 gastric tumors S 49076 inhibits FGFR2 autophosphorylation, downstream signaling and tumor growth at 25 mg/kg/day. In a panel of 53 patient-derived tumors and 14 cell lines of diverse origin growing in three-dimensional in vitro culture, twenty-five (37%) were found to be sensitive to S 49076 at 1 µM or less. In the majority of cases, analysis of the expression, activation and mutation status of MET, AXL, FGFR1/2/3 and other target kinases of S 49076 as well as that of major signaling proteins enabled hypotheses to be made concerning the sensitivity or resistance to S 49076. Moreover, in many of these resistant tumors, a rationale for association of S 49076 with other targeted therapies emerged. Examples of the efficacy of such combined therapies will be shown. Based on these preclinical studies showing a favorable and novel pharmacological profile of S 49076, a phase I study is currently underway in patients with advanced solid tumors.
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 848. doi:1538-7445.AM2012-848
Abstract 851: Epidermal growth factor receptor inhibitor erlotinib prolongs survival in Kras-mutant pancreatic ductal adenocarcinoma by inhibiting gemcitabine-induced mitogen activated protein kinase signaling activation
Authors: Miyabayashi Koji , Ijichi Hideaki , Mohri Dai , Tada Motohisa , Yamamoto Keisuke , Asaoka Yoshinari , Ikenoue Tsuneo , Nakai Yousuke , Isayama Hiroyuki , Omata Masao , Moses Harold , Koike Kazuhiko 
Published: August 2012

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers. New therapeutic approaches to improve the prognosis are highly required. We generated pancreas-specific TGF-beta receptor II (Tgfbr2) knockout mice in the context of Kras activation, which recapitulated clinical and histopathological manifestations of human PDAC, indicating that an impact of blockade of TGF-beta signaling in PDAC progression. An EGFR inhibitor erlotinib showed a superior survival effect in combination with gemictabine, however, the mechanism by which PDAC with extremely frequent KRAS-mutation benefits from EGFR inhibition remains largely unkown. Using the model we investigated the anti-tumor impact and mechanisms of erlotinib in combination with gemcitabine. We treated the mice with elrotinib and gemcitabine. Median survival times were 52.5, 69, and 74 days for control, gemcitabine alone, and gemcitabine + erlotinib, respectively. Gemcitabine alone significantly extended the survival compared to the control. Further, adding erlotinib to gemcitabine prolonged the survival significantly compared to gemcitabine alone. Interestingly, treatment with gemcitabine enhanced the activation of MAPK signaling, which was inhibited by adding erlotinib, even in the KRAS-mutant PDAC in vivo and in vitro. We observed that the gemcitabine-induced MAPK signaling activation was due to induction of EGFR ligands expression and also due to ERBB2 activation in PDAC cells. Erlotinib inhibited the ERBB2 activation, partly by inhibiting heterodimer formation with EGFR and also decreasing ERBB2 protein expression in PDAC cells. This mouse model appears recapitulating chemosensitivity of human PDAC and indicates the significance of ERBBs in PDAC treatment. This model also might provide important insights into the beneficial patient subpopulation and the mechanism of the action of drugs and chemoresistance, in which TGF-beta signaling might be highly involved.
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 851. doi:1538-7445.AM2012-851
Abstract 860: The multi-targeted kinase inhibitor Sunitinib induces apoptosis in colon cancer cells via PUMA
Authors: Sun Jing , Sun Quanhong , Brown Matthew F. , Dudgeon Crissy , Chandler Julie , Zhang Lin , Yu Jian 
Published: August 2012

Abstract
Key words: Sunitinib; PUMA; FoxO3a; Bcl-2 family; colon cancer Purpose: Sunitinib is a FDA approved multi-targeted receptor tyrosine kinase (RTK) inhibitor for treating solid tumors. Inhibition of angiogenesis, immune modulation and induction of apoptosis has been suggested to mediate the anti-tumor effects of sunitinib. However, its cell killing mechanisms are not well-understood. In this study, we investigated the mechanisms and significance of sunitinib-mediated apoptosis in its antitumor activities using colon cancer cells and xenografts. Experimental Design: The expression of various Bcl-2 family proteins, apoptosis and long-term growth in response to sunitinib were examined in colon cancer cells. The mechanism of PUMA induction and effects of PUMA deficiency, BH3 mimetics and 5-FU on sunitinib-induced apoptosis were investigated. The effects of PUMA deficiency in responses to sunitinib were determined in xenografts. Results: We found that consistent PUMA induction mediated by transcription factor FoxO3a plays an important role in the apoptosis induced by sunitinib. PUMA deficiency led to impaired apoptosis and caspase activation in colon cancer cells with either wildtype or mutant p53. Small molecule BH3 mimetics or elevated PUMA levels sensitized colon cancer cells to sunitinib-induced apoptosis. PUMA deficiency significantly blocked apoptosis and therapeutic responses to sunitinib in xenografts. Conclusions: Our results establish a critical role of PUMA in mediating sunitinib sensitivity in colon cancer cells and lack of apoptosis induction as a potential resistance mechanism. Our study suggests modulations of Bcl-2 family proteins as potential biomarkers, and combination of sunitinib with BH3 mimetics or chemotherapeutic agents might improve the treatment efficacy in colon cancer 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 860. doi:1538-7445.AM2012-860
Abstract 875: Marked in vivo efficacy of combined BCLXL and MEK inhibition in KRAS mutant cancers revealed by a pooled shRNA-drug screen for genes that are “synthetically lethal” with MEK inhibitors
Authors: Corcoran Ryan B. , Cheng Katherine A. , Wong Kwok-Kin , Engelman Jeffrey A. 
Published: August 2012

Abstract
Although KRAS is the most commonly mutated oncogene in human cancer, no effective therapies exist for KRAS mutant cancers. Attempts to target KRAS directly or to target single effector pathways downstream of KRAS have met limited success. Previously, our laboratory and others showed that simultaneous targeting of more than one KRAS effector pathway, specifically the MEK-ERK and PI3K-AKT pathways, can cause dramatic responses in KRAS-driven genetically-engineered mouse tumor models. These findings support the promise of targeted therapy combinations for KRAS mutant cancers and have led to clinical trials evaluating combined PI3K/MEK inhibition. We evaluated the efficacy of combined PI3K/MEK inhibition in a panel of 30 KRAS mutant cell lines. Roughly half of all cell lines showed limited sensitivity to this combination, suggesting that combined PI3K/MEK inhibition may only be effective in a subset of KRAS mutant cancers and underscoring the need for additional combination therapy strategies. To develop new targeted therapy combinations for KRAS mutant cancers, we designed a pooled shRNA-drug screen strategy aimed at rapidly identifying genes that, when inhibited, synergize with MEK inhibitors to decrease the viability of KRAS mutant cancer cells. Using this approach, we identified the anti-apoptotic protein BCLXL as a potential target for combination therapy with MEK inhibitors. When tested in vitro against a panel of 30 KRAS mutant cell lines, simultaneous pharmacologic inhibition of BCLXL (using the BH3 mimetic ABT-263) and MEK led to pronounced apoptosis and reduced viability in most cell lines, including many cell lines that were insensitive to combined PI3K/MEK inhibition. In vivo, the combination of ABT-263 and a MEK inhibitor led to marked tumor regressions in KRAS mutant xenograft models and to dramatic and sustained tumor regressions (&gt;70% reduction in tumor size) in a KRAS-driven genetically-engineered mouse model of lung cancer. These findings suggest that combined inhibition of BCLXL and MEK is a promising targeted therapy combination for potential evaluation in clinical trials for patients with KRAS mutant cancers.
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 875. doi:1538-7445.AM2012-875
Abstract 880: Inhibition of MMP14 potentiates the antiglioma effect of TMZ and ionizing radiation
Authors: Ulasov Ilya , Auffinger Brenda , Thaçi Bart , Pytel Peter , Kaverina Natalya , Liu Feifei , Ahmed Atique , Lesniak Maciej 
Published: August 2012

Abstract
Introduction. Glioblastoma multiforme (GBM) is the most common primary central nervous system tumor in adults. The median survival after surgical intervention alone is approximately 6 months and the addition of radiation and chemotherapy (like Temozolomide, TMZ) can only extend this up to 14.6 months. Other treatment options are therefore needed for better disease management and improved survival. We ran an Affymetrix analysis on the Rembrandt Database to determine the role of metalloproteinase expression in the biology of GBMs. High expression of MT1-MMP (MMP14) correlated with a poor patient survival. MMP14, as other metalloproteinases, is a cellular based proteolytic endopeptidase that plays a role in extracellular matrix (ECM) and basic membrane (BM) degradation. In glioma, expression of MMP14 is correlated with tumor invasiveness and associated with the CD133+ phenotype. Inhibition of MMP14 could therefore offer a potential target for the therapy of GBM. Experimental methods. Expression of MMP14 was determined in 100 primary and recurrent gliomas by immunohistochemistry. We performed quantitative RT-PCR and Western blotting analysis of MMP14 expression to investigate the effect of radiation and TMZ on U87 and U251 glioma cells. We used the Ingenuity Software to analyze the relationship between MMP14 and proteins responsible for angiogenesis and cell proliferation. Anti-angiogenic effect of MMP14 knockdown was determined by tube formation assay and angiogenic cytokine array (RayBio). Finally, treatment of MMP14 knockdown of glioma cells with temozolomide and ionizing radiation was analyzed by MTT assay. Results. Genetic silencing of MMP14 leads to inhibition of glioma cell proliferation and cell cycle arrest. We also show that silencing of MMP14 results in downregulation of angiogenic markers at the mRNA and protein level. Furthermore, we have found that inhibition of MMP14 expression in glioma cells improves the therapeutic effect of temozolomide and ionizing radiation. Conclusions. This study suggests that silencing of MMP14 via RNAi technology improves therapeutic effect of TMZ and ionizing radiation on glioma cell proliferation. Therefore, inhibition of MMP14 provides a new target for treatment of gliomas.
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 880. doi:1538-7445.AM2012-880
Abstract 883: Cell-based selection of RNA-aptamers to specifically target glioblastoma cancer stem cells
Authors: Quintavalle Cristina , Ricci-Vitiani Lucia , Esposito Carla Lucia , Martino Simona Di , Cerchia Laura , Maria Ruggero De , de Franciscis Vittorio , Condorelli Gerolama 
Published: August 2012

Abstract
Stem cells are a group of cells, which have two important fundamental properties: self-renewal and multipotency. Stem cells have been identified also in many human cancers on the basis of being both morphologically and functionally distinct from other cells within the heterogeneous tumor mass. According to “cancer stem cell hypothesis,” the cancer stem cells (CSC) would remain unaffected by conventional therapies, and capable of repopulating the tumor and giving rise to cancer recurrence. The possibility to identify highly selective biomarkers on CSC would greatly improve cancer diagnosis and treatment. Recently, nucleic acid-based aptamers have proven useful as reagents for identifying cell surface proteins and for cell typing. Further, their high specificity and low toxicity render them a valid alternative to antibodies for in vivo cell recognition. We have developed the SELEX technology on intact glioblastoma cancer stem cells to generate aptamers as biologically active high affinity ligands for CSC-specific cell surface proteins. The approach has been applied by utilizing glioblastoma differentiated tumor cells as a negative selection, and cancer stem cells obtained from two different patients, as positive selection. Upon 16 cycles of SELEX, we generated a set of 2′-fluoro-pyrimidines containing RNA aptamers that, based on sequence analysis, have been grouped into 5 main families. Best aptamers have been then selected by binding experiments for their ability to distinguish glioblastoma CSC from differentiated tumor cells. We thus determined the binding affinity of each molecule to the cell surface specific targets. Functional experiments will be as well presented to further insight the biological role of the most promising aptamer molecules in the acquisition and maintenance of stem cells properties of glioma cancer cells. Results demonstrate the possibility to generate RNA-based aptamers as potential innovative tools for the selective targeting of cancer stem cells. A proteomic approach will define the specific membrane targets of the selected aptamers
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 883. doi:1538-7445.AM2012-883
Abstract 887: Development of a robust nanoimmunoassay and immunohistochemical assay for asparagine synthetase
Authors: Lorenzi Philip L. , Heathcock Lindsey E. , Aldape Kenneth , Weinstein John N. 
Published: August 2012

Abstract
The enzyme-drug L-asparaginase (L-ASP) has been used for four decades to treat acute lymphoblastic leukemia. However, its unique mechanism of action is still poorly understood, and its clinical efficacy has proven unpredictable. Those problems have prompted a continuing search for biomarkers that predict L-ASP response. We previously found that the expression of asparagine synthetase (ASNS) is strongly negatively correlated with L-ASP anticancer activity in ovarian cancer cell lines, suggesting that L-ASP might be effective against a low-ASNS subset of ovarian cancers if salient characteristics of the cell lines reflect clinical ovarian tumors. However, quantitatively robust, single-antibody assays for ASNS expression have been absent from the literature. We therefore used a capillary-based isoelectric focusing (IEF) platform (the NanoPro 1000) to screen twelve ASNS antibodies for their specificity and sensitivity. Only two antibodies exhibited completely on-target activity (as shown by signal ablation by ASNS siRNA) and sufficient sensitivity. The on-target activity corresponded to a single band on Western Blot and a single peak on the NanoPro 1000, suggesting the existence of just one ASNS protein isoform. Optimized, final NanoPro assay conditions yielded less than 8% CV, a 160-fold dynamic range, and Zα-factor of 0.82, indicating a robust assay that is amenable to high-throughput screening. We next used the best ASNS antibody to develop an immunohistochemistry (IHC) assay for ASNS. As with the NanoPro assay, optimized IHC conditions yielded a large dynamic range of staining intensity, and staining was completely ablated by ASNS siRNA. To test the hypothesis that subsets of various cancers express very low levels of ASNS, we have initiated ASNS IHC of more than 20 tissue arrays representing a wide variety of cancers. Using a 3-point scoring system (0 = negative, 1 = low, 2 = high), preliminary results indicate that 90/136 (66%) of bladder cancers, 29/60 (48%) of bone cancers, 16/76 (21%) of breast cancers, 29/115 (25%) of brain cancers, 51/168 (30%) of colon cancers, and 7/64 (11%) of head and neck cancers are ASNS-negative (score = 0), suggesting that a subset of each cancer type might be sensitive to the drug L-asparaginase. Efforts are underway to apply the NanoPro assay to the NCI-60 cell line panel and to continue performing ASNS IHC to survey tissue arrays for ASNS expression.
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 887. doi:1538-7445.AM2012-887