bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1560: VE-PTP inhibitor AKB-9778 mitigates IL-2-induced VLS and interacts positively with IL-2 against melanoma and renal cancer tumors in mice
Authors: Cao Mingli , Lindner Dan , Borden Ernest , Shalwitz Robert , Yi Taolin 
Published: February 2011

Abstract
IL-2 induces complete responses (CR) durable more than 10 years in a subpopulation of patients with advanced melanoma or renal cell carcinoma, establishing the clinical effectiveness of immunotherapy for human malignancies. However, the application and clinical efficacy of IL-2 have been limited by its major dose-limiting toxicity vascular leak syndrome (VLS), which occurs in the majority (∼65%) of the patients and often necessitates cessation of the cytokine treatment. Being a life-threatening toxicity, VLS is managed by supportive care with no specific treatment. Therapeutics for IL-2-induced VLS might improve the efficacy and tolerance of the cytokine.
Recent studies implicated heightened Ang2 as a potential mediator of VLS via antagonizing Ang1 and thus blocking Tie2/AKT signaling in endothelial cells. Being a regulator of Tie2 phosphorylation, vascular endothelial protein tyrosine phosphatase (VE-PTP) might be targeted to modulate Tie2/AKT signaling although tthe effects and tolerance of targeting VE-PTP were not well-defined.
Our work herein identified compound AKB-9778 as a VE-PTP inhibitor capable of inducing pTie2 and down stream pAKT in endothelial cells, interacting positively with Ang1 and/or Ang2 to increase cellular pTie2 levels, reducing IL-2-induced circulating Ang2 in mice and protecting mice from IL-2-induced VLS. AKB-9778 also interacted positively with IL-2 against B16 melanoma and Renca renal cancer tumors in mice in a tolerated manner. These data provide pre-clinical proof of concept evidence of targeting VE-PTP to mitigate IL-2-induced VLS. AKB-9778 may provide beneficial adjunctive therapy in combination with IL-2 in cancer treatment by reducing VLS and enhancing efficacy.
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 1560.
Abstract 1568: GLPG0187, a small molecule integrin antagonist, shows good safety and decrease in CTX levels in single ascending dose study
Authors: Lorenzon Giocondo , Gheyle Lien , Vets Eva , Namour Florence , Pujuguet Philippe , Clement-Lacroix Philippe , Wigerinck Piet , Vanhoutte Frederic 
Published: February 2011

Abstract
Introduction :
GLPG0187, a small molecule integrin antagonist with nanomolar affinity for the RGD-integrin receptors αvβ1, αvβ3, αvβ5, αvβ6 and α5β1, shows potent anti-angiogenic, anti-metastatic, anti-bone-resorption and anti-tumor activity in vitro and in vivo. Therefore GLPG0187 may offer a promising therapeutic approach for the treatment of integrin receptor expressing tumors and/or metastases.
Methods:
Based on promising preclinical data, a first-in-human study was performed with GLPG0187 to assess the safety and tolerability as well as pharmacokinetic and pharmacodynamic behavior of single ascending doses of the compound. GLPG0187 was administered subcutaneously in a dose range of 17.5 to 315 mg and orally in a dose range of 50 to 1200 mg.
Results:
GLPG0187 was systemically well tolerated with no adverse effects on ECG, vital signs or laboratory parameters. GLPG0187 showed a dose proportional pharmacokinetic profile over the dose range tested. Moreover, GLPG0187 dose proportionally decreased osteoclast activity as measured by plasma CTX (carboxy-terminal collagen crosslinks) levels.
Conclusions:
GLPG0187 was shown to be safe and well tolerated, to have a dose proportional pharmacokinetics and to inhibit osteoclast activity. These results provide further evidence that GLPG0187 could be an effective therapeutic for the treatment of cancer.
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 1568.
Abstract 1569: Antitumor activity of SR16388 against human multiple myeloma in vitro and in vivo
Authors: Chao Wan-Ru , Shi Yihui , Dinh Dominic , Hou Carol , Sambucetti Lidia 
Published: February 2011

Abstract
Multiple myeloma (MM) is the cancer of plasma cells that derive from a clonal disorder of terminally differentiated B cells in the bone marrow. MM is generally thought to be refractory against chemotherapeutics and is incurable. Development of novel agents for the treatment of this disease is urgently needed. Previous studies have indicated that MM cells express estrogen receptors (ERs), and anti-estrogens such as ICI 182,780 and Tamoxifen have demonstrated inhibitory effects on proliferation of MM cell lines as well as on MM cells isolated from patients. MM cells also over-express proangiogenic factors such as VEGF to induce angiogenesis and support their growth and survival. At SRI International, we have developed a steroidal anti-angiogenic molecule (SR16388) that potently inhibits angiogenesis in lung and prostate cancers, and it also binds to ER-α and ER-ß with high affinities in the nanomolar range. In this study, we examined the in vitro and in vivo effects of SR16388 on growth of MM cells. In RPMI-8226 multiple myeloma cells, SR16388 inhibited cell proliferation with an IC50 value of 0.9 µM. Cell cycle analysis revealed that SR16388 arrested the RPMI-8226 cells in G2 phase. In an in vivo murine xenograft model, SR16388 significantly inhibited the growth of RPMI-8226 tumors at the dose levels of 50 and 100 mg/kg with P &lt; 0.05 and P &lt; 0.02 respectively in a dose dependent manner. We are currently examining the molecular effects of SR16388 that contribute to its anti-proliferative and anti-angiogenic effects on MM and other human tumor types. Based on our in vitro and in vivo data, we believe that SR16388 is a promising new therapeutic molecule for the treatment of MM.
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 1569.
Abstract 1570: Silibinin inhibits invasive properties of human breast cancer cell line MDA-MB-231 through suppression of cathepsin B and extracellular signal-regulated kinase-mediated induction of matrix metalloproteinase 2 and 9
Authors: Nejati Mohammad R. , Momeny Majid , Ghaffari Seyed H. , Mojarrad Majid , Emami Amir H. 
Published: February 2011

Abstract
The purpose of the current study is to evaluate the effects of silibinin on human breast adenocarcinoma MDA-MB-231 cells. BrdU cell proliferation assay, Cell-based extracellular signal-regulated kinase (ERK) 1/2 activation assay, cathepsin B activity assay, Gelatin zymography and quantitative real-time RT-PCR were employed to appraise the effects of silibinin on DNA synthesis, ERK 1/2 phosphorylation, cathepsin B activity and gelatinolytic activity in MDA-MB-231 cells. Silibinin inhibited cell proliferation, ERK 1/2 activation, cathepsin B enzymatic levels and gelatinase activity in a dose-dependent manner. In addition, an expressive decrease in mRNA levels of cathepsin B, hyaluronidase-2 (Hyal-2), urokinase plasminogen activator receptor (uPAR), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) coupled with a significant induction in transcriptional levels of tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), Stefin A and Lipocalin 2 were observed. Altogether, these issues show for the first time that silibinin treatment could trammel cell growth and invasive features of a highly invasive human breast cancer cell line, MDA-MB-231, through suppression of ERK 1/2 both directly (through impeding ERK 1/2 phosphorylation) and indirectly (via transcriptional enhancement of Lipocalin 2). Furthermore, cramping enzymatic activity of cathepsin B by silibinin might cripple activation of gelatinases and thereby, reduces invasive potential in MDA-MB-231 cells.
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 1570.
Abstract 1572: The role of MIF signaling in melanoma progression
Authors: Oliveira Camila S. , Yan Xu Guang , Hersey Peter , Zhang Xu Dong , Thorne Rick F. 
Published: February 2011

Abstract
Melanoma is the most life-threatening form of skin cancer and although highly curable at the early stages, metastatic melanoma is incurable. One of the early events in melanoma progression is the activation of ERK and Akt signalling pathways, involved in proliferation, migration and survival. The causes of such kinase activation include mutations in BRAF, N-RAS and PTEN. Besides gene mutation, it has been shown that autocrine production of growth factors can also contribute to ERK and Akt activation in melanoma. As both pathways are believed to contribute to the chemotherapeutic resistance of melanoma cells, an effective treatment should target both ERK and Akt cascades. One potentially attractive target is the cytokine MIF (migration inhibition factor), since MIF can activate both the ERK and the Akt pathways. Targeting of MIF signalling in tumours producing autocrine MIF is already showing promise in prostate, breast and bladder cancers and although limited, some in vitro evidence suggests that MIF is an autocrine factor involved in the growth and invasion of melanoma cells. We have now extended these findings in an immunohistological study showing the universal in vivo expression of MIF in melanoma with increasing expression levels associated with metastatic tumours. MIF signalling can act through both CXCR4 and CD74/CD44 receptors, the latter molecule acting as a co-receptor. Examination of a panel of 20 melanoma cell lines showed 20/20 to express MIF and CD44 with 7/20 also co-expressing CD74. Only 6/20 cell lines showed heterogenous expression of CXCR4. Inhibition of MIF expression using siRNA-mediated gene knockdown decreased the proliferation and cell migration in a number of melanoma cell lines, an effect attributed to effects on cell cycle with a reduction of the number of cells entering S phase. Conversely, addition of exogenous MIF was shown to increase ERK phosphorylation. Taken together, these results suggest a role for MIF in melanoma progression. Future work will aim to determining the molecular nature of the receptors driving MIF signalling in melanoma.
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 1572.
Abstract 1576: Molecular targeting of histone deacetylase 2 for treatment of human hepatocellular carcinoma
Authors: Lee Yun-Han , Andersen Jesper B. , Judge Adam D. , Seo Daekwan , Marquardt Jens U. , Ishikawa Tsuyoshi , Avital Itzhak , Conner Elizabeth A. , MacLachlan Ian , Factor Valentina M. , Thorgeirsson Snorri S. 
Published: February 2011

Abstract
Development of targeted therapeutics for hepatocellular carcinoma (HCC) remains a major challenge. We have recently identified an elevated expression of histone deacetylase 2 (HDAC2) in primary human hepatocellular carcinoma (HCC) and HCC derived cell lines. In this study, we have tested if the downregulation of HDAC2 by siRNA can affect the course of HCC progression in vitro and in vivo. To inactivate HDAC2 gene expression, three HDAC2-specific siRNAs (HDAC2-1, HDAC2-2 and HDAC2-3) were designed and tested for growth inhibition in Huh7 and HepG2 HCC cell lines as determined by MTT assay, FACS analysis and microscopy. To obtain insights into molecular changes caused by HDAC2 silencing, global changes in gene expression were examined by illumina microarray. For in vivo evaluation of HDAC2 as a therapeutic target, we employed orthotopic xenograft model using luciferase-expressing HCC reporter cell line Huh7-luc+ and stable-nucleic-acid-lipid-particle (SNALP) as an optimal carrier of siRNA into liver.
The HDAC2-1siRNA was the most effective in inhibiting Huh7 and HepG2 cell growth (68% and 71%, respectively) which was paralleled by a similar decrease in the levels of target mRNA and protein. HDAC2-deficient cells also exhibited a 1.9-fold increase in apoptosis through activation of caspase-3. The comparison of gene expression profiles in HepG2 cells treated with either control siRNA or HDAC2-1siRNA identified 299 differentially expressed genes. Consistent with in vitro observations, genes functionally involved in apoptosis, such as CDKN1A, SOCS2, TP53I3, and BTG2, were up-regulated while genes associated with cellular metabolic process (e.g. HOXD1, PAK2, SMAD9, CDK4, PCK2 and SKP2) were down-regulated. HDAC2 3/7siRNA, a chemically modified variant of HDAC2-1siRNA displaying a minimal induction of IL-6 in murine Flt3L dendricite cultures, was selected for in vivo treatment of Huh7-luc+-derived HCC. Administration of SNALP- HDAC2 3/7siRNA effectively suppressed xenograft growth as compared to the SNALP-control siRNA treatment. Taken together, these results indicate that HDAC2 is an important regulator of HCC cell growth and survival, and may be an attractive target for systemic therapy of HCC.
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 1576.
Abstract 1613: BTK as a drug target for cancers that harbor inactivating mutations in the DPC4 gene
Authors: Diep Caroline H. , Kassner Michelle , Zhao Yu , Yin Holly , Von Hoff Daniel D. , Han Haiyong 
Published: February 2011

Abstract
The Deleted in Pancreatic Cancer locus 4 (DPC4) is a tumor suppressor gene that is often inactivated in pancreatic and colorectal cancers. In pancreatic adenocarcinomas, the frequency of inactivation of DPC4 is approximately 55%, while in colorectal carcinomas has been reported to be 10% to 35%. The loss of DPC4 has been shown to be associated with the progression and malignancy of pancreatic cancer along with decreased patient survival. We employed a small interfering (siRNA) library based screening strategy to identify potential synthetic lethal partners of the DPC4 gene. We used a kinase focused siRNA library that consisted of two siRNA oligonucleotides for each of the 624 protein kinase genes. A DPC4 isogenic pair, BxPC3-Vector and BxPC3-DPC4 (Wang et al. 2006) were treated by the siRNA oligonucleotides in parallel and the effects of the siRNA oligonucleotides on the growth of the cell lines were then compared. siRNA oligonucleotides that selectively inhibited the cell growth of the BxPC3-Vector cell line were selected as potential positive hits. These genes, once validated, represented potential drug targets that are very specific to cancer cells harboring mutations in the DPC4 gene. One of the top-ranked hits we identified from this screening is the Bruton agammaglobulinemia tyrosine kinase (BTK). With BTK siRNA treatment, BxPC3-Vector cells, which are DPC4 null, showed ∼30% more cell growth inhibition than the BxPC3-DPC4 cells, which are DPC4 wildtype. This selectivity of BTK siRNA against DPC4 null cells was further confirmed in a confirmation screen using two pancreatic cancer cell lines, BxPC3 and PANC-1, which are DPC4 null and DPC4 wildtype, respectively. BTK siRNA also showed significant selectivity against DPC4 deficiency in another pair of DPC4 isogenic colon cancer cell lines, HCT-116 and HCT-116-DPC4-knockout. To validate the BTK siRNA selectivity findings, we evaluated the BTK inhibitor PCI-32765 in our cancer cell line models and observed the same selectively against DPC4 null pancreatic and colon cancer cell lines. These results indicate that BTK is a potential molecular target for pancreas, colon, and other cancers harboring inactivating mutations in the DPC4 gene. (The work was supported by a NCI grant P01CA109552.)
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 1613.
Abstract 1614: Guanylyl cyclase C signaling through vasodilator-stimulated phosphoprotein in lost in colon cancer
Authors: Pelta-Heller Josh , Zuzga David S. , Waldman Scott A. , Pitari Giovanni M. 
Published: February 2011

Abstract
The biochemical pathway(s) induced by guanylyl cyclase C (GCC) regulates the intestinal crypt-villus axis by modulating proliferation, maturation and metabolic programming. During colorectal tumorigenesis, GCC signaling through cGMP becomes dysregulated as a consequence of the reduced expression of GCC endogenous hormones guanylin and uroguanylin. However, the significance of the loss of ligand-dependent signaling by GCC for the human disease remains unclear. Here, immunohistochemical examination of tumor specimens from patients compared to respective normal adjacent tissues revealed that the GCC signaling through vasodilator-stimulated phosphoprotein (VASP), a key regulator of actin polymerization and morphogenetic dynamics, is lost in colon cancer. Interruption of GCC signaling through VASP resulted in tumor depletion of the cGMP-dependent VASP phosphorylation species, and presumably reflected complex alterations of the normal initiation and propagation of the ligand-induced GCC signal. In vitro reconstitution of the ligand-dependent GCC signal through VASP induced a functional remodeling of human cancer cells which assumed a rounded, lamellipodia-free morphology with reduced proliferative and invasive abilities. Importantly, GCC ligand therapy in vivo restored the cGMP-dependent VASP phosphorylation circuit in intestinal tumors of APCmin/+ mice. These findings offer a previously undescribed tumor suppressor mechanism, cGMP-dependent VASP phosphorylation, with high translational potential for the diagnosis and therapy of colon cancer. Reactivation of cGMP signaling through VASP by GCC hormone replacement therapy may represent an innovative paradigm for the treatment of colorectal cancer in patients.
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 1614.
Abstract 1616: The anti-tumor effect of TAE226, dual inhibitor of FAK and IGF-IR, on non-small-cell lung cancer with EGFR mutation
Authors: Otani Hiroki , Toyooka Shinichi , Takaoka Munenori , Sakaguchi Masakiyo , Ueno Tsuyoshi , Yamamoto Hiromasa , Soh Junichi , Kubo Takafumi , Asano Hiroaki , Tsukuda Kazunori , Yamane Masaomi , Oto Takahiro , Kiura Katsuyuki , Huh Nam-ho , Naomoto Yoshio , Miyoshi Shinichiro 
Published: February 2011

Abstract
Background: TAE226 is the small molecule inhibitor that has been originally considered to inhibit focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). FAK and IGF-IR have been reported to be up-regulated in non-small cell lung cancer (NSCLC), suggesting their important roles on pathogenesis of NSCLC. In this study, we examined the anti-tumor effect of TAE226 on NSCLC cells in vitro and in vivo. Methods: We used NSCLC cell lines consisting of 4 EGFR-mutant cell lines (PC9, H3255, HCC827, H1975) and 3 EGFR-wild type cell lines (H1819, H1299, A549). We also used PC9-derived gefitinib-resistant cell line (RPC9). Anti-proliferative effect of TAE226 was examined with MTS assay. The status of EGFR and its downstream molecules was analyzed by Western blotting. The binding affinity of TAE226 to EGFR protein in the presence of ATP was compared between mutant and wild type EGFR proteins. The effect of TAE226 on xenograft mouse models was examined. Results: The value of IC50 (µmol/L) for EGFR-mutant cells (PC-9, H3255, HCC827, H1975 [T790M], and RPC-9 [T790M]) ranged from 0.086 to 0.31 and that of EGFR wild type cells (H1819, H1299, and A549) ranged from 1.4 to 4.7, indicating that EGFR-mutant cells are sensitive to TAE226. Western blotting assay showed that TAE226 preferentially inhibited phospho-EGFR and phospho-AKT. The binding affinity of TAE226 to mutant EGFR protein was 1000 times higher compared with wild-type EGFR protein. TAE226 via oral administration with dose of 30 mg/kg and 60 mg/kg exhibited significant inhibition of tumor growth in EGFR-mutant tumors compared with EGFR-wild type tumors without major toxicity or weight loss. These results suggested that safety of TAE226 within the treatment dose for EGFR-mutant cells in vivo. Conclusions: We indicated that TAE226 showed anti-tumor effect on EGFR-mutant cells and overcame resistance to gefitinib. Our results suggest that TAE226 will be expected as a novel strategy for NSCLC with EGFR mutation regardless of the presence of secondary T790M mutation.
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 1616.
Abstract 1623: The nucleotide metabolizing enzyme dUTPase confers resistance to thymidylate synthase inhibition in non-small cell lung cancer cells
Authors: Wilson Peter M. , LaBonte Melissa J. , Ladner Robert D. 
Published: February 2011

Abstract
Chemotherapeutic agents which target the enzyme thymidylate synthase (TS) have demonstrated efficacy and seen wide-spread clinical implementation in a variety of tumor types for many decades. However, despite significant research efforts to date, little is known about the molecular pathways that regulate clinical response and resistance to TS-inhibiting agents including the fluoropyrimidines. Lung cancer is the major cause of cancer-related deaths worldwide and non-small cell lung cancer (NSCLC) is the most frequent sub-type. Several chemotherapeutic agents that target TS are currently employed in NSCLC treatment including capecitabine, S-1 and pemetrexed. Increased expression of TS is associated with resistance to TS-directed agents in a variety of tumor types including NSCLC. In this study, we analyzed the response of 4 NSCLC cell lines to TS-inhibition. All NSCLC cell lines analyzed demonstrated marked resistance to fluoropyrimidine treatment in the MTS growth inhibition assay despite the presence of TS-inhibited ternary complex. Subsequent analysis revealed that TS gene promoter activity, mRNA and protein expression is induced in NSCLC cell lines exposed to clinically relevant concentrations of 5-FU, FUdR and pemetrexed providing a rational explanation for the resistant phenotype. However, depletion of TS by RNA interference (RNAi) had no sensitizing effects to treatment with the specific TS inhibitor FUdR, suggesting that the induction of TS is not the major determinant of resistance. Conversely, depletion of the nucleotide metabolizing enzyme dUTPase by RNAi completely reversed resistance to FUdR in the MTS assay and potently inhibited colony formation in all 4 NSCLC cell lines analyzed. dUTPase depletion in combination with FUdR treatment was associated with increases in cytotoxic dUTP pools, DNA damage and apoptotic cell death. The results of this study indicate that depletion of dUTPase can rapidly sensitize NSCLC cells to otherwise non-lethal doses of a TS inhibitor. The clinical utility of a dUTPase inhibitor may have the potential to significantly increase antitumor activity in NSCLC patients treated with TS-directed agents.
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 1623.