bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1723: Can histologic patterns of pulmonary adenocarcinoma reflect histologic grade, one of the most important factors of cancer prognosis?
Authors: Hwang Ilseon , Park Keon Uk , Kim Jin Young , Ha Eunyoung
Published: August 2012

Background: Pulmonary adenocarcinoma shows highly heterogeneous histologic pattern. Histologic pattern is suggested to be an important prognostic factor, therefore predominant histologic pattern is emphasized in 2010 IASLC/ATS/ERS classification of pulmonary adenocarcinoma. However, there are a few papers on the prognosis of pulmonary adenocarcinoma according to histologic patterns, especially in various stages. The aim of this study is to evaluate prognosis according to histologic patterns in pulmonary adenocarcinoma with various stages. Methods: We examined 125 cases of surgically resected pulmonary adenocarcinomas with various stages from January 1998 to December 2007. Invasive adenocarcinomas were classified into histologic subtypes which are lepidic, papillary, acinar, solid and micropapillary patterns by 2010 IASLC/ATS/ERS classification. Invasive adenocarcinoma was divided into 2010 classification (I), predominant and second predominant pattern (II), predominant and the worst pattern (III), and modified predominant pattern (IV). Results: Proportions of predominant lepidic, papillary, acinar, solid and micropapillary patterns were 11 (9.3%), 8 (6.8%), 54 (45.8%), 38 (32.2%) and 7 (5.9%), respectively. All histologic classification systems were not correlated with clinical manifestations including age, tumor size, T stage, N stage or recurrence. However, all histologic classification systems were significantly correlated with overall survival rates (p=0.010, 0.044, 0.001, and 0.013) by Kaplan-Meier survival test. In Cox proportional hazard model, histologic pattern was independent factor of prognosis on classification according to I, III, IV (p=0.017, 0.006 and 0.023). Conclusion: Histologic pattern is an independent prognostic factor in pulmonary adenocarcinoma with various stages and histologic patterns of pulmonary adenocarcinoma reflect the degree of histologic differentiation, one of the most important prognostic factor.

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 1723. doi:1538-7445.AM2012-1723
Abstract 173: Targeting the MUC1-C oncoprotein blocks activation of FLT-3/ITD and induces death of acute myeloid leukemia cells
Authors: Liu Suiyang , Kharbanda Surender , Kufe Donald , Stone Richard
Published: August 2012

Acute myeloid leukemia (AML) is an intrinsically resistant disease especially in the 30 % of patients whose blasts have a FLT3-ITD mutation (constitutively activated transmembrane tyrosine kinase due to insertion of between 3 and 300 base pairs in the juxta-membrane coding region). The MUC1 oncoprotein is aberrantly expressed in AML cells; however, there has been no evidence for involvement of MUC1 in FLT3-ITD signaling. We show that the FLT3-ITD associates with the MUC1 oncoprotein thereby leading to a new therapeutic target. We have synthesized MUC1-C peptide inhibitors that penetrate cells and bind to the MUC1-C cytoplasmic domain blocking its oncogenic function. In the present study, we demonstrate that MUC1-C peptide inhibitor treatment of the FLT3-ITD positive human MOLM-14, MV4-11 AML cell lines, and primary blasts from patients with AML, leads to growth arrest and induction of late apoptosis/necrosis. MUC1-C inhibitor-induced cell death of these cells is associated with significant downregulation of phospho-FLT3-ITD, indicating that inhibition of MUC1-C blocks FLT3-ITD activation. Taken together, these findings provide support for the evaluation of the MUC1-C inhibitor, GO-203-2C (an agent now undergoing Phase I evaluation in solid tumors), in the treatment of patients with AML harboring the FLT3-ITD activating mutation.

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 173. doi:1538-7445.AM2012-173
Abstract 1734: Prognostic significance of combinations of RNA-dependent protein kinase and EphA2 biomarkers for NSCLC
Authors: Guo Chengcheng , Shao Ruping , Correa Arlene M. , Behrens Carmen , Fang Bingliang , Roth Jack A. , Wistuba Ignacio I. , Swisher Stephen G. , Lin Tongyu , Pataer Apar
Published: August 2012

RNA-dependent protein kinase (PKR) is an independent prognostic variable in patients with non-small cell lung cancer (NSCLC). In the present study, we investigated the correlation between PKR and 25 other biomarkers for NSCLC, identified the markers that could further improve the prognostic significance of PKR, and elucidated the mechanisms of interaction between these markers and PKR. Tissue microarray samples obtained from 218 lung cancer patients were stained with an anti-PKR antibody and antibodies against 25 biomarkers. Immunohistochemical expression was scored and used for Kaplan-Meier survival analysis. The interaction between PKR and EphA2 in NSCLC cell lines was examined. We found that PKR was associated with EphA2 and that the prognostic information regarding NSCLC provided by the combination of PKR and EphA2 (P/E) was significantly more accurate than that provided by either marker alone. The 5-year overall survival rate in PKRlow/EphA2high patients (20%) was significantly lower than that of PKRhigh/EphA2low patients (74%), PKRhigh/EphA2high patients (55%), and PKRlow/EphA2low patients (55%) (P < 0.0001). We also found that the PKR:EphA2 (P/E) ratio was significantly associated with prognosis (P < 0.0001). Univariate and multivariate Cox analyses revealed that this P/E combination or ratio was an independent predictor of overall survival. In addition, induction of PKR expression reduced EphA2 protein expression levels in NSCLC cell lines. PKR/EphA2 is a significant predictor of prognosis for NSCLC. PKR/EphA2 may be a promising approach to improving screening efficiency and predicting prognosis in NSCLC 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 1734. doi:1538-7445.AM2012-1734
Abstract 1740: Inverse association of depletion of interferon-induced protein with tetratricopeptide repeats 2 with increased distant metastasis in patients with oral squamous cell carcinoma
Authors: Lai Kuo-chu , Liu Chung-Ji , Chang Kuo-Wei , Lee Te-Chang
Published: August 2012

Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2), one of most responsive interferon-stimulated genes, is inversely associated with prognosis of patients with oral cancer. In the present study, we further demonstrated that IFIT2 mRNA and protein expression was positively associated with E-cadherin expression in tissue specimens of oral squamous carcinoma cancer (OSCC). Loss of E-cadherin and IFIT2 was observed at the invasive front, suggesting that loss of IFIT2 may induce EMT and lead to metastasis in OSCCs. Accordingly, we found that OSCC patients with lower IFIT2 (IFIT2 < 50%) levels had higher distant metastatic rates and poorer prognoses compared to OSCC patients expressing higher levels of IFIT2 (IFIT2 ≤ 50%). In stable IFIT2-depleted OSCC cells, we observed epithelial-mesenchymal transition (EMT) and found enhanced cell motility and invasiveness when compared to control cells. Furthermore, our results indicated that atypical protein kinase C (aPKC) signaling was activated in IFIT2-depleted cells. Inhibition of aPKC by a specific myristoylated PKC∈ pseudosubstrate or aPKC siRNA abolished IFIT2 depletion-induced EMT, migration, and invasion, indicating that activation of aPKC signaling plays an essential role in the cellular activities induced by IFIT2 depletion. Our study demonstrates that IFIT2 depletion activates the aPKC pathway and hence induces EMT, cell migration, invasion and metastasis. Taken together, IFIT2, a protein responsible for interferon stimulation, may prevent OSCC from metastasizing and may serve as a prognostic marker.

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 1740. doi:1538-7445.AM2012-1740
Abstract 1757: Elesclomol (STA-4783) is a potent inhibitor of topoisomerase II
Authors: Wu Xing , Yalowich Jack C. , Hasinoff Brian B.
Published: August 2012

Elesclomol (STA-4783; N’1, N’3-dimethyl-N’1, N’3- bis(phenylcarbonothioyl)propanedihydrazide) is an anticancer drug that has received both fast track and orphan drug status from the FDA and is currently undergoing clinical trials. Elesclomol forms a strong 1:1 complex with copper(II) and may exert its anticancer activity through the induction of oxidative stress. In the studies reported here elesclomol was assessed for its ability to inhibit: 1) the growth of the human erythroleukemic K562 cell line and an etoposide-resistant K/VP.5 cell line; 2) the decatenation activity of DNA topoisomerase IIα; and 3) the relaxation activity of DNA topoisomerase I. Elesclomol was also evaluated for its ability to induce topoisomerase IIα-mediated double strand cleavage of pBR322 DNA and to form topoisomerase IIα-DNA covalent adducts in the cell-based ICE assay. Elesclomol inhibited K562 cell growth in the submicromolar concentration range. However, K/VP.5 cells were not cross-resistant. Elesclomol also strongly inhibited the decatenation activity of topoisomerase IIα in the low micromolar concentration range. Elesclomol may also act as topoisomerase IIα poison because it induced formation of linear DNA, though not as strongly as etoposide. In conclusion, these results show that elesclomol may, in part, inhibit cell growth through the targeting of topoisomerase II. Support: CIHR, a Canada Research Chair in Drug Development to B.B.H., a National Institutes of Health grant CA090787 to J.C.Y.

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 1757. doi:1538-7445.AM2012-1757
Abstract 1759: Novel naphthalimide analogs elicit their anti-tumor activity through a dual inhibition of topoisomerase II and Akt signaling pathway
Authors: Gowda A.S. Prakasha , Sk Ugir Hossain , Spratt Thomas E. , Amin Shantu , Sharma Arun K.
Published: August 2012

Naphthalimide derivatives such as mitonafide, a topoisomerase II inhibitor, have shown antitumor activity both in preclinical studies and in phase I and phase II clinical trials. However, it suffers from severe toxicity issues, especially central nervous system (CNS) toxicity. We have recently reported promising naphthalimide analogs designed by incorporating functional groups such as a isothiocyanate (ITC) group which is present in chemicals found in cruciferous vegetables, in place of N, N-dimethyl group in mitonafide. Some of these agents effectively induced apoptosis in melanoma cells and inhibited cell proliferation, and inhibited melanoma tumor growth by ∼60% without any apparent systemic toxicity issues. The ITC group was incorporated in the structure in an attempt to lower the toxicity associated with mitonafide and also because this functionality has been shown to block PI3K/Akt pathway which is activated in majority of cancer types; Akt3 is activated in 70% of sporadic melanomas. The idea was to generate a compound capable of inhibiting not only topoisomerase II similar to mitonafide but also PI3K kinase. In order to evaluate the underlying mechanism of action, we first evaluated topoisomerase-II inhibitory activity of agents relative to mitonafide to check if the new agents retained this property. Relaxation activity of DNA topoisomerase II was determined by measuring the conversion of supercoiled pBR322 plasmid DNA to its relaxed form. Our results indicate that the ITC analogs, NNITC-2 and NITC-6, exhibited significant inhibition for DNA-topoisomerase II similar to mitonafide. Interestingly, corresponding isoselenocyanate (ISC) analog NISC-6 was less effective compared to NITC-6 as a topoisomerase II inhibitor; NNISC-2 on the other hand was equally good as NNITC-2. Furthermore, to test our hypothesis that the addition of ITC group into the structure would make it capable of inhibiting PI3K/Akt pathway, we examined the ability of naphthalimide derivatives to inhibit the total cellular content of human Akt pathway proteins, by Western blot analysis using polyclonal antibodies, in human melanoma cancer cells (UACC903). UACC903 cells treated with ITC derivatives at 0.5, 1 and 5 μM, showed a rapid decrease in Akt pathway proteins level in a dose-dependent manner. In comparison, ISC analogs were less effective. Detailed results of these investigations will be presented.

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 1759. doi:1538-7445.AM2012-1759
Abstract 1775: Characterization of new highly selective and potent PARP-1 inhibitors
Authors: Montagnoli Alessia , Papeo Gianluca , Rainoldi Sonia , Ciavolella Antonella , Sola Francesco , Lupi Rosita , Ciomei Marina , Cirla Alessandra , Scolaro Alessandra , Posteri Helena , Donati Daniele , Felder Eduard , Isacchi Antonella , Pesenti Enrico , Galvani Arturo
Published: August 2012

Poly (ADP-ribose) polymerase 1 (PARP-1) is a key nuclear enzyme that is activated by DNA-strand breaks; activation of PARP-1 protects DNA breaks and chromatin structure and recruits DNA repair and checkpoint proteins to the sites of damage, by modification with poly(ADP-ribose) (PAR) polymers. PARP-2, another nuclear member of the PARP family with largely unknown functions, shares homology with PARP-1 and is also activated by DNA breaks. Embryonic knock out of either PARP-1 or PARP-2 is well tolerated; however, double knockout is embryonic lethal suggesting that inhibiting both PARPs could enhance toxicity. PARP inhibitors in clinical development generally inhibit more than one PARP isoforms. These compounds are synthetic lethal with defects in homologous recombination (HR), and are currently being tested in combination as well as in monotherapy for hereditable cancers deficient in the BRCA1 or BRCA2 genes. Here we describe the in vitro and in vivo properties of a novel class of potent and selective PARP-1 small molecule inhibitors. Starting from a series of derivatives that were found to be active against PARP-1 and PARP-2, an expansion and optimization program was undertaken. This led to the identification of inhibitors with single digit nM affinity for PARP-1 and negligible crossreactivity against PARP-2. Members of this sub-series display single agent cytotoxicity with IC50s below 1 μM in cell lines harboring BRCA mutations, or in cells stably transfected with BRCA-1 short harpin RNA, and more than 100 times selectivity against BRCA wild-type tumor cell lines. Furthermore, these compounds are highly active in other repair deficient backgrounds such as ATM and Mre11 mutated acute leukemias and lymphomas and they compared favorably with reference PARP inhibitors which are in clinical development. Expected mechanism of action was confirmed by observed modulation of PAR induction, in vitro and in vivo. These compounds show high oral bioavailability, good ADME properties and high tolerability. Selection of the candidate most suitable for further development is underway.

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 1775. doi:1538-7445.AM2012-1775
Abstract 179: MicroRNA-29c functions as a tumor suppressor by direct targeting endogenous SIRT1 in hepatocarcinogenesis
Authors: Bae Hyun Jin , Noh Ji Heon , Kim Jeong Kyu , Eun Jung Woo , Jung Kwang Hwa , Kim Min Kyu , Chang Young Gyoon , Park Won Sang , Nam Suk Woo
Published: August 2012

SIRT1 (Sirtuin 1) is the most well-known member of the class III histone deaceylase family which plays key roles in many cellular pathways by deacetylating or interacting with numerous non-histone proteins. Recent evidence has demonstrated that SIRT1 is up-regulated in a variety of human cancers and inhibition of SIRT1 expression or activity induces cancer cell growth retardation, cell cycle arrest and apoptosis. Although the functions of SIRT1 in cancer have been extensively studied, the underlying mechanisms of aberrant regulation of SIRT1 are not clearly understood. In the present study, we identified 5 microRNAs (miRNAs) that were significantly down-regulated in human hepatocellular carcinomas (HCCs) via large-scale miRNA expression analysis with computational prediction of miRNA targeting for SIRT1. Of these, it was found that miR-29c and miR-141 were directly able to suppress endogenous SIRT1 expression, but only miR-29c was able to recapitulate the effects of SIRT1 inactivation in HCC cells. In addition, the expression level of miR-29c was inversely correlated with SIRT1 protein expression levels in a subset of HCC tissues with their corresponding noncancerous tissue. The ectopic expressions of miR-29c in SNU-182 liver cancer cell lines suppressed cell growth and induced cell cycle arrest at G1-phase accompanied with the altered expressions of G1-related cellular components, such as CDK6, CDK2, cyclin D1, cyclin D3, phosphorylation of Rb and E2F1. Taken together, we suggest that loss or down-regulation of endogenous miR-29c causes aberrant overexpression of SIRT1 contributing oncogenic potential to the cells, and that a novel tumor suppression mechanism involving miR-29c may be amenable to epigenetic regulation in human HCC.

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 179. doi:1538-7445.AM2012-179
Abstract 1790: The combination of MGCD265, a Met/VEGFR inhibitor in clinical development, and erlotinib potently inhibits tumor growth by altering multiple pathways including glycolysis
Authors: Bonfils Claire , Beaulieu Normand , Fournel Marielle , Ste-Croix Helene , Besterman Jeffrey M. , Maroun Christiane R.
Published: August 2012

MGCD265 is an oral, multitargeted, receptor tyrosine kinase inhibitor in clinical development. MGCD265 targets the Met, VEGFR1, 2, 3, Tie2 and Ron receptor tyrosine kinases and blocks key pathways regulating cancer development and progression. Met-targeted agents, including MGCD265, have shown early signs of clinical activities when combined with EGFR inhibitors. While this combination is supported by a large body of evidence indicating that Met and EGFR functionally cooperate to amplify activating signals, how the combination of agents targeting these two pathways leads to efficient anti-tumor responses remains to be elucidated. We have previously demonstrated that the combination of MGCD265 with erlotinib achieved greater tumor growth inhibition than treatment with either agent alone in multiple xenografts including a gastric cancer model in which Met is amplified (MKN45). We performed gene expression analyses in this model to gain insight into the molecular mechanisms underlying the efficient anti-tumor activities of MGCD265 in combination with erlotinib. While these studies revealed the inhibition of cell growth and the induction of apoptosis pathways as enhanced by this combination, the regulation of glycolysis surfaced as a novel pathway altered by this combination. Although genes regulating this pathway were partly downmodulated by either agent alone, the combination significantly enhanced this effect. A key mediator of glycolysis, hexokinase 2 (HK2), known to be elevated in cancer cells and essential for the switch to aerobic glycolysis as well as for mitochondrial-initiated cell death, was significantly downregulated by the combination. Furthermore, PFKFB3, PGK, ENO1, PKM2 were also inhibited by the combination. These results suggest that regulating tumor cell glycolysis may present a novel pathway through which MGCD265 could block tumor cell growth. Thus, the inhibition of multiple molecular pathways involved in cancer growth and progression provides a rationale for the clinical development of MGCD265 in combination with erlotinib. Early results from an ongoing Phase I/II clinical trial of MGCD265 in combination with erlotinib has demonstrated encouraging signs of activity in gastric 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 1790. doi:1538-7445.AM2012-1790
Abstract 1799: Hypoxia-induced alterations of renal cell carcinoma cells and their modulation by tyrosine kinase inhibitors
Authors: Leisz Sandra , Erb Susanne , Leich Franziska , Mueller Anja , Seliger Barbara
Published: August 2012

Renal cell carcinoma (RCC) is the most common neoplasm in the adult kidney and its incidence is increasing over the last 20 years. Unfortunately, approximately 30 % of patients are diagnosed at a metastatic stage, which is associated with a poor prognosis and a 5-year survival rate of < 10 %. The clear cell RCC, representing approximately 75 % of RCC lesions, is characterized by a frequent inactivation of the Von-Hippel-Lindau protein (pVHL) resulting in the upregulation of the hypoxia-inducible factor 1α (HIF-1α), which consequently induces the transcription of hypoxia-responsive genes, such as the vascular endothelial growth factor receptor (VEGF) thereby inducing angiogenesis. Thus, the inhibition of angiogenesis is a suitable tool for the therapy of advanced clear cell RCC. During the last decade agents targeting tumor angiogenesis include inhibitors of the VEGF receptor pathway and the mammalian target of rapamycin (mTOR) have been successfully applied for the treatment of this disease. Using proteome-based studies and microRNA arrays hypoxia-regulated miRs and proteins in VHL- versus VHL+ RCC have been identified in the absence or presence of the angiogenesis inhibitors sunitinib and axitinib. (i) A differential miR and protein expression profile exhibiting an inverse correlation was found upon hypoxia, which further differed in VHL- versus wild-type VHL RCC cells. (ii) The hypoxia-regulated miRs and proteins in these cell systems were altered by the tyrosine kinase inhibitors (TKI) sunitinib and axitinib treatment. (iii) Functional analysis of the hypoxia-regulated candidate biomarkers and their modulation by both TKI are currently performed. (iv) The differential expression pattern of miRs and proteins under hypoxia as well as in the absence and presence of both TKIs were confirmed by RT-PCR and Western blot analysis. These data were shown for the first time an effect of sunitinib and axitinib on hypoxia-induced alterations in RCC, which not only leads to a better understanding of the mechanisms of action of both TKIs, but also to the define of novel strategies for the targeted treatment of RCC.

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 1799. doi:1538-7445.AM2012-1799
Abstract 1804: Novel gold derivatives of thiosugars potently inhibit p-STAT3 and downregulate HIF-1α in ependymomas
Authors: Priebe Waldemar , Kato Takayuki , Fokt Izabela , Madden Timothy L. , Conrad Charles A. , Johansen Mary J. , Skora Stanislaw , Nguyen Van N. , Arumugam Jayakumar
Published: August 2012

Ependymoma is the third most common brain tumor in children, representing 5% of all CNS malignancies with an overall survival ranging from 24% to 75% at 5 years. Although auranofin (AF), a gold containing antirheumatic compound, has been tested for a variety of human cancers, the true potential of this compound or its related compounds as anticancer agents has not been fully explored for human cancer. However, recent observations identifying proteasome inhibition and alterations in the JAK/STAT signaling pathways as primary targets for gold compounds in several human cancers indicate that such compounds could be effective anticancer drugs providing a unique mechanism of action. We have recently designed several auranofin analogs (WP1527, WP1528, WP1529, WP1530, WP1531, WP1532, WP1533, WP1534, WP1546, and WP1547) and found that selected AF analogs (WP1529 and WP1532) markedly inhibit the proliferation of BT-58 and 58-10F human ependymoma cell lines. We discovered that ependymoma cell lines were more sensitive to AF than tested glioma cell lines and furthermore selected new analogs more potently inhibited BT-58 ependymoma cell proliferation than parental compound AF. Further analysis demonstrated that auranofin can potently (0.5 µM −1µM) block either constitutively activated or cytokine induced p- STAT3. Anticancer activity of these synthesized analogs has also been assessed in other tumor types including cutaneous T-cell lymphoma (CTCL) and melanoma. Our studies led to discovery of significantly more potent auranofin analogs and highly promising preliminary data warrant further studies to validated clinical potential of lead compound in ependymoma models.

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 1804. doi:1538-7445.AM2012-1804
Abstract 2692: An ongoing Phase II trial of an adenovirus/PSA vaccine for prostate cancer
Authors: Lubaroff David M. , Williams Richard D. , Vaena Daniel , Joudi Fadi , Brown James , Smith Mark , Zehr Pamela , Brown Erica , Eastman Julie , Griffith Karen , Madsen Tammy , Johnson Kristine
Published: August 2012

Introduction and Objectives: Our Phase I adenovirus/PSA vaccine trial has proved that this vaccine is safe. We are conducting a Phase II clinical trial with two separate protocols for patients with recurrent or hormone refractory prostate cancer assessing toxicity, immune responses, and changes in PSA levels. Methods: In Protocol #1 men with recurrent prostate cancer following definitive initial treatment for their disease were placed in one of two arms: Arm A; men receive the vaccine alone at days 0, 30, and 60; Arm B; men receive the vaccine 14 days after the initiation of androgen deprivation therapy (ADT). In Protocol #2 men with hormone refractory disease receive the vaccine alone using the same 3 injection schedule. Each injection consists of 108 pfu of the Ad/PSA vaccine suspended in a collagen matrix. All patients return at regular intervals for physical, chemical, radiologic, and immunologic evaluations. Results: To date forty four patients have been enrolled and have been followed a median of 12 months. The patients have a median age of 71.3 years, and median enrollment PSA levels of 0.62 ng/ml in Protocol #1 and 5.45 ng/ml in Protocol #2. In our preliminary results at this early stage of the trial, 100% of the patients in Protocol #1 and 67% of the patients in Protocol #2 demonstrated anti-PSA T cell responses above preinjection levels. Sixty four percent of the patients demonstrated an increase in PSA doubling time (PSADT). Conclusions: In an attempt to follow up on the success of our Phase I clinical trial of the Ad/PSA vaccine we have initiated a Phase II trial to investigate the therapeutic efficacy of the vaccine in men with recurrent prostate cancer, either following definitive therapy prior to other treatments or hormone refractory. Early results from the first four four patients demonstrate the induction of anti-PSA T cells responses in a high percentage of the vaccinated patients and increase in PSADT in more than half of the patients. No serious vaccine-related toxicities have been identified in the 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 2692. doi:1538-7445.AM2012-2692
Abstract 2749: YM155, a small molecule survivin suppressant, sensitizes human B-cell non-Hodgkin lymphoma to rituximab-induced apoptosis
Authors: Kaneko Naoki , Kita Aya , Mori Masamichi , Sengoku Takanori
Published: August 2012

Survivin is a member of the inhibitor of apoptosis (IAP) family of proteins, and is highly expressed in various tumor types. Given its preferential expression in tumor cells, and its ability to block apoptosis and regulate cancer cell proliferation, survivin appears to be an attractive target for cancer therapy. YM155 is a small molecule survivin suppressant and shows in vitro antiproliferative activity against the broad spectrum of human cancer cell lines, including B-cell non-Hodgkin lymphoma (B-NHL). The continuous infusion of YM155 induced the tumor regression in B-NHL xenograft mice models. Furthermore, our recent study indicated that the combination treatment of YM155 and rituximab induced significant tumor growth inhibition and tumor regression without weight loss. In the present study, we examined the in vitro combination efficacy of YM155 and rituximab, and its underlying signaling pathways involved in the combination effect of YM155 and rituximab. The combination of YM155 at 1 nmol/L and rituximab at 2 ug/mL induced higher sub G1 compared with each single treatment in WSU-DLCL-2 and SU-DHL-4. Rituximab at 2ug/mL decreased phospho-STAT3 level, meanwhile, did not decreased phospho-p38 MAPK and phospho-AKT levels in WSU-DLCL-2 and SU-DHL4. To further characterize the growth inhibitory effect of inactivation of STAT3 pathway, we investigated the cell growth inhibition by AG490, a JAK2 inhibitor and STA-21, a STAT3 dimerization inhibitor in WSU-DLCL-2 and SU-DHL4. The treatment of AG-490 or STA-21 decreased cell viability in dose-dependent manner. Furthermore, the combination of YM155 at 1 nmol/L and AG490 at 10μmol/L or STA-21 at 6μmol/L induced higher apoptosis rate that was evident by the sub G1 fraction and annexin-V induction compared with each single treatment. These results suggested that the growth of human B-NHL is STAT3 dependent manner and the inhibition of STAT3 pathway sensitizes human B-NHL to YM155 induced apoptosis. The present study suggested that survivin suppression by YM155 and the convergence of disabling inhibition of STAT-dependent survival pathway by ritximab would contribute the synergistic combination efficacy. A phase 2 study with YM155 plus rituximab is ongoing in relapsed patients with diffuse large B cell lymphoma.

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 2749. doi:1538-7445.AM2012-2749
Abstract 2764: Effect of PNT2258 combinations with docetaxel, dacarbazine, or vemurafenib on the A375 melanoma xenograft
Authors: Rodrigueza Wendi V. , Whitehead Christopher , Mohammad Ramzi , McGovern J. Patrick , Wick Michael J. , Rasco Drew , Tolcher Anthony W. , Bisgaier Charles L.
Published: August 2012

Bcl-2 and bcl-XL are anti-apoptotic proteins that promote drug resistance and enhance tumor cell survival. Bcl-2 gene amplification occurs in 90% of cutaneous melanomas implicating it as a potential target. PNT100 is a 24-mer unmodified DNA oligonucleotide complementary to a non-coding region of bcl-2. PNT2258, is comprised of PNT100 encapsulated in a unique pH tunable nuclear-targeted liposomes termed SMARTICLES®. Preliminary studies demonstrated fluorescently-labeled PNT100 in a SMARTICLE® is delivered to the cell nucleus and that PNT2258 produces dramatic tumor regression in a diffuse large cell lymphoma xenograft, prolonging survival with a coincident decrease in bcl-2 protein. PNT2258 activity in the A375 melanoma model was assessed as a single agent or in combination in two separate studies. Study 1: PNT2258 alone, IV, 5 days/week for 3 weeks, to mice bearing A375 produced growth delays of 10.4, 7.8, and 7.8 days at 12.5, 8.3, and 5.6 mg/kg/dose, respectively. Docetaxel alone, IV weekly x3, produced growth delays of 19.4 (1/10 TFS), 14.8 (1/10 TFS), and 11.5 days at 30, 20, and 13.3mg/kg/dose. Combination therapy produced growth delays of 45.3 (5/10 TFS), 18.9, 28.1 (2/10 TFS), and 25.0 (3/10 TFS) days at 12.5+30, 12.5+20, 5.6+30, and 5.6+20 mg/kg/dose, respectively. Study 2: PNT2258 alone produced a growth delay of 12 days at 15mg/kg/dose. Dacarbazine alone was ineffective at 80 mg/kg/dose IP. Combination therapy was not superior to PNT2258 alone. In contrast, vemurafenib alone (37.5 mg/kg/dose, PO, BIDx18 days) was highly active producing a growth delay in excess of 30 days, as did the combination of PNT2258+vemurafenib. PNT2258 is currently being evaluated for safety and tolerability in a phase Ia clinical trial. Preliminary mouse and human pharmacokinetics suggest that exposure levels in humans are similar to those producing anti-tumor efficacy in mice. Overall, 1) PNT2258+docetaxel produced a greater than additive effect compared to single agents, 2) PNT2258+dacarbazine was not superior to PNT2258 alone, 3) PNT2258+vemurafenib while highly active, was not superior to vemurafinib therapy alone, and 4) therapeutic PNT2258 exposures have been attained in 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 2764. doi:1538-7445.AM2012-2764
Abstract 2780: Bortezomib induces autophagy in hepatocellular carcinoma through the inhibition of CIP2A independent of proteasome inhibition.
Authors: Yu Hui-Chuan , Hou Duen-Ren , Liu Chun-Yu , Cheng Ann-Lii , Chen Pei-Jer , Chen Kuen-Feng
Published: August 2012

Previously, we have reported that cancerous inhibitor of protein phosphatase 2A (CIP2A) mediates the apoptotic effect of bortezomib in hepatocellular carcinoma (HCC) (Oncogene, 2010). Here, we report the mechanism by which bortezomib induces autophagy in HCC. Our data indicated that bortezomib activated autophagy in a dose- and time- dependent manner in HCC cell lines, including Huh-7, Sk-Hep1, and Hep3B. Bortezomib down-regulated CIP2A, phospho-Akt (P-Akt) and phospho-4EBP1 (P-4EBP1) in a dose- and time- dependent manner in all tested HCC cells. Ectopic expression of CIP2A abolished the effect of bortezomib on autophagy. Cotreatment of bortezomib and calculin A, a PP2A inhibitor, reduced the effect of bortezomib on P-Akt, P-4EBP1, and autophagy. Over-expression of either Akt or 4EBP1 protected cells from bortezomib-induced autophagy. Moreover, we examined the effect of αBtz, a bortezomib derivative that closely resembles bortezomib structurally but with no proteasome activity, in HCC. Interestingly, αBtz demonstrated similar effects to bortezomib on autophagy, CIP2A, P-Akt and P-4EBP1. Furthermore, our in vivo data showed that both bortezomib and αBtz inhibited tumor growth, down-regulated CIP2A, P-Akt and induced autophagy in Huh-7 tumors, suggesting that bortezomib activates autophagy in HCC and this effect is independent to its effect on proteasome. In conclusion, bortezomib induces autophagy in HCC through CIP2A-PP2A-Akt-4EBP1 pathway. Supported by NTUH100P04, NSC99-2314-B-002-017-MY2, NSC100-3112-B-002-013, and NSC100-2325-B-002-036.

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 2780. doi:1538-7445.AM2012-2780
Abstract 326: Aneuploidy-driven clonal diversification underlies tumor phenotype switching
Authors: Gao Chong-Feng , Su Yanli , Woude George Vande
Published: August 2012

The acquisition of an invasive phenotype and its reversion to a proliferative phenotype are crucial steps in tumor metastases. We have been able to reproduce these steps through a combination of in vitro and in vivo methods. We show that proliferative subclones isolated from human carcinoma cells can generate invasive subclones in vitro, which is associated with the epithelial-mesenchymal transition (EMT). Moreover, the invasive mesenchymal clones can reverse their phenotype (MET) through tumorigenesis in vivo. Phenotypic switching occurs with changes in karyotypes, which dictate changes in the chromosome transcriptome and in the expression of genes that account for the phenotypic switching. We conclude that chromosome instability generates the transcriptome diversity, which in the appropriate environment leads to the expansion of clonal variants responsible for malignant progression.

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 326. doi:1538-7445.AM2012-326
Abstract 3863: Aneuploid human colonic epithelial cells are sensitive to AICAR-induced growth inhibition through EGFR degradation
Authors: Ly Peter , Kim Sang B. , Wright Woodring E. , Amon Angelika , Shay Jerry W.
Published: August 2012

Trisomy for chromosome 7 is frequently observed as an initiating event in sporadic colorectal cancer. Although unstable chromosome numbers and recurrent aneuploidies drive a large fraction of human cancers, targeted therapies selective to pre-neoplastic trisomic cells are non-existent. We have previously characterized a trisomy 7 cell line (1CT+7) spontaneously derived from normal diploid human colonic epithelial cells that aberrantly express the epidermal growth factor receptor (EGFR, located on 7p11). Recent studies identified AICAR as a pharmacological inhibitor of aneuploid murine fibroblast proliferation. Here, we report that AICAR induces profound cytostatic and metabolic effects on 1CT+7 cells but not their isogenic diploid counterpart. Dose-response assays demonstrate that 1CT+7 cells are four-fold preferentially sensitive to AICAR compared to diploid cells. Unexpectedly, treatment of 1CT+7 cells with AICAR led to a reversible 3.5-fold reduction (p=0.0025) in EGFR overexpression. AICAR-induced depletion of EGFR protein can be abrogated through inhibition of the proteasome with MG132. AICAR also heavily promoted EGFR ubiquitination in cell-based immunoprecipitation assays, suggesting enhanced degradation of EGFR protein mediated by the proteasome. Moreover, treatment with AICAR reduced EGFR protein levels in a panel of human colorectal cancer cells in vitro and in xenograft tumors in vivo. Our data collectively supports the pharmacological compound AICAR as a novel inhibitor of EGFR protein abundance and as a potential therapeutic agent for aneuploidy-driven colorectal 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 3863. doi:1538-7445.AM2012-3863
Abstract 3904: Pyridylthiazole-based ureas as inhibitors of Rho-associated protein kinases
Authors: Pireddu Roberta , Forinash Kara , Sun Nan N. , Martin Mathew P. , Sung Shen-Shu , Alexander Brian , Zhu Jin-Yi , Guida Wayne C. , Schönbrunn Ernst , Sebti Saïd M. , Lawrence Nicholas J.
Published: August 2012

Rho GTPase is a small G-protein which plays a critical role in signaling pathways and controls cell growth and division. Rho-associated protein kinase (known as ROCK or Rho kinase) is a Ser/Thr protein kinase activated by GTP-bound Rho and phosphorylates target proteins involved in various signal transduction pathways. Rho and the Rho-kinase signalling pathways are implicated in cell morphology, motility, smooth muscle contraction, formation of stress fibres, focal adhesion and cell transformation. ROCKs have been subject to growing attention, having been implicated in a range of therapeutic areas including cardiovascular diseases, CNS disorders, and cancer. Further, the pharmacological inhibition of ROCKs has been suggested as a promising strategy in the prevention of cell invasion, a central event in the process of metastasis. Potent ROCK inhibitors of a new class of 1-benzyl-3-(4-pyridylthiazol-2-yl)ureas have been identified. Remarkable differences in activity were observed for ureas bearing a benzylic stereogenic center. Derivatives with hydroxy, methoxy and amino groups at the meta position of the phenyl ring give rise to the most potent inhibitors (low nM). Substitutions at the para position result in substantial loss of potency. Changes at the benzylic position are tolerated resulting in significant potency in the case of methyl and methylenehydroxy groups. X-ray crystallography was used to establish the binding mode of this class of inhibitors and provides an explanation for the observed differences of the enantiomer series. Potent inhibition of ROCK in human lung cancer cells was shown by suppression of the phosphorylation levels of the ROCK substrate MYPT-1. One of the series, RKI-1447 inhibits migration, invasion and anchorage-independent tumor growth of breast cancer cells and is discussed in an accompanying poster.

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 3904. doi:1538-7445.AM2012-3904
Abstract 3906: Design, synthesis and biological evaluation of 2nd generation ezrin inhibitors for metastatic osteosarcoma
Authors: Kosturko George W. , Bulut Gulay , Hong Sung-Hyeok , Rodriguez Veronica , Brown Milton , Toretsky Jeffrey , Khanna Chand , Paige Mikell , Uren Aykut
Published: August 2012

Though advancements in chemotherapy and surgical techniques have ameliorated treatment of primary osteosarcoma (OS), the metastatic phenotype remains a clinical challenge. Overall five-year survival rates for patients with localized OS have improved to 60-70%, yet survival rates of patients with metastasis remains at 20-30% with mortality linked to metastatis-induced respiratory failure. Therefore, targeting fundamental molecular events that lead to metastasis may yield significant benefit to patients with OS. Accumulating evidence from clinical samples and pre-clinical animal models suggests that ezrin is a key regulator in the metastasis of OS cells. Ezrin is a multifunctional protein that connects the actin cytoskeleton to extracellular matrix through transmembrane proteins and a critical component for cell motility, adhesion and shape. We have recently identified that a small molecule, NSC 668394 acts as a potent and selective inhibitor of ezrin function and inhibits migration in both in-vitro and in-vivo models. Moreover, suppression of ezrin phosphorylation by NSC 668394 significantly reduced the metastatic behavior in cellular and animal models and has thus emerged as an important lead inhibitor. Consequently, we conducted a series of structure-activity-relationship (SAR) studies that monitored direct binding; OS cell migration and HUVEC monolayer invasion in ‘real-time’ with surface-plasmon resonance and electrical impedance technology. From our 2nd generation library, we have designed novel candidate inhibitors which feature enhanced ezrin-binding affinity, and improved anti-migration and anti-invasion activities. In addition to their potency against the different stages of OS metastasis, these compounds possess other desirable attributes for development including good druggable physical-chemical characteristics and are currently undergoing further preclinical evaluation.

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 3906. doi:1538-7445.AM2012-3906
Abstract 3919: Novel model to study NFkB driven resistance to endocrine treatment in breast cancer
Authors: Sas Leen , Laere Steven Van , Peeters Dieter , Marsan Melike , van Schooneveld Eleni , Lardon Filip , van Dam Peter , Dirix Luc , Vermeulen Peter
Published: August 2012

Background: Patients with estrogen receptor (ER)-positive breast cancers are generally treated with endocrine therapy, but in a considerable fraction of patients resistance occurs. Previous research showed that nuclear factor kappa B (NFkB) may play a role in the development of resistance to hormonal therapy. In this study, we investigated the role of NFkB, and its interaction with ER in the development of endocrine resistance by studying breast cancer cell lines with variable ER and NFkB activity. Material and methods: Three gene expression data sets of breast cancer cell lines (GSE12777: Hoeflich et al, 2009; GSE16795: Hollestelle et al, 2009; E-TAM-157: Neve et al, 2005) were retrieved from Gene Expression Omnibus or ArrayExpress. The expression profiles were screened for ER and NFkB target genes to identify cell lines with strong and weak activation of ER and NFkB. Based on these activation profiles, 8 cell lines (MCF7, BT20, CAMA1, MDA-MB-361, MDA-MB-231, MDA-MB-134, MDA-MB-468 and MDA-MB-436) with high and low ER and NFkB activation profiles were selected. Using qRT-PCR on RNA from these cell lines, the expression of 6 biomarkers for endocrine resistance (ADAMDEC1, ITK, ABAT, CLEC7A, ETS1 and STC2) were profiled. 18S and beta-Actin were used as housekeeping genes. Relative expression levels were analyzed in function of ER and NFkB activation. Results: There is a significant lower expression of ADAMDEC1 (P=0.011), ITK (P=0.012) and ETS1 (P<0.001) in the ER-positive cell lines compared to the ER-negative ones, while ABAT (P<0.001) and STC2 (P=0.049) are significant higher expressed in ER-positive cell lines. Comparison of ER-positive/NFkB-negative with ER-positive/NFkB-positive cell lines revealed a difference in expression in 3 of the 6 genes, namely ADAMDEC1 (P=0.037), ITK (P=0.013) and ABAT (P=0.014), showing a higher expression in the double positive cell lines. Conclusion: The construction of a set of breast cancer cell lines with different patterns of combined ER-NFkB activity is a useful tool to unravel the mechanism of ER and NFkB interaction leading to endocrine resistance. In this context, the number of cell lines will be expended. With respect to our data, the expression profiles of ADAMDEC1 and ITK were in line with the expected attenuated responsiveness of the NFkB-positive breast cancer cells to endocrine therapy and therefore might play a role in NFkB-driven resistance to endocrine therapy.

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 3919. doi:1538-7445.AM2012-3919