bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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 &lt; 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

Abstract
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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