bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2917: Design, synthesis and biological evaluation of two chemical classes as novel small molecule Mcl-1 inhibitors
Authors: Bajwa Naval , Abulwerdi Fardokht , Liao Chenzhong , Mady Ahmed , Bernardo Julie Di , Azmi Asfar , Cierpicki Tomek , Stuckey Jeanne , Showalter Hollis , Mohammad Ramzi , Nikolovska-Coleska Zaneta 
Published: August 2012

Abstract
The anti-apoptotic myeloid cell leukemia protein Mcl-1, a member of the Bcl-2 family proteins, has a critical and distinct role(s) in maintaining cell survival and is emerging as an independent and promising therapeutic target. Using structure-based design, two classes of small molecule Mcl-1 inhibitors were developed with IC50 values ranging from 50 nM to 75 μM, based on the lead compounds identified from high throughput screening. The structure-activity relationships (SAR) of these compounds were analyzed and chemical features of both series that are important for potency and selectivity on Mcl-1 were identified. The HSQC-NMR spectroscopy studies combined with molecular docking and dynamics simulations demonstrated that both classes of compounds occupy the BH3 binding site in Mcl-1 protein mimicking two conserved hydrophobic residues from BH3 binding motif. The most potent analogues antagonize Mcl-1 on the functional level and they induce release of cytochrome c, inhibit cell growth and induce apoptosis in Bax/Bak-dependent manner in pancreatic and melanoma cancer cells with high levels of Mcl-1. The knowledge gained through these studies provides promise for future design and expansion of these series towards development of potent small-molecule Mcl-1 inhibitors.
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 2917. doi:1538-7445.AM2012-2917
Abstract 292: Modulation of cyr61/ccn1 expression in human cell lines by the polyphenolic compound resveratrol
Authors: Monzon Ricardo , Prokop Jennifer 
Published: August 2012

Abstract
Resveratrol is the active compound in red grape skin believed to contribute to the protective effects of red wine in heart disease and has been implicated in the modulation of certain cancers. The matricellular protein CCN1/Cyr61 is involved in the regulation of cellular activities that control growth, programmed cell death, cellular motility and cell adhesion. Interestingly, many of the regulatory pathways that affect CCN1/Cyr61 expression are also affected by resveratrol action. In order to examine the possible link between CCN1/Cyr61 action and resveratrol's effects, human cell lines were used to analyze resveratrol's effects on CCN1/Cyr61 expression and function. Increased levels of CCN1/Cyr61 expression were observed in cells treated with resveratrol alone or combined with the stimulatory agents phorbol ester and epidermal growth factor (EGF). Analysis of CCN1/Cyr61 protein expression and cellular functions also revealed modulatory effects of reseveratrol treatment, however the role of upstream regulatory pathways in mediating reseveratrol action has yet to be addressed. Nevetheless, these studies offer preliminary evidence for the regulation of CNN1/Cyr61 expression by a putative modulator of cellular processes involved in heart disease and 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 292. doi:1538-7445.AM2012-292
Abstract 2921: Critical mediation of E2-induced apoptosis through c-Src in long-term estrogen deprived breast cancer cells
Authors: Fan Ping , Griffith Obi L. , Anur Pavana , Kim Helen R. , Gray Joe W. , Jordan V. Craig 
Published: August 2012

Abstract
Our previous publication showed that physiological concentrations of estrogen (E2) could trigger apoptosis of long-term E2 deprived breast cancer cells (MCF-7:5C) (Lewis et al. JNCI 2005; 97:1746-59). This new targeted strategy provides novel therapeutic approaches to endocrine resistant breast cancer. A phase II clinical trial reported that E2 provided a clinical benefit for aromatase inhibitor-resistant advanced breast cancer patients. However, only 30% of patients receive clinical benefit (Ellis MJ et al. JAMA 2009;302:774-80). This prompted us to investigate the mechanisms underlying E2-induced apoptosis to find strategies to increase the therapeutic responsiveness. c-Src is currently of interest, as it is an important adapter protein of ER in breast cancer cells. Here, we found that E2 stimulated c-Src phosphorylation in MCF-7:5C cells and 4-hydroxytamoxifen (4-OHT) could block this stimulation which demonstrated that E2 activated c-Src through ER. The specific inhibitor of c-Src, PP2, could block c-Src activation induced by E2. E2 rapidly activated growth pathways within minutes in MCF-7:5C cells and PP2 could block this non-genomic pathway. E2 was also able to activate Akt/MAPK pathways after 24 hour treatment which could be blocked by inhibition of c-Src. These data showed that c-Src mediated downstream signaling pathways of ER in MCF-7:5C cells. Characteristic E2-induced apoptosis occurred around 72 hour treatment with E2, unexpectedly, inhibition of c-Src could significantly block E2-induced apoptosis which implied that c-Src played a critical role in E2-induced apoptosis. Further examination through transcriptome analysis confirmed that E2 widely induced apoptosis-related pathways. Consistent with the biological experiments, PP2 could completely abolish the apoptosis pathways induced by E2. These data illustrate that c-Src acts as a critical molecule to mediate the downstream signaling of ER (including E2-induced apoptosis) in MCF-7:5C cells. It provides an important rationale for clinical trial with c-Src inhibitors in aromatase inhibitors resistant patients, especially avoiding in combination with physiological levels of E2. Acknowledgements This work (VCJ and JWG) is supported by the SU2C (AACR) Grant (SU2C-AACR-DT0409).
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 2921. doi:1538-7445.AM2012-2921
Abstract 2931: Inherited variation at chromosome 12p13.33 including RAD52 influences squamous cell lung carcinoma risk
Authors: Shi Jianxin , Chatterjee Nilanjan , Rotunno Melissa , Wang Yufei , Pesatori Angela C. , Consonni Dario , Li Peng , Broderick Peter , Henrion Marc , Eisen Timothy , Wang Zhaoming , Chen Wei , Dong Qiong , Albanes Demetrius , Thun Michael , Spitz Margaret , Bertazzi Pier Alberto , Caporaso Neil , Chanock Stephen , Amos Christopher , Houlston Richard , Landi Maria Teresa 
Published: August 2012

Abstract
While lung cancer is largely caused by tobacco smoking, inherited genetic factors play a role in its etiology. Genome-wide association studies (GWAS) in Europeans have robustly demonstrated only three polymorphic variations influencing lung cancer risk. Tumor heterogeneity may have hampered the detection of association signal when all lung cancer subtypes were analyzed together. In a GWAS of 5,355 European smoking lung cancer cases and 4,344 smoking controls, we conducted a pathway-based analysis in lung cancer histologic subtypes with 19,082 SNPs mapping to 917 genes in the HuGE-defined “inflammation” pathway. We identified a susceptibility locus for squamous cell lung carcinoma (SQ) at 12p13.33 (RAD52, rs6489769), and validated it in three independent samples totaling 3,359 SQ cases and 9,100 controls (odds ratio=1.20, Pcombined=2.3×10−8). The combination of pathway-based approaches and information on disease specific subtypes can improve the identification of cancer susceptibility loci in heterogeneous diseases.
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 2931. doi:1538-7445.AM2012-2931
Abstract 2942: RKI-1447, a potent ROCK inhibitor with anti-tumor and anti-invasive activities in breast cancer
Authors: Patel Ronil A. , Forinash Kara D. , Pireddu Roberta , Sun Ying , Martin Mathew P. , Zhu Jin-Yi , Alexander Brian G. , Schonbrunn Ernst , Lawrence Nicholas J. , Sebti Said M. 
Published: August 2012

Abstract
Rho-associated kinases 1 and 2 (ROCKs) are intimately involved in metastasis and this prompted the development of ROCK inhibitors (RKIs) as anti-metastatic agents. Here, we describe the development of RKI-1447 which inhibits ROCK 1 and 2 potently in vitro (IC50s; 14 and 6 nM, respectively) and suppresses the phosphorylation of ROCK substrates MLC2 and MYPT1 in human breast cancer cells (IC50; 100 nM). The crystal structure of the RKI-1447-ROCK1 complex reveals that RKI-1447 binds the hinge region in the ATP binding site. RKI-1447 is highly selective and does not affect the phosphorylation levels of Akt, Erk, Mek and S6. RKI-1447 is also highly selective at inhibiting ROCK-mediated cytoskeleton re-organization (actin stress fiber formation) following LPA stimulation, but does not affect PKA-meditated lamelipodia and filopodia formation following PDGF and bradykinin stimulation, respectively. RKI-1447 inhibits migration, invasion and anchorage-independent tumor growth of breast cancer cells. A structurally-related analog RKI-1313 that is inactive against ROCKs in vitro (IC50 &gt; 10 µM) has little effects on migration, invasion and anchorage-independent growth. Finally, RKI-1447 is highly effective at inhibiting the growth of ErbB2-driven breast tumors in a transgenic animal model.
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 2942. doi:1538-7445.AM2012-2942
Abstract 2948: The role of the RNA binding protein LIN28B in neuroblastoma
Authors: Powers John , Spina Catherine , Collins James , Daley George 
Published: August 2012

Abstract
Neuroblastoma is the most frequent extracranial solid tumor in children, accounting for almost 9% of all childhood cancers and close to 15% of childhood cancer deaths. Amplification of MYCN occurs in up to 40% of neuroblastomas, and is a marker of very poor prognosis. Current treatment strategies for MYCN amplified tumors are ineffective and in desperate need of new therapeutic avenues. The LIN28 A and B RNA binding proteins negatively regulate the let-7 family of pro-differentiation/ tumor suppressor miRNAs, enhance the translation of mRNA binding partners, and are emerging as novel onco-proteins. We show here that LIN28B is highly expressed in neuroblastoma, both in human neuroblastoma cell lines and in neuroblastoma patient samples, with an expression pattern similar to MYCN. The LIN28 proteins have been shown to directly regulate MYC, and knockdown of LIN28B in MYCN-amplified human neuroblastoma cells results in markedly reduced MYCN expression, impaired growth, greater differentiation, and reduced tumor size in mouse xenograft studies, indicating an important functional link between LIN28B and MYCN. Through LIN28B/mRNA co-immunoprecipitation we have discovered that LIN28B binds MYCN mRNA, suggesting a novel mechanism of LIN28B contribution to MYCN activity in high-risk neuroblastoma. In addition, we have also discovered that LIN28B is acetylated within its RNA binding domain, and mutational studies have suggested that modulating this post-translational modification may destabilize LIN28B protein stability. Through proteomic analysis of LIN28B -associated proteins, we have identified an acetyl-transferase as a candidate drug target for disruption of the LIN28B/MYCN oncogenic pathway.
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 2948. doi:1538-7445.AM2012-2948
Abstract 2954: TWIST1 is a critical mediator of KRAS mutant tumorigenesis in human non-small cell lung cancer
Authors: Burns Timothy F. , Dobromilskaya Irina , Murphy Sara C. , Gajula Rajendra P. , Aziz Khaled , Cho Yoon-Jae , Tran Phuoc T. , Rudin Charles M. 
Published: August 2012

Abstract
A large fraction of non-small cell lung cancers (NSCLC) have mutant KRAS, which is associated with poor response to current cytotoxic therapy and a poor prognosis. Although the KRAS signaling pathway has been well characterized, no current therapies target this critical oncogene. Several studies have demonstrated that bypass of senescence in Kras-mediated adenocarcinoma mouse models is essential for tumorigenesis. Therefore, activation of senescence in KRAS mutant NSCLC may be an effective therapeutic strategy. We recently demonstrated that the basic helix loop helix transcription factor Twist1 cooperates with mutant Kras to induce lung adenocarcinoma in transgenic mouse models and that inhibition of Twist1 in these models led to activation of Kras-induced senescence and tumor stasis. In the current study, we examine the role of TWIST1 in KRAS mutant human NSCLC. Silencing of TWIST1 in multiple KRAS mutant NSCLC cell lines resulted in dramatic growth inhibition and either reactivation of oncogene-induced senescence or in some cases, apoptosis. Similar effects were also observed in four KRAS wild type lines, including cell lines with key driver mutations including a cell line with an activating EGFR mutation and a cell line with c-Met amplification. Gene set enrichment analysis of NSCLC cell lines after silencing of TWIST1 revealed a striking cell cycle arrest gene signature. Growth inhibition by silencing of TWIST1 was independent of p53 or Rb/p16 mutational status. Furthermore, activation of oncogene-induced senescence by TWIST1 silencing did not require previously defined mediators of senescence, p21 and p27, nor could this phenotype be rescued by overexpression of SKP2. To extend these observations in vivo, TWIST1 was silenced in both KRAS mutant and wildtype cell lines and these cells were implanted in NOD-SCID mice to assess tumor formation. Interestingly, silencing of TWIST1 in xenograft models preferentially inhibited KRAS mutant tumor formation suggesting that TWIST1 plays a critical in mediating KRAS tumorigenesis. Finally, inducible silencing of TWIST1 resulted in significant growth inhibition of established xenograft KRAS mutant tumors. Together these findings suggest TWIST1 is essential for the establishment and maintenance of KRAS mutant NSCLC tumors and silencing of TWIST1 in KRAS mutant NSCLC represents a novel and promising therapeutic strategy.
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 2954. doi:1538-7445.AM2012-2954
Abstract 2956: High throughput RNAi screening of synthetic lethal genes interacting with the common TP53 mutation R175H
Authors: Imai Hiroo , Kato Shunsuke , Sakamoto Yasuhiro , Kakudo Yuichi , Takahashi Shin , Shimodaira Hideki , Ishioka Chikashi 
Published: August 2012

Abstract
The R175H mutation of p53 which account for approximately 6% of the missense mutations of identified in human cancer is one of the most common mutations, and cancer cells with this mutation stably express the R175H protein in the nucleus. Targeting R175H overexpressing cells by synthetic lethality is one of the extremely effective strategies for cancer therapy. To identify the synthetic lethal gene interacting with R175H, we conducted high throughput screening using a tetracycline-inducible R175H expression system in SF126 cells and comprehensive shRNA library carried by lentivirus. We identified 906 candidate gene suppressions that may lead to accelerated cell growth inhibition in the presence of R175H (p&lt;0.05, n=3). Among these, we selected 50 genes (21 genes from the group with the smallest p-values, 20 genes from the group with the largest fold change, and 9 genes reproduced by different siRNA sequences) for further validation testing. By transfection of siRNA of these candidate genes into five R175H expressing cell lines and four TP53-null cell lines, we selected five candidate genes that significantly lead R175H expressing cells to strong cell growth inhibition. Inhibitor of differentiation 1 (ID1) was one of the five candidate genes, and its suppression by siRNA resulted in the acceleration of growth inhibition in cell lines expressing endogenous R175H; however, this was not observed in TP53-null cell lines. The transient expression of R175H in TP53-null cell lines (PC3) and suppression of ID1 and/or TP53 R175H in cell lines with endogenous R175H revealed that cell growth inhibition by ID1 suppression depended on the expression of R175H, and not that of other common p53 mutants (e.g., R273H). Flow cytometric analysis exhibited that ID1 suppression resulted in G1 arrest, and the arrest was accelerated by the expression of R175H. In conclusion, ID1 is a synthetic lethal gene that interacts with R175H and is considered to be a novel molecular target for cancer therapy in R175H expressing cells.
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 2956. doi:1538-7445.AM2012-2956
Abstract 2960: Factor dependent chromatin structure and nucleosome dynamics
Authors: He Housheng H. , Meyer Clifford A. , Liu Shirley X. , Brown Myles 
Published: August 2012

Abstract
Transcription factor cistromes are highly cell-type specific. Chromatin accessibility, histone modifications and nucleosome occupancy have all been found to play a role in defining these binding locations. Here, we show that hormone-induced DNase I hypersensitivity changes (≥DHS) are highly predictive of androgen receptor (AR) and estrogen receptor (ER) binding in prostate cancer and breast cancer cells, respectively. The chromatin structure prior to binding and the nucleosome occupancy after binding are strikingly different for ER and AR. AR binding is associated with changes in both the local nucleosome occupancy and the DNase I hypersensitivity. In contrast, while globally ER binding is unrelated to changes in nucleosome occupancy, DNase I hypersensitivity dynamics predict the ER cistrome. These findings suggest that AR and ER have distinct modes of interaction with chromatin and that DNase I hypersensitivity dynamics provides a general approach for predicting cell-type specific cistromes.
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 2960. doi:1538-7445.AM2012-2960
Abstract 2962: FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair
Authors: Park Yun-Yong , Jung Sung Yun , Rodriguez-Aguayo4 Cristian , Peng Guang , Lee Se-Ra , Kim Sang Bae , Kim Kyounghyun , Leem Sunhee , Lin Shiaw-Yih , Lopez-Berestein Gabriel , Sood Anil K. , Lee Ju-Seog 
Published: August 2012

Abstract
Transcription factors (TFs) are direct effectors of altered signaling pathways in cancer. To uncover new TFs that would determine clinical outcomes in breast cancer patients, we systematically analyzed gene expression data from breast cancer patients. Our results revealed that forkhead box protein M1 (FOXM1) is the top-ranked survival-associated TF with triple-negative breast cancer. Surprisingly, silencing FOXM1 expression led breast cancer cells to become more sensitive to doxorubicin (Dox). We found that FOXM1-dependent resistance to Dox is mediated by regulating DNA repair genes. We further demonstrated that NF-κB1 interacts with FOXM1 in the presence of Dox to protect breast cancer cells from DNA damage. Finally, silencing FOXM1 expression in a mouse xenograft model significantly sensitized the cells to Dox. Our systematic approaches identified an unexpected role of FOXM1 in Dox resistance by regulating DNA repair genes and FOXM1 may be a promising therapeutic target for sensitizing breast cancer cells to Dox.
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 2962. doi:1538-7445.AM2012-2962
Abstract 2974: Combating breast cancer brain metastasis by targeting Src family kinases
Authors: Zhang Siyuan , Zhang Chenyu , Huang Wen-Chien , Lowery Frank J. , Huang Suyun , Aldape Kenneth D. , Steeg Patricia S. , Yu Dihua 
Published: August 2012

Abstract
Background: Among 1.3 million women diagnosed with breast cancer every year, 10-16% will develop brain metastases. The median survival of patients with brain metastases is less than one year. A most challenging problem is no effective treatment for patients with refractory metastatic breast cancer to the brain. Therefore, novel and effective therapeutic approaches are urgently needed for this population. Recently, our retrospective analyses revealed a significant up-regulation of Src family kinase (SFK) in breast cancer brain metastasis lesions compared with primary tumors. Additionally, HER2-overexpressing breast cancers with Src activation have a higher incidence of brain metastasis. Thus, we hypothesize that activation of SFK plays a critical role in promoting breast cancer brain metastasis. Aims and Methodology: The major aims of this project are: 1) study the role of Src activation in breast cancer brain metastasis; 2) investigate the pre-clinical efficacy of combination Src inhibitor and HER2-targeting therapy Lapatinib in treatment of brain metastasis. We used HER2-overexpressing breast cancer cell line models, in vitro assays of metastasis-properties, and in vivo brain metastasis mouse model (intracarotid artery injection) to test our hypothesis. Results and Conclusions: Src activity is up-regulated in both brain-seek cells lines and human brain metastasis tumors when compared to either parental cells lines or primary breast cancers respectively. To test the role of Src activation in brain metastasis, we established stable cells lines with constitutive-activation of Src. The Src activation enhanced the tumor cell trans-blood brain barrier migration in vitro. Src activation in cells led to a higher brain metastasis incidence in vivo after intracarotid artery injection. We treated Src-activated brain metastasis in vivo with a Src inhibitor saracatinib, a drug under Phase II clinical trial. This Src-targeting treatment decreased the overall incidence of brain metastasis. Combining sarcatinib with EGFR-HER2 dual-targeting agent lapatinib further prolonged the overall survival of tumor bearing mice and significantly inhibited both micro- and macro-metastasis. In summary, novel SFK targeting regimens may be developed as promising therapies for breast cancer patients with brain metastasis.
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 2974. doi:1538-7445.AM2012-2974