bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1534: Identification of LMX1B as a novel oncogene in human ovarian cancer
Authors: Mohapatra Gayatry , He Lei , Guo Lankai , Vathipadiekal Vinod , Sergent Petra , Growdon Whitfield , Rueda Bo , Engler David , Orsulic Sandra , Birrer Michael 
Published: May 2015

Abstract
Ovarian cancers are thought to result from the accumulation of multiple genetic aberrations that transform ovarian and/or fallopian tube surface epithelial cells, allowing for their abnormal growth, proliferation and metastasis. We carried out genome-wide copy-number analysis using array comparative genomic hybridization on a panel of mouse ovarian cancer (OVCA) cell lines previously established in our laboratory. We identified a recurrent focal amplification on mouse chromosomal region 2qB, which contains the LIM homeodomain containing transcription factor 1B (Lmx1b) gene. LMX1B is not expressed in normal human ovary, but is expressed in many human OVCA cell lines and primary tumors. High expression of LMX1B correlates with poor outcome. To clarify the role of LMX1B in ovarian carcinogenesis, we transduced LMX1B into a panel of mouse and human OVCA cell lines and demonstrated that LMX1B strongly promotes migration of cancer cells in culture and accelerates xenograft growth in nude mice. Conversely, knockdown of LMX1B in a human cell line with endogenous high expression of LMX1B inhibits cell migration in vitro and tumor growth in vivo. Microarray analysis of cells overexpressing LMX1B identified NF-κB pathway as a potential mediator of tumor progression and subsequent treatment of NF-κB inhibitor decreased the migratory capacity of these cells. Thus, our data demonstrate that LMX1B functions as an oncogene in OVCA pathogenesis.
Citation Format: Gayatry Mohapatra, Lei He, Lankai Guo, Vinod Vathipadiekal, Petra Sergent, Whitfield Growdon, Bo Rueda, David Engler, Sandra Orsulic, Michael Birrer. Identification of LMX1B as a novel oncogene in human ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1534. doi:10.1158/1538-7445.AM2014-1534
Abstract 156: Autophagic degradation of granzyme B impairs NK-mediated killing of hypoxic tumor cells
Authors: Baginska Joanna , Viry Elodie , Berchem Guy , Poli Aurélie , Noman Muhammad Zaeem , Moer Kris van , Medves Sandrine , Mgrditchian Takouhie , Zimmer Jacques , Oudin Anais , Niclou Simone P. , Bleackley R. Chris , Chouaib Salem , Janji Bassam 
Published: May 2015

Abstract
Natural killer (NK) cells are effectors of the innate immune system, able to kill cancer cells through the release of the cytotoxic protease granzyme B. NK-based therapies have recently emerged as promising anticancer strategies. However, it is well established that hypoxic tumor microenvironment interferes with the antitumor function of immune cells and constitutes a major obstacle for defining cancer immunotherapies. Recent studies demonstrated that autophagy regulates the innate immune response by mechanisms which are not fully understood. In this study, we showed that hypoxia decreases breast cancer cell susceptibility to NK-mediated lysis by a mechanism involving the activation of autophagy in tumor cells. Targeting autophagy was sufficient to restore NK-mediated tumor cell killing. We showed that the resistance of hypoxic tumor cells was neither related to a defect in their recognition by NK cells, nor to a defect in the cytolytic function of NK cells toward hypoxic cells. We provided evidence that autophagy activation degrades NK-derived granzyme B in lysosomes of hypoxic cells making them less sensitive to NK-mediated killing. Genetic and pharmacological inhibition of autophagy restored granzyme B levels and reverted the resistance of hypoxic cells in vitro. Our results highlight autophagy as a critical factor in modulating NK-mediated anti-tumor immune response. We have validated this concept in vivo by showing that targeting autophagy significantly improved NK-mediated tumor shrinking in breast and melanoma models. This study provides a cutting-edge advance in our understanding of how hypoxia-induced autophagy impairs NK-mediated lysis and paves the way for formulating more effective NK-based antitumor therapy by combining autophagy inhibitors.
Citation Format: Joanna Baginska, Elodie Viry, Guy Berchem, Aurélie Poli, Muhammad Zaeem Noman, Kris van Moer, Sandrine Medves, Takouhie Mgrditchian, Jacques Zimmer, Anais Oudin, Simone P. Niclou, R. Chris Bleackley, Salem Chouaib, Bassam Janji. Autophagic degradation of granzyme B impairs NK-mediated killing of hypoxic tumor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 156. doi:10.1158/1538-7445.AM2014-156
Abstract 1575: ARF regulates the stability of p16 protein via REGγ-dependent proteasome degradation
Authors: Kobayashi Takashi , Ogawa Osamu , Abate-Shen Cory 
Published: May 2015

Abstract
The cell cycle regulatory gene INK4A-ARF (CDKN2A) has two alternative transcripts that produce entirely different proteins, namely p14ARF and p16, which have complementary functions as regulators of p53 and pRB tumor suppressor pathways, respectively. The unusual organization of INK4A-ARF has long led to speculation of a need for coordinated regulation of p14ARF and p16. We now show that p14ARF (ARF) regulates the stability of p16 protein in human cancer cell lines, as well as in mouse embryonic fibroblasts (MEFs). In particular, ARF promotes rapid degradation of p16 protein, which is mediated by the proteasome and, more specifically, by interaction of ARF with one of its subunits, REGγ. Furthermore, this ARF-dependent destabilization of p16 can be abrogated by knock-down of REGγ or by pharmacological blockade of its nuclear export. Thus our findings have uncovered a novel crosstalk of two key tumor suppressors mediated by a REGγ-dependent mechanism.
Citation Format: Takashi Kobayashi, Osamu Ogawa, Cory Abate-Shen. ARF regulates the stability of p16 protein via REGγ-dependent proteasome degradation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1575. doi:10.1158/1538-7445.AM2014-1575
Abstract 1594: Transgenic overexpression of NanogP8 in the mouse prostate does not initiate tumorigenesis nor promotes tumor development in the Hi-Myc mouse model
Authors: Gong Shuai , Liu Bigang 
Published: May 2015

Abstract
Nanog1 is a homeobox transcription factor critical for the self-renewal and pluripotency of ES cells. NanogP8 is a retrotransposed homolog of Nanog1 preferentially expressed in somatic cancer cells. Work from our lab has shown that shRNA-mediated knockdown of NanogP8 in prostate, breast, and colon cancer cells inhibits tumor regeneration whereas inducible overexpression of NanogP8 in somatic cancer cells promotes cancer stem cell phenotypes and properties. A key unanswered question is whether tissue-specific overexpression of NanogP8 is sufficient to promote tumor development in vivo. To address this question, we generated a NanogP8 transgenic mouse model in which the NanogP8 cDNA derived from a primary prostate cancer was driven by the ARR2Pb promoter to direct prostate-specific expression. IHC analysis revealed that human NanogP8 was expressed mainly in the mouse prostate and the expression levels varied from lobe to lobe, with the highest expression in the lateral and ventral lobes. The ARR2Pb-NanogP8 transgenic mice were viable, developed normally, and did not form spontaneous tumors during the observation period of &gt;2 years. In addition, both wild-type and ARR2Pb-NanogP8 transgenic prostates responded similarly to castration and regeneration and did not develop any tumors. These results indicate that overexpression of human NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis in both androgen intact and deprived conditions. We then crossed the ARR2Pb-NanogP8 transgenic mice with ARR2Pb-Myc (i.e., Hi-Myc) mice and found that the double transgenic (i.e., ARR2Pb-NanogP8; Hi-Myc) mice showed similar tumor incidence and histology to the Hi-Myc mice. Unexpectedly, we found white dots in the ventral lobes of the double transgenic mice, which are currently being characterized. Taken together, our present work demonstrates that transgenic overexpression of NanogP8 in the mouse prostate does not initiate tumorigenesis nor promotes tumor development in the Hi-Myc mouse model. These results are consistent with our recent findings that NanogP8 overexpression fails to initiate tumorigenesis in a K14-NanogP8 transgenic model. Our results are also consistent with others' recent work showing that NanogP8 overexpression in transgenic animals is insufficient to initiate mammary tumor development.
Citation Format: Shuai Gong, Bigang Liu. Transgenic overexpression of NanogP8 in the mouse prostate does not initiate tumorigenesis nor promotes tumor development in the Hi-Myc mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1594. doi:10.1158/1538-7445.AM2014-1594
Abstract 1635: Discovery of novel SMAC mimetics as selective IAP inhibitors
Authors: Wang Jin , Li Wei 
Published: May 2015

Abstract
Inhibitor of apoptosis (IAP) proteins are widely considered as promising cancer drug targets, especially for drug-resistant tumors. Mimicking the IAP-binding motif of second mitochondria-derived activator of caspases (SMAC) is a rational strategy to design potential IAP inhibitors. In this report, we used the bioactive conformation of AVPI tetrapeptide in the N-terminus of SMAC as a template and performed a shape-based virtual screening against a drug-like compound library to identify novel IAP inhibitors. Top hits were subsequently docked to available IAP crystal structures as a secondary screening followed by validation using in vitro biological assays. Four novel hit compounds were identified to potently inhibit cell growth in two human melanoma (A375 and M14) and two human prostate (PC-3 and DU145) cancer cell lines. The best compound, UC-112, has IC50 values ranging from 0.7 to 3.4 µM. UC-112 also potently inhibits the growth of P-glycoprotein (P-gp) overexpressed multidrug-resistant cancer cells, strongly activates capase-3/7 and caspase-9 activities, and selectively down-regulates survivin level at a concentration as low as 1 µM. Co-incubation of UC-112 with a known proteasome inhibitor (MG132) rescued survivin inhibition, consistent with the anticipated mechanism of action for UC-112. As a single agent, UC-112 strongly inhibits tumor growth and reduces both XIAP and survivin levels in an A375 human melanoma xenograft model. Overall, our study identified novel scaffolds, especially UC-112, as new platforms on which potent and selective IAP antagonists can be developed.
Citation Format: Jin Wang, Wei Li. Discovery of novel SMAC mimetics as selective IAP inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1635. doi:10.1158/1538-7445.AM2014-1635
Abstract 1637: Discovery of ATR kinase inhibitors from natural products
Authors: Wang Hui-Chun , Lee Alan Yueh-Luen , Wu Chin-Chung , Wu Yang-Chang 
Published: May 2015

Abstract
Inhibition of the DNA damage checkpoint and repair functions is a promising approach to improve chemosensitivity. Ataxia telangiectasia and Rad3-related protein (ATR) is an important checkpoint kianse responsible for organizing both normal and stressful DNA replication. In previous, we discovered a natural compound protoapigenone (WYC02) and its synthetic derivate WYC0209 are able to inhibit ATR-mediated Chk1 phosphorylation, impair the G2/M checkpoint, and improve cancer sensitivity to cisplatin both in vitro and in vivo. Although all evidences convince ATR signaling is disrupted by WYC compounds, the effect of compounds on ATR kinase activity is still unknown. In this study, we further provide evidences to prove that WYC02 and WYC0209 are undoubted ATR inhibitors by using of in vitro kinase assay. The data showed WYC0209 inhibits ATR kinase activity at least 4 times greater than WYC02, and enhances MDA-MB-231cells sensitivity to DNA replication-affecting agents such as doxorubicin, mitomycin C, and etoposide, but has little or no effect to mitosis-affecting microtubule inhibitor palcitaxol. The result of this study proposes a strategy to improve most of current chemotherapeutics in which aim to selective disrupting DNA replication in fast growing cancers.
Citation Format: Hui-Chun Wang, Alan Yueh-Luen Lee, Chin-Chung Wu, Yang-Chang Wu. Discovery of ATR kinase inhibitors from natural products. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1637. doi:10.1158/1538-7445.AM2014-1637
Abstract 1641: Structure-based design and development of pyrazolopyridine-based inhibitors of Mcl-1
Authors: Abulwerdi Fardokht A. , Mady Ahmed S.A. , Perdih Andrej , Stuckey Jeanne A. , Showalter Hollis D. , Nikolovska-Coleska Zaneta 
Published: May 2015

Abstract
The anti-apoptotic myeloid cell leukemia protein Mcl-1, a member of the Bcl-2 family proteins, has emerged as a promising therapeutic target. Mcl-1 is overexpressed in many human cancers which has been associated with inferior survival, poor prognosis and resistance to chemotherapies. Disruption of Mcl-1 interaction with its pro-apoptotic partners through small molecules is a viable strategy to overcome Mcl-1 mediated resistance to apoptosis. Targeting Mcl-1 protein represents a promising strategy either alone or in combination with other therapies.
Applying an integrated screening approach through combining high throughput and virtual screenings, several novel chemical classes were identified as Mcl-1 inhibitors. Compound 38 with a pyrazolopyridine scaffold was selected as a promising high throughput lead for medicinal chemistry efforts. Using reported chemistry a focused library of analogs of 38 was generated. Through HSQC protein-observed NMR studies and chemical shift mapping, the binding of the lead compound 38 was characterized and confirmed to be the BH3 binding pocket of Mcl-1. Computational modeling guided by NMR studies was applied in lead optimization and rational design of more potent analogs. Structure-activity relationship was established utilizing two different competitive platforms of fluorescent polarization and surface plasmon resonance, and confirmed by HSQC NMR spectroscopy. The binding affinity of this class of compounds was improved more than twenty fold in comparison with the lead compound 38. In vitro binding, functional and cell-based assays were performed in order to determine selectivity profile against five members of Bcl-2 family, mechanism of action and cellular activity of analogs with improved potency. The obtained results show promise for further chemical modification and development of pyrazolopyridine-based inhibitors of Mcl-1.
Citation Format: Fardokht A. Abulwerdi, Ahmed S.A. Mady, Andrej Perdih, Jeanne A. Stuckey, Hollis D. Showalter, Zaneta Nikolovska-Coleska. Structure-based design and development of pyrazolopyridine-based inhibitors of Mcl-1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1641. doi:10.1158/1538-7445.AM2014-1641
Abstract 1643: BMS-983970, an oral pan-Notch inhibitor for the treatment of cancer
Authors: Gavai Ashvinikumar V. , Zhao Yufen , O'Malley Daniel , Fink Brian , Quesnelle Claude , Norris Derek , Chen Libing , Kim Soong-Hoon , Han Wen-Ching , Gill Patrice , Shan Weifang , Balog Aaron , Tebben Andrew , Rampulla Richard , Wu Dauh-Rurng , Zhang Yingru , Mathur Arvind , Wang Haiqing , Yang Zheng , Ruan Qian , Moore Robin , Rodrigues David , Ranasinghe Asoka , D'Arienzo Celia , Tye Ching Kim , Su Ching , Everlof Gerry , Yarde Melissa , Cvijic Mary Ellen , Menard Krista , Wen Mei-Li , Trainor George , Fischer Bruce , Hunt John , Vite Gregory , Westhouse Richard , Lee Francis 
Published: May 2015

Abstract
Deregulation of the Notch pathway has been shown to be oncogenic in numerous tissue types including T-cell acute lymphoblastic leukemia (T-ALL), breast cancer, non-small cell lung cancer, and colorectal carcinoma. Notch signal activation can cause uncontrolled proliferation, restrict differentiation leading to increased self-renewal capacity, evasion of apoptosis, and enhancement of angiogenesis and metastasis. There is increasing evidence that Notch plays a role in the maintenance and survival of cancer stem cells. γ-Secretase mediates the Notch signaling pathway by releasing the Notch intracellular domain (NICD) which translocates to the nucleus and binds to the transcription factor CSL to activate transcription of various target genes. BMS-906024 is a potent pan-Notch inhibitor that demonstrated robust anti-tumor activity at tolerated doses in multiple tumor xenograft models. It is being evaluated in Phase 1 clinical studies. BMS-906024 is being administered IV (once weekly) in the clinic and the projected human efficacious dose is 4 - 6 mg. Based on the preclinical data, the projected human half-life of BMS-906024 is in the 37 h - 124 h range.
This presentation will describe further structure-activity relationships in the 1,4-benzodiazepinone series that culminated in the identification of BMS-983970 as an oral-pan-Notch inhibitor. Pharmacokinetic properties and in vivo evaluation of BMS-983970 in T-ALL and solid tumor xenograft models will be presented.
Citation Format: Ashvinikumar V. Gavai, Yufen Zhao, Daniel O'Malley, Brian Fink, Claude Quesnelle, Derek Norris, Libing Chen, Soong-Hoon Kim, Wen-Ching Han, Patrice Gill, Weifang Shan, Aaron Balog, Andrew Tebben, Richard Rampulla, Dauh-Rurng Wu, Yingru Zhang, Arvind Mathur, Haiqing Wang, Zheng Yang, Qian Ruan, Robin Moore, David Rodrigues, Asoka Ranasinghe, Celia D'Arienzo, Ching Kim Tye, Ching Su, Gerry Everlof, Melissa Yarde, Mary Ellen Cvijic, Krista Menard, Mei-Li Wen, George Trainor, Bruce Fischer, John Hunt, Gregory Vite, Richard Westhouse, Francis Lee. BMS-983970, an oral pan-Notch inhibitor for the treatment of cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1643. doi:10.1158/1538-7445.AM2014-1643
Abstract 1645: Discovery of AMG 232, an inhibitor of the MDM2-p53 interaction: From lead to a clinical candidate
Authors: Li Zhihong 
Published: May 2015

Abstract
The p53 tumor suppressor is controlled by MDM2, which binds p53 and negatively regulates its transcriptional activity and stability. Many tumors overproduce MDM2 to impair p53 function. Therefore, restoration of p53 activity by inhibiting the p53-MDM2 binding represents an attractive novel approach to cancer therapy. We previously reported the discovery AM-8553, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction (Rew et al. J. Med. Chem. 2012, 55, 4936). We report here continued research on the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface that led to the discovery of variety of sulfonamides and sulfones which gave rise to substantial improvements in biochemical and cellular potency. Further work led to discovery of AMG 232, which is currently being evaluated in human clinical trials for the treatment of cancer. AMG 232 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties. The compound interacts specifically with the p53-binding pocket of MDM2 and releases the p53 protein from negative control. Treatment of cancer cells expressing wild-type p53 with AMG 232, stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest and apoptosis. The compound showed excellent efficacy in a number of mouse tumor xenograft models and was well tolerated in preclinical toxicology studies at therapeutically relevant dosages.
Citation Format: Zhihong Li. Discovery of AMG 232, an inhibitor of the MDM2-p53 interaction: From lead to a clinical candidate. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1645. doi:10.1158/1538-7445.AM2014-1645
Abstract 1649: Extent and location of tumor infiltrating lymphocytes in colon cancer predicts outcome to adjuvant active specific immunotherapy
Authors: Hooijberg Erik , Turksma Annelies W. , Shamier Marc , Lam Kevin , Coupe Veerle MH , Weger Vincent A. de , Belien Jeroen AM , Eertwegh Alfons J. van den , Meijer Gerrit A. , Meijer Chris JLM 
Published: May 2015

Abstract
Purpose: We investigated the prognostic and predictive value of tumor infiltrating lymphocytes (TIL) in colorectal cancer in a cohort of patients who previously took part in a trial on adjuvant Active Specific Immunotherapy (ASI).
Experimental Design: We determined the numbers of CD3+ and CD8+ cells in archival tumor samples of 110 colorectal cancer patients as total infiltrating TIL, intraepithelial TIL and stromal TIL. Survival curves were used to determine the prognostic and predictive value of TIL.
Results: Patients with microsatellite instable (MSI) tumors had higher numbers of intraepithelial CD3+ and CD8+ TIL compared to patients with microsatellite stable (MSS) tumors. Patients with MSI tumors had a good prognosis. Patients with MSS cancers with high intraepithelial or stromal TIL numbers had a better prognosis compared to those with low TIL numbers. Significant survival benefits were found for the disease specific survival (DSS) and recurrence free interval (RFI) for patients with high infiltrates of stromal CD3+ or intraepithelial CD8+ cells. Additionally high numbers of total CD8+ and high stromal CD8+ cells gave a significant difference in RFI compared to low TIL numbers. The numbers of TIL found in MSS tumors also have predictive value with respect to response to adjuvant ASI treatment. Compared to controls significance was reached in ASI treated patients with high total CD3, high stromal CD3 or high stromal CD8 numbers in DSS as well as RFI.
Conclusion: ASI therapy is effective in patients with MSS colorectal tumors harboring high numbers of preexisting stromal CD3 or CD8 positive TIL.
Citation Format: Erik Hooijberg, Annelies W. Turksma, Marc Shamier, Kevin Lam, Veerle MH Coupe, Vincent A. de Weger, Jeroen AM Belien, Alfons J. van den Eertwegh, Gerrit A. Meijer, Chris JLM Meijer. Extent and location of tumor infiltrating lymphocytes in colon cancer predicts outcome to adjuvant active specific immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1649. doi:10.1158/1538-7445.AM2014-1649