bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4690: Novel Ring1B-Bmi1 small molecule inhibitors target leukemia stem cells
Authors: Shukla Shirish , Gray Felicia , Ying Weijang , Cho Hyoje , Zhao Qingjie , Miao Hongzhi , Purohit Trupta , Grembecka Jolanta , Cierpicki Tomasz 
Published: July 2016

Abstract
Leukemia is a clonal neoplastic disorder which possesses a rare population of cells, termed leukemia stem cells (LSCs), capable of limitless self-renewal and are necessary to initiate, sustain or regenerate the disease. Targeting LSCs self-renewal not only would offer substantial therapeutic benefit but also likely to be essential and sufficient for selective eradication of LSCs. BMI1, polycomb group protein, has been identified and shown to be required for self-renewal of LSCs. Bmi1 alongwith Ring1B constitute enzymatic active unit of Poly-comb Repressive Complex 1(PRC1) and execute gene silencing through histone H2A lysine119 ubiquitination (H2AK119ub). Considering Bmi1 as a key regulator of self-renewal, targeting Bmi1 activity could impair LSCs self-renewal ability and may represent a new therapeutic approach for leukemia. Thus, in this study we aimed to develop and characterize novel small molecule inhibitors for Ring1B - Bmi1. Using NMR fragment-based screening and extensive medicinal chemistry optimization we developed WY332 that binds to Ring1B-Bmi1 with low micromolar affinity. Further characterization of the WY332 demonstrated selective reduction in Ring1B-Bmi1 mediated H2AK119ub levels in in vitro and in leukemic cells. Contrary, structurally similar and less potent compound displayed similar effect at much higher concentrations establishes that higher binding affinity of potent inhibitor is associated with blocking Ring1B-Bmi1 E3 ligase activity. Further evaluation of lead inhibitor, WY332, in colony formation assay using leukemic cells demonstrated significant decrease in the number and size of the colonies indicated that interference with Ring1B- Bmi1 activity alter the frequency of LSCs colony forming potential. Moreover, expression analysis of CD11b and CD34, cell surface markers associated with myeloid differentiation and AML LSCs phenotype, in WY332 treated TEX cells revealed marked increase in CD11b expression and significantly decreased CD34 expression establishes the specific effect of our Ring1B-Bmi1 small molecule inhibitors on induction of differentiation in leukemic cells. Interestingly, gene expression analysis of TEX cells treated with WY332 revealed significant increase in expression of genes suppressed in LSCs. Overall, these compounds represent the novel small molecule inhibitors of Ring1B-Bmi1 which inhibit E3 ubiquitin ligase activity and impair leukemic stem cell self-renewal capacity.
Citation Format: Shirish Shukla, Felicia Gray, Weijang Ying, Hyoje Cho, Qingjie Zhao, Hongzhi Miao, Trupta Purohit, Jolanta Grembecka, Tomasz Cierpicki. Novel Ring1B-Bmi1 small molecule inhibitors target leukemia stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4690.
Abstract 4692: Targeting the BET bromodomain proteins and anti-apoptotic protein BCL2 in small cell lung cancer
Authors: Lam Lloyd T. , Lin Xiaoyu , Faivre Emily , Yang Ziping , Huang Xiaoli , Bellin Ricky , Lu Xin , Shen Yu , Uziel Tamar 
Published: July 2016

Abstract
10% to 15% of all lung cancers are small cell lung cancer (SCLC), named for the size of the cancer cells when seen under a microscope. SCLC often starts in the bronchi near the center of the chest. It usually grows and spreads quickly to distant parts of the body before it is diagnosed. Unfortunately, no new treatment has been identified in the past 30 years for patients with SCLC. The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. In hematologic cancers, BET proteins have been shown to regulate expression of MYC and other oncogenic transcription factors that drive disease pathology. Pharmacologic inhibition of BET binding to acetylated proteins has been shown to inhibit tumor growth in MYC-dependent cancers, such as acute myeloid leukemia, multiple myeloma and neuroblastoma. Here, we demonstrate that ∼40% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor ABBV-075. Whereas most SCLC cell lines undergo cell cycle arrest with ABBV-075 treatment, a few cell lines undergo apoptosis. Sensitivity does not correlate with MYC status (amplification/expression). However, downregulation of anti-apoptotic protein BCLxL and BCL2 by ABBV-075 was observed in sensitive SCLC cells. Synergy was observed when co-treating BET inhibitor and BCL2 inhibitors, venetoclax (ABT-199) or navitoclax (ABT-263), and it positively correlated with BCL2 expression. Thus, high BCL2 protein expression could potentially be a biomarker predictive of these therapeutic combinations. The potential higher synergy with venetoclax may be explained by downregulation of BCLxL with BET inhibition and potent activity of venetoclax against BCL2. Our studies have provided evidence for treating SCLC by BET inhibition and/or combination with BCL2 inhibitors and a rationale for the clinical development of BET inhibitors in this disease with high unmet medical need.
Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.
Citation Format: Lloyd T. Lam, Xiaoyu Lin, Emily Faivre, Ziping Yang, Xiaoli Huang, Ricky Bellin, Xin Lu, Yu Shen, Tamar Uziel. Targeting the BET bromodomain proteins and anti-apoptotic protein BCL2 in small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4692.
Abstract 470: Application of sequencing, liquid biopsies and patient derived xenografts for personalized medicine in melanoma
Authors: Girotti Maria R. , Gremel Gabriela , Lee Rebecca , Galvani Elena , Rothwell Dominic , Viros Amaya , Mandal Amit Kumar , Lim Kok Haw Jonathan , Saturno Grazia , Furney Simon J , Baenke Franziska , Pedersen Malin , Rogan Jane , Swan Jacqueline , Smith Matthew , Fusi Alberto , Oudit Deemesh , Dhomen Nathalie , Brady Ged , Dive Caroline , Marais Richard 
Published: July 2016

Abstract
BRAF/MEK inhibitors and immunotherapies have revolutionized care for patients with advanced melanoma, improving expected median survival from 9 months to 25-30 months, but the majority of patients still die of their disease. Personalized medicine strives to individualize and improve patient care. To individualize treatment decisions in advanced melanoma we analyzed 364 samples from 214 patients. We performed whole exome sequencing (WES) and circulating tumor DNA (ctDNA) analysis, and we developed patient derived xenografts (PDX). WES and targeted sequencing of ctDNA allowed us to predict responses to therapy and to identify and monitor mechanisms of resistance. WES of tumors revealed new therapeutic strategies in BRAF V600 wild-type and BRAF inhibitor-resistant melanoma and we validated these in patient derived xenografts (PDX). Thus, we describe a powerful combination of techniques for personalized medicine to improve the management of melanoma patients.
Citation Format: Maria R. Girotti, Gabriela Gremel, Rebecca Lee, Elena Galvani, Dominic Rothwell, Amaya Viros, Amit Kumar Mandal, Kok Haw Jonathan Lim, Grazia Saturno, Simon J Furney, Franziska Baenke, Malin Pedersen, Jane Rogan, Jacqueline Swan, Matthew Smith, Alberto Fusi, Deemesh Oudit, Nathalie Dhomen, Ged Brady, Caroline Dive, Richard Marais. Application of sequencing, liquid biopsies and patient derived xenografts for personalized medicine in melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 470.
Abstract 4707: Investigating the role of EZH2 as a therapeutic target in clear cell renal cell carcinoma (ccRCC)
Authors: Wei Darmood , Ricketts Christopher J. , Schmidt Laura S. , Yang Youfeng , Vocke Cathy D. , Linehan William M. 
Published: July 2016

Abstract
Enhancer of zeste homolog 2 (EZH2) is a key component of the polycomb repressive complex 2 (PRC2). EZH2 is frequently overexpressed in a wide variety of human malignancies including non-Hodgkin lymphoma, gastric cancer, pancreatic cancer, and lung cancer. Thus it has potential to become a therapeutic target. Characterization of EZH2 as a therapeutic target in clear cell renal cell carcinoma (ccRCC) has not been fully explored. ccRCC have been defined by mutation of the von Hippel-Lindau (VHL) tumor suppressor gene in combination with chromosome 3p loss. Recent sequencing efforts have revealed that several chromatin remodeling genes encoded on chromosome 3p are often mutated, of which PBRM1 is the most frequent (41%). The PBRM1 gene codes for the BAF180 protein, a SWI/SNF chromatin remodeling complex subunit. Loss of BAF180 in ccRCC may disrupt the PBAF variant of the SWI/SNF complex. The SWI/SNF complex remodels the chromatin landscape by either sliding or evicting the nucleosomes from the chromatin. This chromatin remodeling modulates the accessibility to promoter regions by transcriptional machinery. It is through this mechanism that the SWI/SNF complex can regulate a range of cellular processes. It has been demonstrated that the SWI/SNF complex can act antagonistically to the PRC2 complex by evicting PRC2 complex from the promoters of tumor suppressors such as CDKN2A/p16. Disruption of the SWI/SNF complex would impede the eviction of the PRC2 complex, similarly observed in SNF5-deficient malignant rhabdoid tumors. Therefore, we hypothesize that PBRM1 inactivation disrupts specific SWI/SNF complexes allowing EZH2 to bind and repress target tumor suppressor genes. Thus inhibition of EZH2 in ccRCC may present as a targeted therapeutic option in tumors with PBRM1 mutations. We have investigated EZH2 in ccRCC cell lines with PBRM1 mutations and observed that these cells lines have overexpression of EZH2 in comparison to RPTEC (renal cortex proximal tubule epithelium cell line). We examined the effects on two EZH2 inhibitors (GSK126 and EPZ6438) on ccRCC cell lines both in vitro and in vivo. Our preliminary data suggests EZH2 inhibition results in reduced growth of ccRCC cell lines with PBRM1 mutations.
Citation Format: Darmood Wei, Christopher J. Ricketts, Laura S. Schmidt, Youfeng Yang, Cathy D. Vocke, William M. Linehan. Investigating the role of EZH2 as a therapeutic target in clear cell renal cell carcinoma (ccRCC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4707.
Abstract 472: A digital sorting-based detection and isolation assay for single disseminated cancer cells from lymph nodes of melanoma patients
Authors: Scheitler Sebastian , Weidele Kathrin , Alberter Barbara , Werno Christian , Klein Christoph A. , Polzer Bernhard 
Published: July 2016

Abstract
We recently showed that sentinel lymph node (SLN) disaggregation followed by immunocytology enables precise quantification of disseminated cancer cells (DCC). We demonstrated that this approach has a 20-fold higher sensitivity to detect melanoma DCCs than routine histopathology and that the DCC density (DCCD, defined as the number of DCCs per million lymph node cells) together with ulceration state and tumor thickness enables individual risk prediction superior to current AJCC guidelines (Ulmer et al., PLoS Medicine, 2014). Here, we present the adaptation of this method to a semi-automated workflow, including automated single cell detection and isolation by DEPArrayTM technology for subsequent molecular analysis of DCCs from SLN of melanoma patients.
The developed workflow includes a mechanical disaggregation of lymph node tissue and collection of the mononuclear cells after Percoll density centrifugation. Several tumor cell enrichment methods were tested (CellSearch® and size-based enrichment technologies), however, failed to process cell suspensions generated from lymph nodes due to clumping of cells during the enrichment procedure. Tumor cell enrichment using MACS depletion of CD45+ cells delivered approx. 50% of spiked-in cell line cells with a mean depletion rate of lymphocytes and erythrocytes &gt; 98%. To prevent limitations in DCC detection caused by phenotypic heterogeneity of tumor cells, we established a double staining against two melanoma-associated markers gp100 and MCSP. Individual melanoma cells are then detected and isolated by DEPArrayTM technology enabling single cell whole genome amplification (Ampli1TM) for subsequent molecular analysis as assessment of copy number alterations (e.g. by arrayCGH) or sequence analysis for melanoma specific point mutations (e.g. BRAF or NRAS). We successfully applied the workflow to first SLN samples from melanoma patients.
The established workflow enables a standardized detection of single DCCs from lymph nodes of melanoma patients applicable in clinical diagnostic labs. Automated single cell isolation and subsequent molecular analysis of DCCs is feasible within short time after SLN biopsy. In the future, this approach could help to select individualized therapies for melanoma patients.
Citation Format: Sebastian Scheitler, Kathrin Weidele, Barbara Alberter, Christian Werno, Christoph A. Klein, Bernhard Polzer. A digital sorting-based detection and isolation assay for single disseminated cancer cells from lymph nodes of melanoma patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 472.
Abstract 4727: ST7612AA1: focus on a drug candidate, front-runner of a new generation of HDAC inhibitors
Authors: Giannini Giuseppe , Milazzo Ferdinando Maria , Battistuzzi Gianfranco , Vesci Loredana 
Published: July 2016

Abstract
After more than 20 years of research in the field of HDAC inhibitors, the oncological armamentarium has significantly enriched with new approved drugs. Currently, four drugs, Vorinostat (Zolinza; 2006), Romidepsin (Istodax; 2009) Belinostat (Beleodaq; 2014) and Panobinostat (Farydak; 2015) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and multiple myeloma, respectively. A fifth, Chidamide (Epidaza; 2015), has been recently approved by the China Food and Drug Administration for the treatment of PTCL.
Beyond them, more than twenty are currently under pre-clinical and clinical investigation as single agent and in combination therapies against different cancers and in other several novel therapeutic indications. However, it is to emphasize a feature: among all these, no one, with the exception of the natural product Romidepsin, is a thiol derivative.
After efforts lasted years, now we have selected ST7612AA1 - a new thiol-ω(γ-lactam amide) SAHA analogues, potential front-runner of a new generation of HDAC inhibitors, [1] highly competitive respect to other HDAC inhibitors drugs, orally administered with a negligible toxicity.
ST7612AA1 displays low-nanomolar inhibitor activity on HDACs, being especially powerful on HDAC6 isoform, associated to a wide spectrum of antitumor activity, both in vitro and in vivo [2]; it can be industrially developed with a quick and easy synthetic process [3]. Moreover, it has also been investigated as an enhancer in antiretroviral therapy against HIV, aimed to eradicate the viral reservoirs [4].
All these results encouraged further enrichment experiments with ST7612AA1 as a drug candidate, which is currently in a phase of pre-clinical evaluation.
The overall profile of ST7612AA1, including synthesis and a comprehensive pharmacological characterization, will be presented.
[1] G. Giannini et al. J Med Chem. 2014, 57, 8358-8377
[2] L. Vesci et al. Oncotarget 2015, 6, 5735-48
[3] G. Battistuzzi, G. Giannini. Bioorg. Med. Chem .Lett. 2015, submitted
[4] R. Badia Antiviral Research 2015, 123, 62-69
Citation Format: Giuseppe Giannini, Ferdinando Maria Milazzo, Gianfranco Battistuzzi, Loredana Vesci. ST7612AA1: focus on a drug candidate, front-runner of a new generation of HDAC inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4727.
Abstract 4737: New platinum (Pt)-based anticancer agents, bearing a PtN2SO coordination core, for treating advanced melanoma
Authors: To Kenneth K.W. , Chong Peace , Au-Yeung. Steve C.F. 
Published: July 2016

Abstract
The aim of this project is to demonstrate the potential utility of a new series of platinum (Pt) compounds having a PtN2SO coordination core in treating advanced melanoma. There is currently an unsatisfied medical need for a more effective treatment of advanced melanoma, which is notorious for its prominent resistance to conventional chemotherapeutic drugs due to elevated DNA repair capacity and dysregulation of cancer apoptotic pathways. Platinum (Pt)-based anticancer drugs, exemplified by cisplatin, are key component in combination chemotherapy. They bind to DNA and form mainly the DNA-Pt bifunctional crosslink, subsequently leading to apoptosis to mediate cell death. A series of new Pt(II) compounds possessing a bidentate ligand modified from oxaliplatin has been synthesized, with one of the oxygen ligating atom substituted for a sulfur atom (resulting in a PtN2SO coordination core structure). This novel design is to minimize competition from protein and other bionucleophiles for the Pt drug but maximize drug-DNA interaction. We hypothesize that the unique features of the new PtN2SO compounds may make them good candidates for treating advanced melanoma by (i) overcoming DNA repair-mediated drug resistance; and (ii) generating excess reactive oxygen species (ROS) to selectively trigger apoptosis in melanoma cells. The new compounds were found to be more cytotoxic than cisplatin in a panel of human and mouse melanoma cell lines. Importantly, the new compounds were also found to be minimally affected by Pt resistance, which is presumably caused by the formation of unique DNA-Pt monoadduct and reduced DNA repair. DNA-platination study in melanoma cell lines revealed that the new PtN2SO compounds are able to form more DNA-Pt adducts and there was less repair than treatment with cisplatin. The new compounds were also found to cause a greater induction of the MAPKs (p38, JNK and ERK) than cisplatin to mediate apoptosis. On the other hand, at equipotent concentration, some of the new Pt compounds were found to generate more ROS than cisplatin as indicated by a general fluorescent dye-based oxidative stress indicator. Interestingly, the cytotoxicity of the new compounds were blocked to a greater extent than cisplatin by ROS scavengers, suggesting a more prominent role played by ROS in mediating the cytotoxicity of the new compounds. Our study thus advocates further investigation of the new PtN2SO compounds in treating advanced melanoma.
Citation Format: Kenneth K.W. To, Peace Chong, Steve C.F. Au-Yeung. New platinum (Pt)-based anticancer agents, bearing a PtN2SO coordination core, for treating advanced melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4737.
Abstract 4742: Comparison of enhancement of the antitumor effect of CDDP by PXR antagonists
Authors: Kishimoto Shuichi , Yasuda Megumi , Tomita Megumi , Yamane Yuki , Suzuki Ryosuke , Fukushima Shoji 
Published: July 2016

Abstract
We have already found that a nuclear receptor PXR can modulate the cytotoxicity of CDDP for cancer cells, and ketoconazole, a PXT antagonist, can be an agent enhancing the antitumor activity of CDDP due to increase of the intracellular platinum content as the mechanism. However, nuclear receptor ligands have a variety of functions, and there is a possibility that PXR antagonist may enhance the cytotoxicity of CDDP through the mechanism other than the inhibition of transporter-mediated efflux of CDDP. The goal of this study was to compare the enhancing ability of three PXR antagonists, ketoconazole (KTZ), phenethyl isothiocyanate (PEITC) and metformin (MFM), for the antitumor effect of CDDP and clarify the contribution of inhibition of the efflux transporter as the mechanism of PXR antagonist. Cell lines used in this study were human hepatoma cell line HepG2. Changes in mRNA expression were assessed by real-time RT-PCR, and the ability of apoptosis induction was assessed as caspase-3 activity. Total intracellular platinum contents were determined by ICP-AES. When HepG2 cells were treated for 24 hr with 10 μM of CDDP, no change of caspase-3 activity was observed when compared to control cells. Also, 30 μM of KTZ, 30 μM of PEITC or 5 mM of MFM had no affect on the caspase-3 activity in treated cells compared with control cells. When KTZ, PEITC or MFM was exposed to HepG2 cells from 24 hr before treatment and during 24-hr treatment with 10 μM of CDDP, the caspase-3 activity was significantly increased to 461%, 355% and 326% of the control, respectively, in comparison with that in CDDP alone. When HepG2 cells were treated for 8 hr with 25 μM of CDDP, the intracellular platinum content was 110 ng/mg protein. On the other hand when KTZ, PEITC or MFM was exposed to HepG2 cells from 24 hr before treatment and during 8-hr treatment with 25 μM of CDDP, the intracellular platinum content was apparently increased to 227%, 491% and 161% of CDDP alone, respectively. Three PXR antagonists resulted in an increase in the intracellular platinum content that seems to be due to inhibition of the platinum efflux transporter, but there is no correlation between increase in intracellular platinum content and enhancement of antitumor activity by PXR antagonists. These results concluded that PXR antagonist can be an agent enhancing the antitumor activity of CDDP, but the ability of PXR antagonist for enhancing antitumor activity of CDDP can not be determined from only the increase in the intracellular platinum content.
Citation Format: Shuichi Kishimoto, Megumi Yasuda, Megumi Tomita, Yuki Yamane, Ryosuke Suzuki, Shoji Fukushima. Comparison of enhancement of the antitumor effect of CDDP by PXR antagonists. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4742.