bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1226: Highly specific ATR inhibitors as a therapeutic approach for a broad spectrum of cancers
Authors: Butler Laura R. , Ragland Ryan L. , Breslin Hank J. , Gill Tina , George Erin , Simpkins Fiona , Brown Eric J. , Gilad Oren 
Published: July 2016

Abstract
Ataxia Telangiectasia and Rad3-related (ATR) and Checkpoint kinase 1 (CHK1) stabilize stalled replication forks and prevent their collapse into DNA double strand breaks (DSBs). Inhibition of ATR in cells experiencing oncogenic stress or harboring other cancer-associated defects synergistically increases the formation of DSBs and causes synthetic lethality. Thus specific targeting of ATR represents an emerging strategy to treat a broad spectrum of cancers, most notably those that currently lack effective treatments.
Atrin Pharmaceuticals has synthesized a novel series of small molecules that inhibit ATR at low nanomolar concentrations in cultured cells. These compounds have the highest known potency for inhibiting ATR and maintain &gt;800-fold lower cellular activity towards other kinases of the same family (ATM, DNA-PKcs and mTOR), which are substantially off-targeted by previously reported ATR inhibitors. Atrin's lead compound (ATRN-119), as a single agent, selectively kills cancer cells subjected to oncogenic stress, alternative lengthening of telomeres (ALT) or loss of double strand break (DSB) homologous recombination repair mechanism (BRCA1 or BRCA2 deficiency). Furthermore, ATRN-119 cytotoxicity is synergistically enhanced when combined with conventional chemotherapeutics, such as etoposide, cisplatin and olaparib. Therefore, this inhibitor can be used in combination with other therapeutics to potentiate its anti-tumor activity.
In vivo studies of RAS oncogene driven HCT116 p53-null flank tumors in mice demonstrate the ability of our lead compound to slow tumor progression, with minimal toxicity to tissues under normal proliferative control, including the bone marrow and intestine. Additionally, mice engrafted with BRCA2-mutant patient-derived ovarian tumors show a significant reduction in progression after 5 weeks treatment (100 mg/kg BID) of ATRN-119, and display no toxicity or significant weight loss. Thus, ATRN-119 is highly efficacious in suppressing tumor growth in multiple murine models, including suppression of patient-derived BRCA2-mutant ovarian cancer, suggesting that the clinical application of the ATRN series will provide a new and effective treatment for human malignancies with fewer side effects than conventional chemotherapies.
Citation Format: Laura R. Butler, Ryan L. Ragland, Hank J. Breslin, Tina Gill, Erin George, Fiona Simpkins, Eric J. Brown, Oren Gilad. Highly specific ATR inhibitors as a therapeutic approach for a broad spectrum of cancers. [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 1226.
Abstract 1228: Indolo-pyrido-isoquinolin based alkaloid inhibits epithelial-mesenchymal transition and stemness via activation of p53-miR34a axis
Authors: Nagalingam Arumugam , Avtanski Dimiter. B , Tomaszewski Joesph , Prabhakar Risbood , Difillippantonio Michael , Mears Brian , Saxena Neeraj , Malhotra Sanjay , Malhotra Sanjay , Sharma Dipali 
Published: July 2016

Abstract
The tumor suppressor p53 plays a critical role in suppressing cancer growth and progression and is the most frequently mutated and functionally inactivated gene in all human malignancies. Owing to its widespread alteration/inactivation in cancer, p53 is an attractive target for the development of new targeted therapies. We synthesized several indolo-pyrido-isoquinolin based alkaloids to restore/activate p53 function and examined their therapeutic efficacy using NCI-60 screening. Here, we provide molecular evidence that one of these compounds, 11-Methoxy-2,3,4,13-tetrahydro-1H-indolo[2’,3’:3,4]pyrido[1,2-b]isoquinolin-6-ylium-bromide (termed P18 or NSC-768219) inhibits growth and clonogenic potential of cancer cells. P18 treatment results in downregulation of mesenchymal markers and concurrent upregulation of epithelial markers as well as inhibition of migration and invasion. Experimental epithelial-mesenchymal-transition (EMT) induced by exposure to TGFβ/TNFα is also completely reversed by P18. Importantly, P18 also inhibits mammosphere-formation along with a reduction in the expression of stemness factors, Oct4, Nanog and Sox2. We show that P18 induces expression, phosphorylation and accumulation of p53 in cancer cells. P18-mediated induction of p53 leads to increased nuclear localization and elevated expression of p53 target genes. Using isogenic cancer cells differing only in p53 status, we show that the alteration of mesenchymal and epithelial genes, inhibition of migration and invasion of cancer cells mediated by P18 is p53-dependent. Furthermore, P18 increases miR-34a expression in p53-dependent manner and inhibition of mammosphere-formation by P18 is further enhanced by miR-34a mimic. Collectively, these data provide evidence that p53-miR-34a activation by P18 may represent a promising therapeutic strategy for the inhibition of growth and progression of cancer.
Citation Format: Arumugam Nagalingam, Dimiter. B Avtanski, Joesph Tomaszewski, Risbood Prabhakar, Michael Difillippantonio, Brian Mears, Neeraj Saxena, Sanjay Malhotra, Sanjay Malhotra, Dipali Sharma. Indolo-pyrido-isoquinolin based alkaloid inhibits epithelial-mesenchymal transition and stemness via activation of p53-miR34a axis. [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 1228.
Abstract 1234: Galeterone-induced degradation of the androgen receptor involves inhibition of deubiquitinating enzymes
Authors: Dransfield Daniel T. , Namdev Nivedita , Jacoby Douglas B. , Ferrante Karen 
Published: July 2016

Abstract
Galeterone is a highly selective oral small molecule drug candidate that disrupts androgen receptor (AR) signaling through degradation of the AR, is a potent CYP17 lyase inhibitor, and possesses AR antagonist activity. Galeterone-induced AR degradation was observed in models having either full-length AR or known constitutively active truncated forms of the AR receptor that lack the ligand binding domain (LBD), AR-V7 and AR567es, suggesting the LBD of the AR is not required for galeterone-dependent AR degradation. Further, galeterone-induced AR degradation activity is blocked by co-administration of the proteasome inhibitor MG132. Along these lines, galeterone-induced AR degradation can be blocked by selective knock-down of the E3 ligases, Mdm2 and CHIP. We utilized a series of biochemical and cell-based in vitro methodologies to further elucidate and characterize additional signaling molecules participating in the proteasomal-dependent mechanism of galeterone-induced AR degradation. We screened a panel of 22 deubiquitinating enzymes (DUBs) in vitro and demonstrated that galeterone selectively inhibited enzymatic activity of two of the DUBs, USP12 and USP46. Separately, we used surface plasmon resonance to demonstrate a dose-dependent direct binding of galeterone to each of USP12 and USP46, alone or when pre-complexed with UAF1. USP12 is a co-activator of the AR, and selective knock-down of this DUB has been shown to increase AR degradation. USP12/USP46 have also been linked to regulation of phosphatases (PHLPPs) through ubiquitination. PHLPPs dephosphorylate AKT, providing an important regulatory mechanism for controlling the PI3K/AKT pathway. It is known that galeterone induces an increase in pAKT and pMdm2, the latter being a substrate of activated AKT. This suggests that inhibition of USP12/USP46 may regulate pAKT levels through enhanced degradation of PHLPPs via increased ubiquitination. These data support a differentiating mechanism of galeterone from other AR targeting agents whereby inhibition of USP12/USP46 leads to enhanced AR degradation.
Citation Format: Daniel T. Dransfield, Nivedita Namdev, Douglas B. Jacoby, Karen Ferrante. Galeterone-induced degradation of the androgen receptor involves inhibition of deubiquitinating enzymes. [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 1234.
Abstract 1269: Enhanced cytotoxicity in primary human metastatic melanoma cells via inhibition of the transient receptor potential melastatin-2 (TRPM2) channel
Authors: Koh David W. , Blake Steven D. , Powell Daniel P. 
Published: July 2016

Abstract
The transient receptor potential melastatin-2 (TRPM2) cation channel was previously identified as a potential target in various cancers, where its pharmacologic inhibition caused increased DNA damage and the selective eradication of cancer cells. In this study, we utilized several human primary metastatic melanoma cell lines, in which we analyzed TRPM2 and its isoforms, and evaluated the ability of TRPM2 inhibition to modulate cell death.
As TRPM2 is known to exist as a plasma membrane cation channel in noncancerous cells, we investigated the localization of TRPM2 in melanoma cells. In three lines of primary human metastatic melanoma cells, TRPM2 was localized in the nucleus, as compared to an extra-nuclear localization in noncancerous primary epidermal keratinocyes. Because TRPM2 exists in several isoforms in cancer cells, we investigated the cellular localization of these isoforms. Subcellular fractionations demonstrated that only full-length TRPM2 was localized to the nucleus in primary human metastatic melanoma cells, whereas two smaller isoforms were localized exclusively in the cytoplasmic fraction.
Treatment with the TRPM2 inhibitor, clotrimazole, caused decreased proliferation in all three lines of primary human metastatic melanoma cells. Further, treatment with the DNA alkylating agent, temozolomide (TMZ), led to increased levels of cell death in melanoma cells pretreated with clotrimazole, but not in noncancerous primary epidermal keratinocyes after pretreatment. Similar increases in cell death were observed after RNAi silencing of TRPM2 followed by TMZ treatment.
Taken together, this study demonstrated that TRPM2 inhibition selectively increases cell death in primary human metastatic melanoma cells. Further, the data suggests that, similar to our previous results in breast adenocarcinoma cells, full-length TRPM2 appears to have a novel role in melanoma cell growth and survival. The results therefore suggest that TRPM2 is a potential target in melanoma, where its inhibition may cause the selective eradication of metastatic melanoma.
Citation Format: David W. Koh, Steven D. Blake, Daniel P. Powell. Enhanced cytotoxicity in primary human metastatic melanoma cells via inhibition of the transient receptor potential melastatin-2 (TRPM2) channel. [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 1269.
Abstract 1275: Suppression of platelet aggregation and tumor metastasis by anti-podoplanin mAbs recognizing a novel CLEC-2 binding domain
Authors: Sekiguchi Takaya , Takemoto Ai , Fujita Naoya 
Published: July 2016

Abstract
Tumor-induced platelet aggregation promotes tumor growth and hematogenous metastasis by secreting growth factors from platelets, by avoiding immune system and shear stress, and by stimulating the formation of tumor emboli in microvasculature. Thus, tumor-platelet interaction could be a promising target for cancer therapy. We previously identified a sialoglycoprotein podoplanin, also known as Aggrus, as a key factor in tumor-induced platelet aggregation enhancing tumor metastasis. Podoplanin is expressed in various cancers and reported to be a candidate for cancer stem cell marker. Podoplanin-induced platelet aggregation depends on binding to its platelet receptor CLEC-2. Here, we report the discovery of a novel platelet aggregation-stimulating domain PLAG4 in human podoplanin critical for the binding to CLEC-2. Mutant analyses indicated that PLAG4 exhibits a predominant CLEC-2 binding ability and platelet-aggregating function when compared to the previously reported PLAG3. Moreover, mutation of both PLAG3 and PLAG4 domains could almost completely attenuate its CLEC-2 binding ability and its platelet-aggregation activity. To validate the inhibitory effect against PLAG4 domain, we established anti-PLAG4-neutralizing monoclonal antibodies (mAbs), PG4D1 and PG4D2. Both mAbs recognized PLAG4 domain and exhibited a high affinity to podoplanin. We confirmed those neutralizing ability against PLAG4-CLEC-2 interaction and platelet aggregation. Remarkably, the administration of each mAbs significantly suppressed pulmonary metastasis of podoplanin expressing tumor.
Taken together, we suggest that PLAG4 is the novel CLEC-2 binding and platelet aggregation-stimulating domain on podoplanin and has a role in podoplanin-mediated metastasis formation. Blocking the podoplanin-CLEC-2 interaction targeting PLAG3 or PLAG4 would be a promising strategy for suppressing hematogenous metastasis.
Citation Format: Takaya Sekiguchi, Ai Takemoto, Naoya Fujita. Suppression of platelet aggregation and tumor metastasis by anti-podoplanin mAbs recognizing a novel CLEC-2 binding domain. [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 1275.
Abstract 1281: Prostaglandin D synthase is a potential novel therapeutic agent for the treatment of gastric carcinomas expressing PPARγ
Authors: Yashiro Masakazu , Fukuoka Tatsunari , Kinoshita Haruhito , Masuda Go , Kitayama Kishu , Miki Yuichiro , Morisaki Tamami , Hasegawa Tsuyoshi , Hirakawa Kosei 
Published: July 2016

Abstract
Background & Aims: The antitumor activity of prostaglandin (PG) D2 has been demonstrated against some types of cancer, including gastric cancer. However, exogenous PGD2 is not useful from a clinical point of view because it is rapidly metabolized in vivo. The aim of this study was to clarify the antitumor efficacy of an alternative, PGD2 synthase (PGDS), on gastric cancer cells. This is the first report showing that PG synthase is a promising agent for the treatment of gastric carcinomas that express peroxisome proliferator-activated receptor γ (PPARγ).
Methods: The effects of PGD2 and PGDS on the proliferation of gastric cancer were examined in vivo and in vitro for five human gastric cancer cell lines. The expression levels of PGD2 receptors and PPARγ were evaluated by RT-PCR. The effects of PGD2 and PGDS on the expression of c-myc and cyclin D1 were examined by Western blotting in the presence or absence of a PPARγ antagonist.
Results: PPARγ was expressed in gastric cancer cell lines, but PGD2 receptors were not. PGD2 and PGDS significantly decreased the proliferation of gastric cancer cells that highly expressed PPARγ. PGDS increased the PGD2 production of gastric cancer cells. A PPARγ antagonist significantly suppressed the growth-inhibitory effects of PGD2 and PGDS. Expression of c-myc and cyclin D1 was significantly decreased by PGD2; this inhibitory effect was suppressed by the PPARγ antagonist. Both PGD2 and PGDS significantly decreased subcutaneous tumor growth in vivo. Tumor volume after PGDS treatment was significantly less than after PGD2 treatment. PGD2 decreased the proliferation of gastric cancer cells through PPARγ signaling.
Conclusion: PGDS and PGD2 decreased the proliferation of gastric cancer via the PPARγ pathway. PGDS is a promising therapeutic agent for gastric cancer and PPARγ might be a predictive biomarker for PGDS treatment in gastric cancer.
Citation Format: Masakazu Yashiro, Tatsunari Fukuoka, Haruhito Kinoshita, Go Masuda, Kishu Kitayama, Yuichiro Miki, Tamami Morisaki, Tsuyoshi Hasegawa, Kosei Hirakawa. Prostaglandin D synthase is a potential novel therapeutic agent for the treatment of gastric carcinomas expressing PPARγ. [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 1281.
Abstract 1293: JQ1 sensitivity of patient-derived xenograft models of cholangiocarcinoma
Authors: Miller Aubrey L. , Garcia Patrick L. , Gamblin Tracy L. , Council Leona N. , Cui Xiangqin , Bradner James E. , Yang Eddy S. , Yoon Karina J. 
Published: July 2016

Abstract
Cholangiocarcinoma (CCA) is a lethal malignancy arising from cholangiocytes in any part of the biliary tree. The incidence of CCA has been on the rise worldwide, and the prognosis and clinical outcome have remained essentially unchanged for 30 years. The majority of patients are diagnosed at late stage, and surgery continues to be the only cure. Patients receive systemic chemotherapy with the first-line combination therapy comprising gemcitabine and cisplatin. Median survival for these patients is &lt;12 months, emphasizing the need to improve current treatment. A step toward improving outcome is the pre-clinical evaluation of novel therapeutics. Recently the bromodomain and extra-terminal domain (BET) inhibitor JQ1 has been shown to suppress tumor growth in preclinical models of multiple tumor types. The therapeutic effect of JQ1 has been attributed, at least in part, to its ability to inhibit c-Myc expression. 95% of CCA tumors express c-Myc and its down-regulation has been shown to reduce the invasive potential of CCA cells, suggesting that c-Myc contributes to CCA phenotype. Our lab recently evaluated the efficacy of the BET inhibitor JQ1 in CCA patient-derived xenograft mouse models. JQ1 suppressed CCA tumor growth in 2 of the 3 models.
To determine gene products whose upregulation or downregulation is responsible for the differences in sensitivity to JQ1 among our CCA models, we generated expression profiles of tumors from vehicle control and JQ1 treated mice using NanoString technology (nCounter PanCancer Pathways panel). Our data demonstrate that JQ1 inhibited the expression of c-Myc to a greater extent in the sensitive models than in the insensitive model. Expression array data showed further that gene products involved in cell cycle and DNA repair pathways were also decreased by JQ1. Of particular interest were two transcriptional targets of c-Myc, Chk1 and BRCA2, each of which is involved in DNA damage response. Immunohistochemistry staining confirmed expression profile analyses. We conclude that the inhibition of cell cycle and DNA repair genes may contribute to the mechanism of action of JQ1 in CCA tumors.
Citation Format: Aubrey L. Miller, Patrick L. Garcia, Tracy L. Gamblin, Leona N. Council, Xiangqin Cui, James E. Bradner, Eddy S. Yang, Karina J. Yoon. JQ1 sensitivity of patient-derived xenograft models of cholangiocarcinoma. [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 1293.
Abstract 1318: Pancreatic cancer therapy using polyion micelles co-loaded with cyclopamine and paclitaxel
Authors: Zhao Jun , Wu Chunhui , Wen Xiaoxia , Li Junjie , Huang Qian , Ma Ying , Ullrich Stephen , Wang Huamin , Fleming Jason , Li Chun 
Published: July 2016

Abstract
Sonic hedgehog (SHH) signaling pathway is an important regulator during the initiation and progression of pancreatic cancer, and sustained activation of this pathway contributes to excessive deposition of tumor stroma and maintenance of tumor-initiating cells. Cyclopamine, a potent inhibitor of the SHH pathway, has shown promising antitumor efficacy. However, cyclopamine is insoluble in water and is highly toxic, and cyclopamine monotherapy did not effectively inhibit tumor growth in a range of preclinical pancreatic cancer models. We hypothesized that polyion complex polymeric micelles that simultaneously deliver cyclopamine and paclitaxel (M-CPA/PTX) would display greater efficacy against pancreatic tumor than micelles loaded with cyclopamine alone (M-CPA) or paclitaxel alone (M-PTX). We tested this hypothesis in cell cultures and in an orthotopic human pancreatic cancer Miapaca-2 xenograft model and a genetically engineered mouse model of pancreatic ductal carcinoma (PDAC), the KPC model. Our results showed that M-CPA interrupted the SHH pathway by antagonizing the smoothened receptor, reduced expression of Gli-1 transcription factor, and inhibited proliferation of Miapaca-2 cells and stroma-producing human pancreatic stellate cells. In Miapaca-2 cells, M-CPA decreased the fraction of CD133+ cells (cancer stem cells) and decreased tumorsphere formation, whereas M-TXL increased the fraction of CD133+ cells and tumorsphere formation. M-CPA negated the stimulation of human pancreatic stellate cells by exogenous SHH ligands. In vivo, M-CPA/PTX reduced tumor cell proliferation, depleted tumor stroma, and increased tumor vasculature density, leading to effective inhibition of tumor growth in Miapaca-2 xenografts. In the KPC model, M-CPA/PTX significantly prolonged media survival of mice with PDAC compared to non-treatment control mice. In conclusion, M-CPA/PTX was an effective strategy to treat pancreatic cancer. (supported in part by the Viragh Family Foundation and the John S. Dunn Foundation)
Citation Format: Jun Zhao, Chunhui Wu, Xiaoxia Wen, Junjie Li, Qian Huang, Ying Ma, Stephen Ullrich, Huamin Wang, Jason Fleming, Chun Li. Pancreatic cancer therapy using polyion micelles co-loaded with cyclopamine and paclitaxel. [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 1318.