bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4850: The minor groove binding agent quinacrine inhibits growth and increases apoptotic death in diffuse intrinsic pontine glioma tumor cells
Authors: Guo Huizi , Kaur Harpreet , Akhtarkhavari Sepehr , Eberhart Charles G. , Raabe Eric H. 
Published: August 2018

Abstract
Diffuse intrinsic pontine glioma (DIPG) is an invasive, incurable and aggressive pediatric brain tumor found in the brainstem. Improved understanding of the biology of DIPG tumors is urgently needed to develop novel treatments. Our previous studies have shown that DIPG tumors and cell lines express high levels of the DNA-binding stem cell factor high mobility group AT-hook 2 (HMGA2).. Targeting HMGA2 using lentiviral shRNA decreased DIPG cell invasion, proliferation and increased apoptosis in our studies. We hypothesized that inhibiting HMGA2 using DNA minor groove binding drugs like quinacrine would decrease DIPG proliferation and increase apoptotic cell death. We used three DIPG cell lines (JHHDIPG1, JHHDIPG16A, and SUDIPG13) to test the effect of quinacrine. Quinacrine has traditionally been used as an anti-malarial drug and is known to strongly bind to DNA. We used BrdU incorporation as a measure of proliferation and expression of cleaved caspase-3 (CC-3) as a measure of apoptosis. Treatment of DIPG cells with quinacrine showed a dose dependent increase in cell death (CC-3 expression) from 3uM to 20uM, with the most effective doses being from 3uM to 5uM. In all three DIPG cell lines, treatment with 1uM to 5uM quinacrine showed a significant reduction in cell proliferation (BrdU) from 3uM to 5uM compared to vehicle-treated cells (P&lt;0.0001). Additionally, treatment of DIPG cell lines with 1uM to 5uM quinacrine showed a significant increase in apoptotic cell death (CC-3 expression) compared to vehicle control cells from 3uM to 5uM (P&lt;0.001). Our data suggests that minor groove binding agents like quinacrine could be effective therapies for this lethal brain tumor. Our future studies are aimed at testing the efficacy of quinacrine in inhibiting DIPG tumorigenicity and elucidating the mechanism of action.
Citation Format: Huizi Guo, Harpreet Kaur, Sepehr Akhtarkhavari, Charles G. Eberhart, Eric H. Raabe. The minor groove binding agent quinacrine inhibits growth and increases apoptotic death in diffuse intrinsic pontine glioma tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4850.
Abstract 4853: Regulation of proteolytic repair of Top2 covalent complexes
Authors: Sun Yilun , Nitiss Karin C. , Nitiss John L. 
Published: August 2018

Abstract
DNA topoisomerases (topos) play an essential role in nuclear processes such as replication, transcription, and chromosome segregation. These enzymes regulate DNA topology by introducing transient breaks in DNA with formation of transient protein/DNA covalent complexes. These complexes can be trapped by aberrant DNA structures, and are also the basis for anti-cancer drugs that target topos. Since topos can be trapped on DNA, leading to strand breaks with protein adducts at the site of the breaks, cells require DNA repair pathways to process protein adducts. We have examined the repair of the type II topos (Top2) in yeast and mammalian cells. We developed a sensitive assay to detect ubiquitylation and other post-translational modifications (PTMs) of Top2 trapped on DNA in S. cerevisiae and have shown that the proteasome plays a key role in repair of Top2 damage induced by the anti-cancer drug etoposide. We demonstrated that sumoylation of Top2 is induced by etoposide, and that deletion of the SUMO ligase Siz2 prevents etoposide induced sumoylation. Deletion of either of the genes encoding the ubiquitin ligase Slx5/Slx8 led to decreased ubiquitylation of trapped Top2. The mammalian ortholog of Slx5/Slx8 is Rnf4, and it too plays a role in ubiquitylation and degradation of Top2 trapped by etoposide. A human cell line completely lacking Rnf4 is defective in ubiquitylation of Top2β, one of the two mammalian Top2 isoforms. Interestingly, repair of the Top2α isoform is unaffected in an Rnf4 knockout cell line. Proteolysis of trapped Top2 is also subject to negative regulation. The UBA domain protein UBAP2L, (also termed NICE4) is amplified in various cancers. Knockout of the UBAP2L increases proteolysis of trapped Top2. Levels of trapped Top2α and Top2β are decreased in the absence of UBAP2L, and the level of trapped Top2 returns to the wild type level when MG132 is added, indicating UBAP2L regulates the proteasome mediated degradation of Top2. UBAP2L physically interacts with Top2β as determined by co-immunoprecipitation, and the interaction is not seen in Rnf4 knockout cells. Finally, knockout of UBAP2L confers high level resistance to etoposide. Our results provide insights to the response of cancer cells to Top2 targeting agents.
Citation Format: Yilun Sun, Karin C. Nitiss, John L. Nitiss. Regulation of proteolytic repair of Top2 covalent complexes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4853.
Abstract 4855: Indotecan (LMP400), Imidotecan (LMP776) and LMP744: A new class of non-camptothecin TOP1 inhibitors selective for cancer cells with homologous recombination deficiencies and high SLFN11 expression
Authors: Pommier Yves , Marzi Laetitia , Ohler Zoe Waever , Szabova Ludmila , Sharan Shyam , Murai Junko , Cushman Mark 
Published: August 2018

Abstract
To relax DNA supercoiling, topoisomerase I (TOP1) induces DNA cleavage complexes (TOP1cc). These TOP1cc can be trapped by camptothecin, leading to replication induced DNA double-strand breaks (DSB). Widely used, camptothecin derivatives have known limitations. It is now possible to overcome these limitations with the non-camptothecin indenoisoquinolines currently in clinical trials (LMP400, LMP776 and LMP744). Homologous recombination (HR) and its key components BRCA1, BRCA2 and PALB2 are needed to repair DSB induced by TOP1 inhibitors (Maede, Y et al. 2014). It has been shown that BRCA1 is a determinant of response to camptothecins in addition to Olaparib. Also, Schlafen11 (SLFN11) expression has been demonstrated to be a highly penetrant determinant of response to camptothecin derivatives (Zoppoli, G et al. 2012). To rationally select patients for phase 2 clinical trials based on cancer-specific genomic alterations, we have determined whether HR components deficiency or SLFN11 expression are determinants of LMPs response. Using isogenic cell lines, we assessed the survival after treatment with the LMPs. We found that SLFN11-positives cells are 10-times hypersensitive to LMPs compare to WT cells. Also, BRCA1-, BRCA2- and PALB2-deficient cells are 3- to 5- times hypersensitive to the LMPs. Adding Olaparib led to a greater cell death, especially in HR-deficient (HRD) cells. Our results show that the indenoisoquinolines are active at nanomolar concentrations and that HR deficiency and SLFN11 expression are strong drug response determinants. They also demonstrate that the LMPs synergize with Olaparib. These findings provide a rationale for personalized treatment and further clinical trials with the indenoisoquinolines in HR-deficient cancers.
Citation Format: Yves Pommier, Laetitia Marzi, Zoe Waever Ohler, Ludmila Szabova, Shyam Sharan, Junko Murai, Mark Cushman. Indotecan (LMP400), Imidotecan (LMP776) and LMP744: A new class of non-camptothecin TOP1 inhibitors selective for cancer cells with homologous recombination deficiencies and high SLFN11 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4855.
Abstract 486: MicroRNA-30 family members inhibit breast cancer invasion, osteomimicry, and bone destruction by directly targeting multiple bone metastasis-associated genes
Authors: Croset Martine , Pantano Francesco , Kan Casina , Bonnelye Edith , Descotes Francoise , Alix-Panabières Catherine , Lecellier Charles , Bachelier Richard , Allioli Nathalie , Hong Saw See , Bartkowiak Kai , Pantel Klaus , Clézardin Philippe 
Published: August 2018

Abstract
MicroRNAs (miRNAs), which are master regulators of gene expression, have emerged as key players in cancer metastasis. Here, we established miR-30 family members (miR-30a, miR-30b, miR-30c, miR-30d and miR-30e) as breast cancer bone metastasis suppressor genes. Low expression levels of miR-30s in primary tumors of breast cancer patients were associated with poor relapse-free survival. Additionally, miR-30s levels were significantly lower in estrogen receptor (ER)-negative/progesterone receptor (PR)-negative tumors than in their hormone-responsive counterparts. Overexpression of miR-30s in ER/PR-negative breast cancer cells resulted in the reduction of bone metastasis burden in vivo. MiR-30s overexpression also reduced tumor outgrowth, when tumor cells were implanted subcutaneously in animals. In vitro, miR-30s did not affect tumor cell proliferation, but inhibited tumor cell invasion. Furthermore, miR-30s restored bone homeostasis by reversing the in vitro effects of the tumor cell conditioned medium on stimulation of osteoclastogenesis and inhibition of osteoblastogenesis. We identified a number of genes associated with osteoclastogenesis stimulation (IL-8, IL-11), osteoblastogenesis inhibition (DKK-1), tumor cell osteomimicry (RUNX2, CDH11) and invasiveness (CTGF, ITGA5, ITGB3) that were direct and/or indirect targets for repression by miR-30s. Among these genes, integrin ITGA5 was a previously unknown miR-30 target. By silencing ITGA5 in ER-/PR-negative breast cancer cells, colonization of the bone marrow by tumor cells was drastically reduced in vivo. Overall, our data indicate that miR-30s employ multiple mechanisms to impede breast cancer bone metastasis. These findings may pave the way to a new field of therapeutic interventions in breast cancer patients with bone metastasis.
Citation Format: Martine Croset, Francesco Pantano, Casina Kan, Edith Bonnelye, Francoise Descotes, Catherine Alix-Panabières, Charles Lecellier, Richard Bachelier, Nathalie Allioli, Saw See Hong, Kai Bartkowiak, Klaus Pantel, Philippe Clézardin. MicroRNA-30 family members inhibit breast cancer invasion, osteomimicry, and bone destruction by directly targeting multiple bone metastasis-associated genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 486.
Abstract 4860: A novel class of small-molecule inhibitors of galectin-1 for prostate cancer therapy
Authors: Liu Ruiwu , Shih Tsung-Chieh , Kiss Sophie , Li Xiaocen , Wang Ting , Huynh Jonathan S. , Wu Chun-Te , Duan Yong , Ghosh Paramita M. , Lam Kit S. 
Published: August 2018

Abstract
Galectin-1 (Gal-1) is a multifunctional carbohydrate-binding protein and plays a key role in cancer cell proliferation, apoptosis, cell cycle, tumor angiogenesis and evasion of immune responses. It is also directly involved in the process of angiogenesis and tumor immune escape. An elevated level of Gal-1 has been found in many cancers, including prostate cancer. We show by immunohistochemistry in human prostate tissue that Gal-1 expression level was very low in all non-tumor samples and highly expressed in prostate cancer tissues. In addition, Gal-1 was progressively upregulated from low- , intermediate- to high-grade prostate cancer. Taken together, Gal-1 is an excellent therapeutic target against cancer. Yet, no inhibitors against Gal-1 have been approved by the FDA for cancer treatment due to lack of potent, specific and in vivo effective molecules. We recently discovered a novel small-molecule inhibitor of Gal-1, named LLS2, through a high-throughput one-bead two-compound combinatorial library approach. LLS2 exhibits cytotoxic activity against prostate cancer and ovarian cancer cells. We synthesized a series of LLS2 analogs and performed structure-activity relationship studies, leading to a more potent inhibitor LLS30 that induced apoptosis in castration-resistant prostate cancer cells expressing high levels of Gal-1. Molecular modeling study showed LLS30 bound to the sugar-binding groove of Gal-1. In enzalutamide (ENZ)-resistant 22Rv1 prostate cancer cells expressing high levels of Gal-1 and androgen receptor (AR) splice variants, LLS30 could inhibit expression of AR splice variants and sensitize the cells to ENZ in a dose-dependent manner. Downregulation of Gal-1 by siRNA prevented the expression of alternatively spliced AR variants. More importantly, LLS30 showed potent in vivo antitumor efficacy and synergistic activities with docetaxel and ENZ against PC-3 and 22Rv1 prostate cancer models, respectively. Blood chemistry test from the treated animal showed minimum effect of LLS30 on the liver and kidney functions, implying low toxicity. LLS30 is an excellent drug candidate for preclinical development as a novel prostate cancer therapeutic.
Citation Format: Ruiwu Liu, Tsung-Chieh Shih, Sophie Kiss, Xiaocen Li, Ting Wang, Jonathan S. Huynh, Chun-Te Wu, Yong Duan, Paramita M. Ghosh, Kit S. Lam. A novel class of small-molecule inhibitors of galectin-1 for prostate cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4860.
Abstract 4863: Targeting the NFAT1-MDM2-MDMX network for prostate cancer therapy
Authors: Qin Jiang-Jiang , Li Xin , Wang Wei , Zhang Ruiwen 
Published: August 2018

Abstract
The MDM2 and MDMX oncogenes are overexpressed in human prostate cancer, promoting tumor growth and metastasis. We recently demonstrate that the transcription factor NFAT1 activates MDM2 oncogene, independent of p53. The present study was designed to examine the effectiveness of targeting the NFAT1-MDM2-MDMX network for prostate cancer therapy. We identified a natural product NFAT1-MDM2 inhibitor, Inulanolide A (InuA) in the present study. The anticancer activity of InuA and its effects on the expression and stability of NFAT1, MDM2, and MDMX were examined in human prostate cancer cell lines with different genetic background, including LNCaP (p53 wild-type, AR positive), PC3 (p53 null, AR negative) and DU145 (p53 mutant, AR negative) cells. Our molecular docking studies predicted the binding ability and binding sites of InuA on NFAT1, MDM2, and MDMX. Its binding affinity and specificity were investigated using recombinant proteins and biotinylated InuA. To further demonstrate the specificity of InuA in targeting NFAT1-MDM2-MDMX network and the importance of NFAT1-MDM2-MDMX network in InuA's anticancer activity, the transient overexpression (OE) and knockdown (KD) experiments of these genes, as well as the pharmacological activators and inhibitors of NFAT1 signaling, were used. Our results indicated that InuA directly bound to the DNA binding domain of NFAT1, leading to a marked inhibition of MDM2 transcription. The compound also bound to the RING domains of MDM2 and MDMX with high affinity, inhibited the MDM2-MDMX binding, and enhanced MDM2 protein degradation. InuA inhibited the proliferation, migration, and invasion of prostate cancer cells, regardless of their p53 status and AR responsiveness. The expression of NFAT1, MDM2, and MDMX were important for InuA's anticancer activity, as demonstrated using the cancer cell lines with transient OE and KD of these genes. In conclusion, InuA represents a novel class of NFAT1-MDM2-MDMX inhibitor, and inhibiting the NFAT1-MDM2-MDMX network may be a promising strategy for prostate cancer therapy. (Supported by NIH R01 CA186662 and R01CA214019 and ACS RSG-15-009-01-CDD.)
Citation Format: Jiang-Jiang Qin, Xin Li, Wei Wang, Ruiwen Zhang. Targeting the NFAT1-MDM2-MDMX network for prostate cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4863.
Abstract 4868: BI 907828: A novel, potent MDM2 inhibitor that is suitable for high-dose intermittent schedules
Authors: Rudolph Dorothea , Gollner Andreas , Blake Sophia , Rinnenthal Jörg , Wernitznig Andreas , Weyer-Czernilofsky Ulrike , Haslinger Christian , Garin-Chesa Pilar , Quant Jens , McConnell Darryl B. , Moll Jürgen , Norbert Kraut 
Published: August 2018

Abstract
MDM2 inhibitors block the interaction between the Tumor Protein p53 (TP53) and MDM2, its key negative regulator, and represent a new therapeutic concept for cancer therapy. MDM2 inhibitors are designed to restore p53 activity in TP53 wild-type tumors. Several MDM2 inhibitors are currently being evaluated in early clinical development with mainly daily dosing regimens. However, recent clinical data suggest myelosuppression as an on-target, dose-limiting toxicity for this class of inhibitors. Particularly, thrombocytopenia could limit the clinical utility of MDM2 inhibitors. Hence there is a need to mitigate these side effects and to improve the therapeutic window. One approach is less frequent dosing to allow bone marrow recovery while still maintaining efficacious exposure levels and clinical activity. Here we present data on BI 907828, a novel and potent MDM2 inhibitor with optimized drug-like properties including a reliable, dose-linear PK across species with good bioavailability after oral dosing that allows various dose schedules. Remarkably, a single oral dose of 2 mg/kg led to tumor regressions in a SJSA-1 xenograft model in all treated mice, as did treatment on a daily low dose schedule. Data on PK, PD and efficacy relationships in this xenograft model will be presented including dose-dependent induction of TP53 target genes and markers of apoptosis. Moreover, BI 907828 significantly prolonged the survival by more than 50 days with a daily oral dose of 2.5 mg/kg in a difficult to treat disseminated MOLM-13 AML model, as noted by profiling of a clinical-stage MDM2 inhibitor. In summary, BI 907828 is a novel, potent, orally bioavailable MDM2 inhibitor that shows excellent efficacy with daily low dose but also intermittent high dose schedules in preclinical models of cancer.
Citation Format: Dorothea Rudolph, Andreas Gollner, Sophia Blake, Jörg Rinnenthal, Andreas Wernitznig, Ulrike Weyer-Czernilofsky, Christian Haslinger, Pilar Garin-Chesa, Jens Quant, Darryl B. McConnell, Jürgen Moll, Kraut Norbert. BI 907828: A novel, potent MDM2 inhibitor that is suitable for high-dose intermittent schedules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4868.
Abstract 4869: Discovery and characterization of highly potent and selective USP7 inhibitors and benchmarking against clinical MDM2 antagonists
Authors: Gavory Gerald , O'Dowd Colin , Arkoudis Elias , Barker Oliver , Cassidy Eamon , Dossang Anthony , Flasz Jakub , Helm Matt , Hughes Caroline , McClelland Keeva , Miel Hugues , Odrzywol Ewa , Page Natalie , Harrison Tim 
Published: August 2018

Abstract
Given the importance of USP7 in known oncogenic pathways and its emerging role in immuno-oncology, the identification of USP7 inhibitors has attracted considerable interest in the scientific community. However, despite substantial efforts over the past 15 years, the development of genuine deubiquitinase (DUB) inhibitors, which exhibit both drug-like properties and a well-defined mechanism of action, has proven particularly challenging.
In this study, we report the application of UbiPlexTM, our purpose-built DUB drug discovery platform, to USP7. In particular, we detail the identification, optimization and detailed characterization of a new class of non-covalent and highly potent USP7 inhibitors (IC50 &lt; 10 nM). In addition, these inhibitors have shown exquisite selectivity for USP7 over other DUBs and proteases. We also disclose high-resolution co-crystal structures of USP7 in complex with these inhibitors that reveal an allosteric mode of binding.
Further profiling in cells demonstrated potent target engagement with endogenous USP7 (EC50 &lt;20 nM). In line with the known biology of USP7, this effect induced the proteasomal degradation of MDM2, concomitant stabilization of p53 and induction of p21 in multiple cell lines. The identification and parallel profiling of inactive enantiomers further validated the on-target effect of our lead molecules. Finally, we report the identification of cell lines hyper-sensitive (EC50 &lt; 30 nM) to USP7 inhibitors in both haematological and solid cancer cell line settings and demonstrate equal or superior activity when compared to clinically relevant MDM2 antagonists.
In summary, this work exemplifies the tractability and druggability of USP7 as a cancer target and provides new insights and directions for the potential clinical development of USP7 inhibitors.
Citation Format: Gerald Gavory, Colin O'Dowd, Elias Arkoudis, Oliver Barker, Eamon Cassidy, Anthony Dossang, Jakub Flasz, Matt Helm, Caroline Hughes, Keeva McClelland, Hugues Miel, Ewa Odrzywol, Natalie Page, Tim Harrison. Discovery and characterization of highly potent and selective USP7 inhibitors and benchmarking against clinical MDM2 antagonists [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4869.
Abstract 4884: OXPHOS: A novel target for cancer therapy in oncogene addicted tumor
Authors: Hirpara Jayshree L. , Qing Jie Eu , Wong Andrea , Ohi Naoto , Takeshi Tsunoda , Goh Boon Cher , Pervaiz Shazib 
Published: August 2018

Abstract
Cancer cells are highly dependent on glycolysis over oxidative phosphorylation (OXPHOS). However, there is emerging evidence that (a) dysfunctional OXPHOS may be a major factor driving oncogene addiction and (b) feedback activation of the transcription factor STAT3 is a common surrogate survival pathway in oncogene addicted cancer cells. As such, invasive cancers exhibit enhanced oxidative phosphorylation, mitochondrial biogenesis and mitochondrial oxygen consumption rate. Therefore, inhibiting OXPHOS and STAT3 activity could have potential therapeutic implications for oncogene addicted and OXPHOS-dependent cancers. Here we report that oncogene addicted non-small cell lung carcinoma (NSCLC) cell line HCC827 and its gefitinib resistant clone and malignant melanoma cell line A375 and its vemurafanib resistant clone have significantly higher OXPHOS activity. In addition, these cells express higher level of the mitochondrial electron transport chain complex I protein (NDUFA9) and increased complex I activity as well as higher mitochondrial DNA copy number. Of note, significantly increased activity of STAT3 is detected in oncogene addicted cancer cells, and the increased mitochondrial oxygen consumption and complex I activity could be significantly inhibited by a novel small molecule inhibitor of STAT3, OPB-51602. The latter is shown to be an effect that might be independent of the STAT3 inhibitory activity of the small molecule compound. Most importantly, the novel STAT3 inhibitor showed strong activity in three different murine models of carcinogenesis as well as in patients treated with the STAT3 inhibitor. These data provide evidence that oncogene addicted cancer cells switch to OXPHOS over glycolysis and serve as proof of principle for identifying targeted new OXPHOS inhibitor in recalcitrant cancers.
Citation Format: Jayshree L. Hirpara, Jie Eu Qing, Andrea Wong, Naoto Ohi, Tsunoda Takeshi, Boon Cher Goh, Shazib Pervaiz. OXPHOS: A novel target for cancer therapy in oncogene addicted tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4884.