bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C76: A novel small molecule inhibitor of constitutive androstane receptor (CAR) that resensitizes doxorubicin-resistant neuroblastoma cells
Authors: Cherian Milu T. , Takwi Apana A. , Lin Wenwei , Chen Taosheng 
Published: May 2016

Abstract
This study aims to identify new specific small molecule inhibitors of the xenobiotic receptor CAR (constitutive androstane receptor) which could be used to increase sensitivity of resistant cancer cells to chemotherapeutics.
CAR and PXR are xenobiotic sensors that respond to drugs and endobiotics by modulating the expression of metabolic genes that enhance detoxification and elimination. Elevated levels of drug metabolizing enzymes and efflux transporters resulting from CAR activation promote the elimination of chemotherapeutic agents leading to reduced therapeutic effectiveness. Interestingly, all previously reported CAR inverse-agonists are also activators of PXR thus rendering them mechanistically counterproductive in tissues expressing both receptors. Using a directed screening approach, we discovered a potent small molecule, CINPA1, capable of reducing CAR-mediated transcription with an IC50 of ∼70 nM, without activating PXR. CINPA1 is a specific xenobiotic inhibitor and has no general cytotoxic effects up to 25 μM. CINPA1 effectively inhibits CAR-mediated gene expression in all donors of human hepatocytes that express CAR endogenously. The mechanisms by which CINPA1 inhibits CAR function were extensively examined. We show that CINPA1 association with the CAR ligand binding domain results in increased corepressor interaction and reduced recruitment of coactivators. In addition, chromatin immunoprecipitation in the presence of CINPA1 illustrates reduced CAR binding to the promoter regions of target genes.
Multidrug resistance in tumors after chemotherapy can be associated with errant CAR activity, as in the case of neuroblastoma. Treatment of doxorubicin-resistant neuroblastoma cells with CINPA1 resulted in reduced CAR activity and subsequent decrease in drug-transporter levels. In doxorubicin-resistant UKF-NB3 (neuroblastoma) cells, CINPA1 treatment increased doxorubicin sensitivity and decreased cell growth. This suggests that CAR inhibitors used in combination with existing chemotherapeutics could potentially be utilized to attenuate multidrug resistance and resensitize chemo-resistant cancer cells.
Citation Format: Milu T. Cherian, Apana A. Takwi, Wenwei Lin, Taosheng Chen. A novel small molecule inhibitor of constitutive androstane receptor (CAR) that resensitizes doxorubicin-resistant neuroblastoma cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C76.
Abstract C91: Reversible lysine specific demethylase-1 inhibition is synergistic with docetaxel in castrate refractory prostate cancer
Authors: Gupta Sumati , Weston Alexis , Bearss Jared , Sharma Sunil 
Published: May 2016

Abstract
Lysine specific demethylase-1 (LSD-1) expression correlates with poor survival in prostate cancer. LSD-1 is also key in androgen receptor signaling in androgen sensitive and castration refractory prostate cancer. LSD-1 is a chromatin modifying enzyme that in conjunction with its binding partners functions as an ‘erasor’ in the Epigenetic code process and demethylates lysine 4 and 9 residues on H3 protein resulting in gene repression or activation. Specifically in prostate cancer it demethylates H3k9me2 playing an important role in androgen receptor signaling promoting myc expression. Docetaxel chemotherapy is effective in prostate cancer but limited by toxicity and development of resistance. In this study we demonstrate synergy between LSD-1 inhibition and docetaxel in castrate refractory cell lines. We further demonstrate that LSD-1 inhibition is effective in docetaxel resistant cell lines. Cell survival assays were performed with HCI2509 on castrate refractory and docetaxel resistant prostate cancer cell lines. Histone methylation and myc expression were assessed. Colony formation assays, cell cycle analysis, xenograft studies were performed. Synergy studies were performed to assess the combination of 2509 and docetaxel. HCI2509 is cytotoxic to castrate refractory and docetaxel resistant prostate cancer cell lines in low micromolar doses. Treatment with HCI2509 resulted in dose dependent increase in H3K4me2, H3K4me3, H3K9me2 levels and decrease in myc protein. RT-PCR showed a significant decrease in MYC expression upon treatment with HCI2509. Cell cycle progression was arrested at G0/G1 upon treatment with 2509 with inhibition of colony formation at 10 to 100 fold lower concentrations. PC3 xenografts in mice showed significant reduction in tumor burden upon treatment with 2509 with increased H3K9me2 marks and reduced myc protein levels. LSD-1 inhibition with HCI2509 has therapeutic potential in castrate refractory and docetaxel resistant prostate cancer. It inhibits myc expression and sensitizes castrate refractory prostate cancer to docetaxel.
Citation Format: Sumati Gupta, Alexis Weston, Jared Bearss, Sunil Sharma. Reversible lysine specific demethylase-1 inhibition is synergistic with docetaxel in castrate refractory prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C91.
Abstract CN03-01: Toxicities from immunomodulatory antibodies: An overview
Authors: Italiano Antoine 
Published: May 2016

Abstract
immunomodulatory monoclonal antibodies used to strengthen the immune system against cancer have shown remarkable efficacy for patients with advanced melanoma and non-small cell lung cancer and are likely to significantly improve the survival of patients with several other malignancies.
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an adverse event of unknown etiology, associated with drug exposure and consistent with an immune phenomenon. Immune related adverse events (irAEs) may be predicted based on the nature of the compound and its mechanism of action. An irAE can occur shortly after the first dose or several months after the last dose of treatment. Such irAE represent a unique spectrum of side effects including dermatologic, gastrointestinal, hepatic, endocrine, and other less common inflammatory events. Even if most of them are mild and transient, they can be ocasionally severe or fatal. We will review the specific side effects of antibodies targeting the PD-1/PDL1, CTLA-4 and CSF1 receptors and discuss their physiopathology and potential impact on patient management.
Citation Format: Antoine Italiano. Toxicities from immunomodulatory antibodies: An overview. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr CN03-01.
Abstract CN05-04: Serial killing of tumor cells by cytotoxic T cells: Mechanisms and implications for therapy
Authors: Friedl Peter 
Published: May 2016

Abstract
Cytotoxic T lymphocytes (CTL) eliminate tumor target cells in an antigen and cell-contact dependent manner, both spontaneously and when activated by immunotherapy. Lethal hit delivery is considered to be a rapid and binary “yes/no” process under conditions of high immunogenicity. In tissues, killing efficacy further depends upon sequential conjugation of CTL with multiple target cells, termed “serial killing.” Here we show that elimination of cancer cells results from a cooperative process executed by multiple CTL engaging sequentially with the same target cell. Migrating CTL transit between target cells and cooperate to initiate apoptosis by a series of sublethal interactions (additive cytotoxicity), whereas individual conjugations rarely reached thresholds to induce apoptosis. Consequently, in invading B16F10 melanoma tumors treated with adoptive T cell therapy in vivo, serial engagements and tumor-cell apoptosis induction were confined to regions with high CTL density, which supported CTL accumulation and additive cytotoxicity. Highest rates of serial engagements followed by tumor eradication were reached in the invasive tumor front where moving tumor cells and CTL collided within the same pro-migratory tissue compartment, suggesting invading tumor cells as target for immunotherapy. Thus, additive cytotoxicity requires CTL cooperation and serial engagements with target cells to deliver cumulative sublethal events and successfully eradicate solid tumor cells. The need for additive “hits” has implications for topographic mechanisms of immune evasion of tumor cells as well as immune intervention to enhance CTL accumulation and cooperation.
Citation Format: Peter Friedl. Serial killing of tumor cells by cytotoxic T cells: Mechanisms and implications for therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr CN05-04.
Abstract ED01-02: Gene-modified T cells as biotherapeutics for cancer
Authors: Gottschalk Stephen 
Published: May 2016

Abstract
Adoptive immunotherapy of T cells may have significant advantages over alternative immunotherapeutic approaches such as cancer vaccines since the phenotype, activity and specificity of expanded cells can be analyzed prior to injection. T cells can be genetically engineered prior to infusion to modify the antigens they target, increase their potency, and reduce their susceptibility to tumor-mediated immune inhibition. Genetic modification also allows T cells to be tracked in vivo to learn their fate. Adoptive transfer of T cells has been most successful after hematopoietic stem cell transplantation (HSCT) as prophylaxis and therapy for viral associated disease. In addition, the adoptive transfer of tumor infiltrating lymphocytes (TILs) in combination with lymphodepleting chemotherapy has shown promising long-term antitumor effects in patients with melanoma. Lastly, the adoptive transfer of T cells that have been genetically engineered to be tumor specific has resulted in impressive clinical responses, especially in patients with hematological malignancies. Despite these successes, clinical studies have also highlighted current limitations of adoptively transferred immune cells, including limited expansion in vivo, lack of homing to tumor sites, and toxicities due to recognition of normal tissues. In my talk I will review the current status of T-cell therapy for cancer with special focus on solid tumors and genetically modified T cells.
Citation Format: Stephen Gottschalk. Gene-modified T cells as biotherapeutics for cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr ED01-02.
Abstract LB-A20: Novel Dual Oncogenic Target Inhibitor against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K)
Authors: Ross Brian D. , Hong Hao , Wang Hanxiao , A, Nino Charles , Van Dort Marcian E. 
Published: May 2016

Abstract
The Ras/MEK/ERK and PI3K/Akt/mTor pathways play a central role in the regulation of normal cell growth, division and differentiation. Dysregulation of these signaling pathways driven by oncogenic mutations/activation leading to elevated kinase activity has been demonstrated in many human cancers. Strong evidence suggests the existence of a feedback loop with crosstalk between these two signaling cascades leading to redundancy in survival pathways. Consequently, monotherapy targeting a single cascade may be insufficient to induce tumor cell death due to drug resistance mechanisms. Initial biological results are presented from a series of novel small molecule kinase inhibitors specifically designed to simultaneously target both MEK1 and PI3K. Structural analogs of the ATP-competitive PI3K inhibitor ZSTK474 and the ATP-noncompetitive class of MEK inhibitors PD0325901, respectively, were covalently combined to provide single compound dual inhibitors. Inhibitors showed potent MEK1 inhibition (0.015 &lt; IC50 (nM) &lt; 56.7) and PI3K inhibition (54 &lt; IC50 (nM) &lt; 341) in tumor cell culture inhibition assays. Cellular efficacy studies were accomplished and revealed several of the designed inhibitor analogs demonstrated near complete inhibition of MEK1 and PI3K kinase activity by western blot analysis in A549 lung adenocarcinoma and D54 glioma cell lines at concentrations as low as 5 μM. Inhibitors also produced dose-dependent decreases in cell viability in these cell lines similar to that displayed with the combined administration of equivalent doses of ZSTK474 and PD0325901. In vivo evaluation of selected compounds was undertaken to evaluate oral bioavailability and activity. In preliminary studies conducted in D54 glioma tumor bearing mice, a 95% and 67% inhibition of tumor ERK1/2 and Akt phosphorylation, respectively, was found at 2 h post-administration as determined by western blot analysis. This study reveals that dual targeted small molecules designed to inhibit MEK1/PI3K pathways were effective in target modulation in intact mouse tumor models. Overall, this study details a highly novel approach for combined MEK1/PI3K inhibition with first in vivo results.
Citation Format: Brian D. Ross, Hao Hong, Hanxiao Wang, Charles A, Nino, Marcian E. Van Dort. Novel Dual Oncogenic Target Inhibitor against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A20.
Abstract LB-A25: PTEN loss promotes phosphorylation-dependent acetylation and inhibition of SPOP tumor suppressor
Authors: An Jian , Huang Haojie 
Published: May 2016

Abstract
The Cullin 3-based E3 ubiquitin ligase substrate-binding protein SPOP is inactivated in approximately 8-15% of human prostate cancers due to gene mutation. Intriguingly, SPOP mutations and inactivation of the PTEN tumor suppressor in human prostate cancers are mutually exclusive. However, it is unclear whether SPOP remains functionally active in PTEN-deficient prostate cancer cells. In the current study, we demonstrate that PTEN loss induces phosphorylation and nuclear exportation of SPOP. We identify a putative cyclin-dependent kinase (CDK) phosphorylation site (serine 222) in SPOP BTB domain, a motif interacting with Cullin 3 and demonstrate that PTEN loss induces SPOP cytoplasm accumulation in a manner dependent on CDK2-mediated phosphorylation of SPOP at serine 222. We further show that serine 222 phosphorylation impairs dimerization and the E3 ligase activity of SPOP without affecting its interaction with Cullin 3. We also identify a potential p300 acetylation site in the C-terminal nuclear localization sequence of SPOP. We demonstrate that acetylation by p300 promotes SPOP translocation from nucleus to cytoplasm and this effect is enhanced by CDK2-mediated phosphorylation of SPOP at serine 222. In contrast, Sirt 2 and Sirt 6 of the sirtuin family are verified to be responsible for deacetylation of SPOP. In the conditional Pten knockout prostate cancer mouse model, Pten deletion induces cytosolic accumulation of SPOP, but the process is reversed in Pten and p300 double knockout prostatic cells. Collectively, our findings reveal cytoplasmic localization and enzymatic inactivation of SPOP as a previously uncharacterized mechanism that contributes to PTEN loss-induced prostate tumorigenesis. They also suggest that blocking SPOP cytoplasm localization represents a viable therapeutic option for treatment of prostate cancers harboring PTEN inactivation.
Citation Format: Jian An, Haojie Huang. PTEN loss promotes phosphorylation-dependent acetylation and inhibition of SPOP tumor suppressor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A25.
Abstract LB-B03: miR-24 acts as a tumor suppressor and radiosensitizer by targeting Jab1/CSN5 functions
Authors: Claret Francois X. , Wang Sumei , Pan Yunbao , Yang Huiling 
Published: May 2016

Abstract
Radiotherapy is the standard therapy for head and neck cancer; however, radioresistance can hinder successful treatment and is likely to give rise to local recurrence and distant metastatic relapse. Recent studies revealed the role of microRNA (miRNA)-mRNA mediated regulation in tumorigenesis; however, whether specific miRNAs regulate tumor radioresistance and can be exploited as radiosensitizing agents remains unclear. The purpose of this study was to identify an miRNA signature from differentially expressed miRNAs in radioresistance. Here, we report that miR-24 acts as a tumor suppressor and radiosensitizer in nasopharyngeal carcinoma (NPC) cells and mouse models by targeting Jab1/CSN5 and that loss of miR-24 is highly associated with poor survival. When combined with irradiation, miR-24 acted as a radiosensitizer in NPC cells. Jab1/CSN5 functioned in a manner opposite that of miR-24 in NPC tumorigenesis and radioresistance. We demonstrated that miR-24 inhibits Jab1/CSN5 translation, leading to tumor growth inhibition, and sensitizes NPC tumors to radiation in vivo. Moreover, miR-24 inhibits DNA damage repair by targeting JAB1/CSN5. Finally, comparative analysis of paired samples of primary and matched recurrent NPC tissues showed that miR-24 levels were significantly lower and Jab1/CSN5 levels were higher in recurrent NPC than in primary NPC. Our findings identify miR-24 as a tumor suppressor and radiosensitizer miRNA and reveal a new therapeutic strategy for radioresistant tumors.
Citation Format: Francois X. Claret, Sumei Wang, Yunbao Pan, Huiling Yang. miR-24 acts as a tumor suppressor and radiosensitizer by targeting Jab1/CSN5 functions. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B03.
Abstract LB-B08: Somatic mutation detection from liquid biopsy-derived cellular aggregates formed by magnetic 3D bioprinting
Authors: Tseng Hubert , Amato Robert J. , Brobey Reynolds , Ionescu-Zanetti Cristian , Jensen Jeff , Gage Jacob , Desai Pujan , Liao Angela , Dehghani Mehdi , Rosenblatt Kevin , Souza Glauco 
Published: May 2016

Abstract
Background - A challenge in the analysis of circulating tumor cells (CTCs) is their scarcity and the inability to expand them for further analysis. To overcome this obstacle, we used magnetic 3D bioprinting to form CTC spheroids that could grow. The principle of magnetic 3D bioprinting is the magnetization of cells with nanoparticles and their subsequent printing into spheroids. For this project, CTCs were aggregated into close contact to facilitate interactions and growth in culture. We then demonstrated the ability to perform next generation sequencing (NGS) of the spheroids to detect somatic mutations from renal and prostate cancers.
Methods - Blood samples from prostate and kidney cancer patients were enriched for CTCs (Isoflux, Fluxion Biosciences), from a starting blood volume of 7.5-14 mL. CTCs were isolated immunomagnetically for EpCAM+ EGFR+ cells, then enumerated for CK+ CD45-. The cells were then magnetized by incubation with NanoShuttle (NS, Nano3D Biosciences) and printed into spheroids in 384-well plates. After 4 d of growth, the cells were lysed and DNA was amplified by whole genome amplification (WGA) with the NGA kit (Fluxion Biosciences) and quantified via qPCR. Targeted libraries were sequenced using the PGM (ThermoFisher) sequencing instrument; data was analyzed using a customized variant calling/filtering pipeline based on standard Ion Reporter alignment tools and VarSeqTM for variant filtering and functional interpretation.
Results - CTCs were successfully aggregated using magnetic 3D bioprinting and grew over 4 d. For both prostate and renal cancers, we then demonstrated the detection of somatic variants within a majority of the samples. Using the commercial Oncomine® test kits (ThermoFisher), we found a median of 5 COSMIC variants (32 total) per sample using cell cultures.
Conclusions - We successfully developed a method to aggregate CTCs using magnetic 3D bioprinting, expanded them, and then identified somatic mutations using NGS. This procedure may form the basis of a liquid biopsy-derived molecular testing platform for monitoring urological tumor progression and planning treatment strategies.
Citation Format: Hubert Tseng, Robert J. Amato, Reynolds Brobey, Cristian Ionescu-Zanetti, Jeff Jensen, Jacob Gage, Pujan Desai, Angela Liao, Mehdi Dehghani, Kevin Rosenblatt, Glauco Souza. Somatic mutation detection from liquid biopsy-derived cellular aggregates formed by magnetic 3D bioprinting. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B08.