bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2590: Nano-exosomes with miRNA: A new therapeutic approach
Authors: Kuppa Sudeepti , Rada Balazs , Roberts Arthur , Murph Mandi M. 
Published: August 2019

Abstract
Access to reliable and effective therapeutics for patients suffering from aggressive triple-negative breast cancer (TNBC) has been clinically challenging to achieve due to lack of targetable mutations and high heterogeneity in the tumor cells. Therapeutic approaches to reduce mortality in the TNBC patient subset requires an innovative and targeted approach to drug delivery, which is presented here in the form of labeled-exosomes. In this study, we have developed a novel method to bioengineer exosomes, where an antibody is covalently bonded to a fatty acid, which is then anchored into the exosomal membrane to create labeled-exosomes. Our data demonstrate that labeled-exosomes can contain up to 700,000-fold higher miRNA concentrations and can deliver miRNA cargo with increased efficiency into MDA-MB-231 TNBC cells. Results further reveal that insertion of a specific antibody-label to the exosomal membrane significantly increases microRNA uptake into MDA-MB-231 cells, and is further enhanced in cells overexpressing that same antibody marker on their surface. The customizable bioengineering of the labeled-exosomes makes it a highly versatile tool to target cells based on surface marker expression and increase miRNA or other therapeutic cargo delivery. Most importantly, the relevancy of this model reaches far beyond its success in just TNBC cells and can also be translated to several different disease models that require specific targeting with an encapsulated miRNA or therapeutic. We believe this is a novel and exciting utilization of exosomes with a high degree of customization based on surface markers on the target cell, as well as microRNA cargo loaded into the exosome to inhibit a specific oncogene.
Citation Format: Sudeepti Kuppa, Balazs Rada, Arthur Roberts, Mandi M. Murph. Nano-exosomes with miRNA: A new therapeutic approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2590.
Abstract 2598: Developing small molecule inhibitors that target androgen receptor signaling in castration-resistant prostate cancer
Authors: Chandrasekaran Balaji , Tyagi Ashish , Kolluru Venkatesh , Vadhanam Aakash M. , Baby Becca von , Gorle Suresh , Sirimulla Suman , Ramisetti Srinivasa R. , Sharma Arun K. , Ankem Murali K , damodaran Chendil 
Published: August 2019

Abstract
The transcription factor, androgen receptor (AR) is a key driver and plays an important role in prostate cancer. Androgen ablation therapy and brachytherapy remains the standard treatment of advanced prostate cancer, but unfortunately, it is not curative, and eventually the disease returns as lethal castration-resistant prostate cancer (CRPC). Previously we have reported that Urolithin A (Uro A), a natural compound, inhibits AR signaling and suppresses the growth of CRPC. Now, we have developed a series of pro-drug conjugates of Uro A and our initial structure-activity relationship (SAR) studies led to the identification of three small molecules as lead compounds. Hence, we investigated the effects of all three compounds and dissected their molecular mechanism in cell culture and mouse models of CRPC. All the three compounds more effectively inhibited the growth CRPC cell lines than the parent compound Uro A. Based on their IC50 concentration; we identified a novel compound (ASR-600) that demonstrated better efficacy by inhibiting AR signaling in CRPC cell lines than the parental compound Uro A. The model system and molecular dynamics (MD) stimulation studies suggest that ASR600 bind to the ligand-binding domains of AR and blocks the conformation changes, that allows AR to phosphorylate and degrade in the cytosol. Further, our thermal shift assay confirmed ASR 600 binds to AR in presence and absence of Dihydrotestostreone. Our ongoing in vivo studies, may suggest whether oral administration of ASR-600 effectively inhibits the tumor growth raised from CRPC cell lines (C4-2B, 22RV1 and enzalutamide resistance C4-2B) in xenografted mice. These observations provide a rationale for devising novel therapeutic agent based on ASR 600 for the treatment of CRPC
Citation Format: Balaji Chandrasekaran, Ashish Tyagi, Venkatesh Kolluru, Aakash M. Vadhanam, Becca von Baby, Suresh Gorle, Suman Sirimulla, Srinivasa R. Ramisetti, Arun K. Sharma, Murali K Ankem, Chendil damodaran. Developing small molecule inhibitors that target androgen receptor signaling in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2598.
Abstract 260: Identifying cancer drug sensitivity using live cell imaging dynamic BH3 profiling of solid tumor core biopsies
Authors: German Rebecca , Lavrova Elizaveta , Hagan Timothy , Chipashvili Otari , Sicinska Ewa , Cleary James , Ng Kimmie , Letai Anthony , Bhola Patrick 
Published: August 2019

Abstract
Given the rapid development of new small molecule cancer therapeutics, there is a growing need for predictive diagnostics to match cancer patients with optimal therapies. We previously developed a precision medicine technology with a functional phenotypic readout called dynamic BH3 profiling (DBP). DBP exposes cancer cells to drugs and measures induction of apoptotic cell death signaling after 24 hours ex vivo. Nonetheless, the application of DBP to core biopsies from metastatic tumors or other limited samples remains a technical challenge. Here, we adapt the DBP protocol for use on samples with small numbers of cells such as core biopsies. We maximize information returned per cell by imaging mitochondrial integrity in response to BH3 peptide exposure over time. We first show that the adapted protocol works in limited numbers of cancer cell lines, and in limited cells from the MMTV-PyMT genetically engineered mouse model of breast cancer. Specifically, we show that our ex vivo DBP predictions of the MMTV-PyMT mouse tumor matches known in vivo response. Finally, we apply our modified protocol to patient derived xenografts of colon cancer and primary patient colon tumors. We expect that our adapted protocol will find utility as a clinical biomarker, and as a method to optimize pre-clinical drug testing.
Citation Format: Rebecca German, Elizaveta Lavrova, Timothy Hagan, Otari Chipashvili, Ewa Sicinska, James Cleary, Kimmie Ng, Anthony Letai, Patrick Bhola. Identifying cancer drug sensitivity using live cell imaging dynamic BH3 profiling of solid tumor core biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 260.
Abstract 2607: BPTF role in melanoma progression and BRAF resistance therapy
Authors: Dar Altaf A. , Majid Shahana , Semir David de , Bezrookove Vladimir , Nosrati Mehdi , Kashani-Sabet Mohammed 
Published: August 2019

Abstract
Bromodomain PHD finger transcription factor (BPTF) plays an important role in chromatin remodeling, but its functional role in tumor progression is incompletely understood. Here we reveal new pro-oncogenic roles for BPTF in promoting tumor cell proliferation and resistance to targeted therapies. shRNA-mediated BPTF silencing suppressed the proliferative capacity (by 65.5%) and metastatic potential (by 66.4%) of melanoma cells. Elevated BPTF mean copy number greater than 3 was observed in 28 of 77 (36.4%) melanomas. BPTF overexpression predicted poor survival in a cohort of 311 melanoma patients (distant metastasis-free survival, p=0.03, and disease-specific survival p=0.008), and promoted resistance to BRAF inhibitors in melanoma cell lines. Metastatic melanoma tumors progressing on BRAF inhibitors contained low BPTF-expressing, apoptotic tumor cell sub-clones, indicating the continued presence of drug-responsive sub-clones within tumors demonstrating overall resistance to anti-BRAF agents. These studies demonstrate multiple pro-tumorigenic functions for BPTF, and identify it as a novel target for anti-cancer therapy. They also suggest the combination of BPTF targeting with BRAF inhibitors as a novel therapeutic strategy for melanomas with mutant BRAF.
Citation Format: Altaf A. Dar, Shahana Majid, David de Semir, Vladimir Bezrookove, Mehdi Nosrati, Mohammed Kashani-Sabet. BPTF role in melanoma progression and BRAF resistance therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2607.
Abstract 2614: CCAR2 acetylation establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition
Authors: Johnson Gavin S. , Rajendran Praveen , Li Li , Chen Ying-Shiuan , Dashwood W. Mohaiza , Nguyen Nhung , Ulusan Ahmet M. , Ertem Furkan , Zhang Mutian , Sun Deqiang , Huang Yun , Wang Shan , Leung Hon-Chiu E. , Lieberman David , Beaver Laura M. , Ho Emily , Bedford Mark T. , Chang Kyle , Vilar Eduardo , Dashwood Roderick H. 
Published: August 2019

Abstract
There continues to be interest in targeting epigenetic ‘readers, writers and erasers’ for the treatment of cancer and other pathologies. A mechanistic understanding is frequently lacking, however, for the synergy observed when combining deacetylase and bromodomain inhibitors. We identified cell cycle and apoptosis regulator 2 (CCAR2) as an early target for acetylation in colon cancer cells treated with sulforaphane (SFN). N-terminal acetylation of CCAR2 diminished its interactions with histone deacetylase 3 (HDAC3) and β-catenin, interfering with Wnt coactivator functions of CCAR2, including in cells harboring genetically encoded CCAR2 acetylation. Protein domain arrays and pull-down assays identified acetyl ‘reader’ proteins that recognized CCAR2 acetylation sites, including BRD9 and members of the bromodomain and extraterminal domain (BET) family. The BET inhibitor JQ1 synergized with SFN in colon cancer cells, and suppressed tumor development effectively in a preclinical model of colorectal cancer. Studies with SFN+JQ1 in combination implicated a BET/BRD9 acetyl switch, and a shift in the pool of acetyl ‘reader’ proteins in favor of BRD9 regulated target genes. These results highlight the competition that exists among the ‘readers’ of acetylated histone and non-histone proteins, and provide a mechanistic basis for potential new therapeutic avenues involving epigenetic combination treatments.
Citation Format: Gavin S. Johnson, Praveen Rajendran, Li Li, Ying-Shiuan Chen, W. Mohaiza Dashwood, Nhung Nguyen, Ahmet M. Ulusan, Furkan Ertem, Mutian Zhang, Deqiang Sun, Yun Huang, Shan Wang, Hon-Chiu E. Leung, David Lieberman, Laura M. Beaver, Emily Ho, Mark T. Bedford, Kyle Chang, Eduardo Vilar, Roderick H. Dashwood. CCAR2 acetylation establishes a BET/BRD9 acetyl switch in response to combined deacetylase and bromodomain inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2614.
Abstract 2619: DNA damage agents promote TFEB function and induce pro-survival autophagy signals
Authors: Marchand Benoit , Boucher Marie-Josée 
Published: August 2019

Abstract
The transcription factor EB (TFEB) was identified as a master regulator of autophagy and lysosomal biogenesis. We recently demonstrated that TFEB is aberrantly regulated in pancreatic cancer (PDAC) cells. Interference with TFEB impairs PDAC cell growth supporting an important role for TFEB in maintaining PDAC cell phenotype. Given the limited impact of chemotherapeutic drugs in the context of PDAC, we aimed at testing whether the aberrantly regulated TFEB in PDAC cells could confer resistance to DNA damage agents, commonly used in PDAC therapeutic regimens.
Methods: Experiments were performed in PDAC cells (MIA PaCa2, PANC1). The DNA damage agents gemcitabine, 5-FU, cisplatin and doxorubicin were used. Autophagic flux was measured upon 4-hours treatment with bafilomycin A1.
Results: Treatment with DNA damage agents 1) increased the autophagic flux in PDAC cells. This autophagic signal was associated with 2) the dephosphorylation and nuclear accumulation of TFEB. The mTORC1 pathway is well-known to regulate TFEB phosphorylation and nuclear localization of TFEB. 3) However, the impact of the DNA damage agents on TFEB appeared independent of the mTORC1 pathway since no modulation in the phosphorylation of the mTORC1 target S6K1 was observed. To delineate whether TFEB influenced the response to DNA damage agents, we generated stable populations of PDAC cells expressing a non-targeting or shRNA targeting TFEB. Interfering with TFEB function 4) prevented the autophagic response upon treatment with DNA damage agents. This correlated with 5) increased accumulation of DNA damage and 6) increased sensitivity to the DNA damage agents.
Conclusion: Our results suggest that DNA damage agents can induce a pro-survival autophagic response involving TFEB. Interfering with TFEB function limits the autophagic response and leads to increased sensitivity to DNA damage agents. Altogether, our results suggest that the aberrantly expressed TFEB in PDAC cells could confer resistance to DNA damage agents by, among others, promoting autophagy and limiting DNA damage accumulation.
Citation Format: Benoit Marchand, Marie-Josée Boucher. DNA damage agents promote TFEB function and induce pro-survival autophagy signals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2619.
Abstract 2622: Plasma growth diefferentiation factor-15 is and independen marker for aggressive disease in endometrial cancer
Authors: Engerud Hilde 
Published: August 2019

Abstract
Objective: Better biomarkers are needed in order to identify patients with endometrial carcinoma at risk of recurrence and who may profit from a more aggressive treatment regimen. Our objective was to explore the applicability of plasma growth differentiation factor 15 (GDF-15) as a marker for recurrent disease, as well as a marker for poor prognosis and lymph node metastases.
Methods: EDTA-blood samples were obtained from 235 patients with endometrial cancer before primary surgery. For 36 of these patients, matching blood samples were collected at time of recurrence. Blood samples were also collected from 78 patients with endometrial hyperplasia. Plasma GDF-15 was measured by an enzyme-linked immunosorbent assay (ELISA). Preoperative pelvic MRI scans for 141 patients were investigated in parallel for imaging variables.
Results: Preoperative plasma level of GDF-15 was significantly higher for patients who experienced recurrence (1780 ng/L; 95% CI; 518-9475 ng/L) than for patients who did not develop recurrent disease (1236 ng/L; 95% CI; 307-7030 ng/L) (p&lt;0.001). Plasma levels of GDF-15 at recurrence (2818 ng/L, 95% CI 2088-3548 ng/L) were significantly higher than plasma levels of GDF-15 measured at time of primary diagnosis (1857 ng/L, 95% CI; 1317-2398 ng/L) (p=0.001). High plasma level GDF-15 independently predicts recurrent disease (OR=3.14; 95% CI 2.10-4.76) and lymph node metastases (OR=2.64; 95% CI 1.52-4.61). Patients with high plasma level of GDF-15 had significantly larger tumor volume (p=0.008).
Conclusion: Elevated plasma level of GDF-15 is associated with aggressive disease and lymph node metastasis in endometrial carcinoma. GDF-15 may be helpful in indicating recurrent disease.
Citation Format: Hilde Engerud. Plasma growth diefferentiation factor-15 is and independen marker for aggressive disease in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2622.
Abstract 2630: Inhibition of bone morphogenetic protein receptor 2 increases mitochondrial permeability and the downregulation of XIAP in lung cancer cells
Authors: NeMoyer Rachel E. , Langenfeld Elaine , Langenfeld John 
Published: August 2019

Abstract
Bone morphogenetic protein receptor (BMP) inhibitors have been shown to induce death of lung cancer cells, which involves the downregulation of x-linked inhibitor of apoptosis protein (XIAP). XIAP is a potent inhibitor of executioner caspases that promotes resistance to many chemotherapeutic agents. The mechanism by which inhibiting BMP signaling downregulates XIAP has not been elucidated. We find that the BMP inhibitors JL5 and DMH2 downregulate XIAP and enhances cell death of TRAIL, Taxol, and AEG a Smac mimetic. JL5, which inhibits both type I and type II BMP receptors, enhances cell death of cancer therapeutics by decreasing the expression of XIAP, which leads to an increase in caspase activity. The downregulation of XIAP is mediated by the inhibition of the BMP type II receptor and not the BMP type I receptors. Knockdown of BMPR2 but not the BMP type I receptors increases mitochondrial permeability resulting in the release of cytochrome c and Smac/Diablo into the cytosol. These studies suggest that the inhibition of BMPR2 increases cytosolic Smac/Diablo that inhibits XIAP enhancing apoptotic cell death of cancer therapeutics.
Citation Format: Rachel E. NeMoyer, Elaine Langenfeld, John Langenfeld. Inhibition of bone morphogenetic protein receptor 2 increases mitochondrial permeability and the downregulation of XIAP in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2630.
Abstract 2640: DKK1 overexpression might induce crizotinib resistance
Authors: Seo Ha Young 
Published: August 2019

Abstract
NSCLC patients with pleural effusions tend to show progressive status and malignant features. Newly established lung cancer cell lines from pleural effusions, SNU-2550 and SNU-2563 were harboring ALK rearrangement and they were originally sensitive to crizotinib. After treated with regular crizotinib treatment and recovery at least 1 year, crizotinib-resistant cell lines (SNU-2550CR and SNU-2563CR) that became resistant to crizotinib more than 5 times were established. And then, whole exome sequencing (WES) and RNA-seq were operated in order to understand way to acquire resistance. According to WES result, there were differences in mutations between parental cell lines and resistant cell lines. For example, mutations in MKNK2, IGFN1, PRSS1 and FOXA2 genes were only present in SNU-2550CR not SNU-2550. Variations of ESX1, PRSS1, PCDHA4 and AGAP3 genes were observed in only SNU-2563CR. When the differences were studied and visualized via SPIA two-way evidence plot and heatmap, genes related with cell cycle, p53 and Wnt pathway were commonly changed in RNA expression level. In fact, there were expressional differences in genes related those pathways such as MAPK2, DKK1, APC and GSK3b genes. Among them, Dkk1 expression level was more than doubled in two set. Through those analysis, we examined differences between parental cell lines that have sensitive reactivity and resistant cell lines that acquired resistance. When crizotinib resistance was induced, Dkk1 expression was elevated. Augmentation of Dkk1 expression level induces the level of overall β-catenin expression, and cytoplasmic β-catenin tends to be concentrated adjacent to membrane and into nucleus region. Therefore, Dkk1 can be considered as a factor that is related to crizotinib resistance by up-regulating Wnt/β-catenin pathway in lung cancer. Acquired resistance to crizotinib is major predicament especially when there is ALK rearrangement. Studying the mechanism of crizotinib resistance therefore improves the prognosis of ALK rearrangement lung cancer. We found that Dkk1 overexpression might be correlated to crizotinib resistance.
Note: This abstract was not presented at the meeting.
Citation Format: Ha Young Seo. DKK1 overexpression might induce crizotinib resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2640.
Abstract 2657: GSTP mediated S-glutathionylation of GRP78 attributes to multiple myeloma resistance
Authors: Ye Zhiwei , Zhang Jie , Tew Kenneth D. , Townsend Danyelle M. 
Published: August 2019

Abstract
The proteasome inhibitor bortezomib (Btz) is used in the treatment of multiple myeloma (MM), but its efficacy is restricted by the wide-spread occurrence of resistance. MM cells have the highest rate of secretion of proteins with disulfide bonds and are exquisitely dependent upon redox balance and accurate protein folding. Our results showed that some important redox enzymes, including glutathione transferase P (GSTP) are upregulated in Btz-resistant cells. While GSTP was originally described as a phase II detoxification enzyme, our laboratory has ascribed a thiolase activity catalyzing the forward S-glutathionylation reaction, a post-translational modification (PTM) through reversible addition of glutathione to thiolate anions of cysteines in target proteins. Although primarily cytosolic, GSTP has been reported in the nuclear and mitochondrial compartments. We recently showed that GSTP is localized at high concentrations in the endoplasmic reticulum (ER) and regulates a number of redox active proteins through S-glutathionylation; these include glucose-regulated protein (GRP78). Proteomic analysis revealed that both cys41 and cys 420 of GRP78 were subject to S-glutathionylation and this PTM altered the activity of GRP78, enhancing its holdase activity, while concomitantly decreasing its foldase activity. This alters protein folding and contributes to the Btz-resistant phenotype of MM. Our data also support the principle that drugs that target the ER protein folding machinery significantly alter local redox conditions. Thapsigargin (Thg) is an inhibitor of SERCA, interfering with the functional activities of calcium-dependent chaperones, while tunicamycin (TuM) inhibits N-linked glycosylation. Btz resistant cells showed marked levels of cross-resistance (2-10 fold) to both. Linking such results with GSTP/redox, the absence of GSTP (from GSTP knockout mice) makes both bone marrow derived dendritic and mouse embryonic fibroblast cells more sensitive to Btz, ThG and TuM. The nature of the cross-resistance patterns and the fact that the presence of GSTP in drug naïve cells also confers resistance provides a rational platform for studying redox-based mechanisms as causative in resistance. Moreover, inhibition of GSTP with Telintra restored Btz sensitivity, decreased S-glutathionylation and increased expression of markers of UPR induced apoptosis. We conclude that altered GSTP expression and S-glutathionylation of key ER-localized proteins are significant contributors to drug response and resistance in MM treated with Btz.
Citation Format: Zhiwei Ye, Jie Zhang, Kenneth D. Tew, Danyelle M. Townsend. GSTP mediated S-glutathionylation of GRP78 attributes to multiple myeloma resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2657.