bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1661: Temozolomide suppresses a doxorubicin resistant follicular dendritic cell sarcoma in a patient derived orthotopic xenograft mouse model
Authors: Oshiro Hiromichi , Tome Yasunori , Hoffman Robert M. , Nishida Kotaro 
Published: September 2020

Abstract
Introduction: Follicular dendritic cell sarcoma (FDCS) is a very rare and highly refractory soft tissue sarcoma. The CHOP chemotherapy has been used as systemic therapy for FDCS, which includes cyclophosphamide, doxorubicin (DOX), vincristine, and prednisolone. However, FDCS has poor clinical outcome even though CHOP therapy was administered. A FDCS patient tumor was previously implanted orthotopically in the biceps femoris of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model in our laboratory at AntiCancer Inc. The FDCS patient had resistance to DOX in clinical setting. We previously found the FDCS PDOX model had resistance to DOX as well as clinical settings. In the present study, we evaluated the efficacy of temozolomide (TMZ), trabectedin (TRAB), and pazopanib (PAZ) on the DOX resistant FDCS PDOX model.
Methods: The FDCS PDOX mouse model was established and randomized into five groups of eight mice, respectively. Group 1, Control (Ctrl) treated with PBS, i.p.; Group 2, DOX, 2.4 mg/kg, i.p., weekly; Group 3, PAZ, 50 mg/kg, oral gavage, daily; Group 4, TRAB, 0.15 mg/kg, i.v., weekly; Group 5, TMZ, 25 mg/kg, oral gavage, daily. Treatment term was for 2 weeks. Treatment efficacy was evaluated based on tumor volume ratio (tumor volume after treatment relative to tumor volume at the beginning of treatment) and histopathology. Adverse event was evaluated based on body weight ratio. Tumor volume and body weight were assessed 2 times per week.
Results: Tumor volume ratio was the Ctrl group: 11.35±4.50, DOX: 8.24±1.87, PAZ: 9.67±4.66, TRAB: 6.97±3.23, TMZ: 4.28±1.41, respectively. TMZ significantly arrested the FDCS PDOX model compared to the control group (p&lt;0.05). PAZ and TRAB did not have significant efficacy compared to the Ctrl group (p=0.93, p=0.41). In H&E-staining, partial necrosis was detected only in PDOX tumors treated with TMZ. There was no significant difference of body weight among all groups.
Conclusion: The FDCS PDOX model was resistant to DOX as well as in the clinical settings demonstrating concordance of the FDCS model and clinic. TMZ was the most effective for the FDCS PDOX mouse model established from a patient who failed DOX treatment. There is possibility that TMZ has effective to FDCS patients who has resistant to the first line chemotherapy.
Citation Format: Hiromichi Oshiro, Yasunori Tome, Robert M. Hoffman, Kotaro Nishida. Temozolomide suppresses a doxorubicin resistant follicular dendritic cell sarcoma in a patient derived orthotopic xenograft mouse model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1661.
Abstract 1682: Epithelial-mesenchymal heterogeneity of high-grade serous ovarian carcinoma samples correlates with let-7 levels and predicts tumor growth and metastasis
Authors: Unternaehrer Juli , Chirshev Evgeny , Hojo Nozomi , Bertucci Antonella , Sanderman Linda , Nguyen Anthony , Wang Hanmin , Suzuki Tise , Brito Emmanuel , Martine Shannalee , Castañón Christine , Mirshahidi Saied , Vazquez Marcelo , Oberg Kerby C. , Ioffe Yevgeniya J. 
Published: September 2020

Abstract
Objective: Patient-derived samples present an advantage over current cell line models of high grade serous ovarian cancer (HGSOC), which are flawed in terms of being reliable and phenotypically faithful models of in vivo HGSOC. To improve upon cell line models of HGSOC, we characterized a panel of patient-derived cells to determine their epithelial and mesenchymal characteristics, invasiveness, proliferation, stemness, and in vivo growth.
Experimental procedures: Patient-derived xenograft (PDX) models of HGSOC were analyzed in vitro for phenotypic (RNA, let-7 miRNA, and protein expression, flow cytometry) and functional aspects including growth in spheroids, wound healing assays, invasion assays and in vivo (orthotopic PDX) growth characteristics.
Results: Samples fell along the spectrum from epithelial to mesenchymal, and all had hybrid characteristics. Those toward the more epithelial end of the spectrum were most active in self-renewal assays, and grew most robustly in orthotopic xenograft models. Chemoresistance correlated both with the mesenchymal state and with BRCA2 wild type status. Loss of microRNA let-7 (lethal-7) is an important component of the cancer stem cell phenotype, and we observed an inverse association between let-7 expression and the epithelial state. We observed lower levels of let-7, more efficient spheroid and tumor formation, and increased sensitivity to platinum-based chemotherapy in cells with the most epithelial phenotype.
Conclusions: Surprisingly, in these HGSOC cells, stemness could be dissociated from invasiveness: epithelial cells (those with least let-7 expression) were less migratory, but more tumorigenic, than the mesenchymal cells with higher let-7 expression. We conclude that epithelial/mesenchymal state and let-7 expression are valuable predictors of HGSOC proliferation, in vitro self-renewal, and tumor burden in vivo.
Citation Format: Juli Unternaehrer, Evgeny Chirshev, Nozomi Hojo, Antonella Bertucci, Linda Sanderman, Anthony Nguyen, Hanmin Wang, Tise Suzuki, Emmanuel Brito, Shannalee Martine, Christine Castañón, Saied Mirshahidi, Marcelo Vazquez, Kerby C. Oberg, Yevgeniya J. Ioffe. Epithelial-mesenchymal heterogeneity of high-grade serous ovarian carcinoma samples correlates with let-7 levels and predicts tumor growth and metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1682.
Abstract 1702: Cancer stem cell marker DCLK1 correlates with tumorigenic immune infiltrates in the colon and gastric adenocarcinoma microenvironments
Authors: Qu Dongfeng , Wu Xiangyan , Weygant Nathaniel , Peng Jun , Houchen Courtney 
Published: September 2020

Abstract
Immunotherapy that has proved efficacy in several solid cancers plays a partial role in improving clinical outcomes of advanced gastrointestinal (GI) cancers. There is an unmet need to find new immune-related therapeutic targets. Doublecortin-like kinase 1 (DCLK1) marks tuft cells which are recognized as cancer initiating cells and regulators of the type II immune response, and has been studied for its role in many cancers including colon and gastric cancers, but its role in tumor immunity remains unexplored. In the current study, we analyzed colon and gastric cancer RNA sequencing data from 283 and 415 patients respectively from The Cancer Genome Atlas (TCGA). High DCLK1 expression predicted the worse clinical outcomes in colon and gastric cancer patients and correlated with increased immune and stromal components. Further analysis indicated that DCLK1was strongly linked to infiltration of multiple immune cell types, especially TAMs and Tregs, and strongly correlated with increased CD8+ T cell inhibitors TGFB1 and CXCL12 and their receptors, suggesting it may contribute to TAM-mediated inhibition of CD8+ T cells. Interestingly, we found that DCLK1 was a prognostic biomarker in left-sided colon cancer which has worse outcomes and demonstrates a reduced response to existing immunotherapies. In conclusion, our results demonstrate that DCLK1 is linked with functional regulation of the tumor microenvironment and may have potential as a prognostic biomarker and adjuvant target to promote immunotherapy sensitivity in colon and gastric cancer patients.
Citation Format: Dongfeng Qu, Xiangyan Wu, Nathaniel Weygant, Jun Peng, Courtney Houchen. Cancer stem cell marker DCLK1 correlates with tumorigenic immune infiltrates in the colon and gastric adenocarcinoma microenvironments [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1702.
Abstract 1751: BPI-23314: A novel orally bioavailable small molecular BET inhibitor with target protein degradation activity
Authors: Guo Jing , Xu Yan , Yan Dan , Yu Bo , Yu Weiwei , Chen Haibo , Xu Xiaofeng , Liu Xiangyong , Lan Hong , Ding Lieming , Wang Jiabing 
Published: September 2020

Abstract
The Bromo- and Extra-Terminal (BET) proteins, BRD2, BRD3, and especially BRD4, play important roles in transcriptional regulation of many oncogenes like MYC or BCL2, thus makes it an attractive drug target in multiple pathological settings, particularly in cancer. Earlier BET inhibitors, while effectively bind and inhibit the activity of BRD4, adversely induce compensatory accumulation of the target protein, that may account for their limited preclinical and clinical efficacy. Herein, we report BPI-23314, a potent, selective, and orally available small molecular BET bromodomain inhibitor, which possesses potent target inhibition activity as well as target protein degradation property. In vitro, BPI-23314 induced dose-dependent growth inhibition in a wide range of cancer cell lines, including those from AML, MM, DLBCL, NSCLC, TNBC, and CRPC, etc. Quantitative RT-PCR revealed that BPI-23314 markedly affected the transcription of genes encoding MYC, BCL2, and HEXIM1, thus induced G1 cell cycle arrest and apoptosis in MV-4-11 AML cell line. In vivo, oral administration of BPI-23314 led to tumor growth suppression or regression in multiple xenograft models of AML and MM. Transcriptional modulation of MYC, BCL2 and HEXIM1 were confirmed in BPI-23314-treated xenografts and in normal monkey, supporting their potential as pharmacodynamic biomarkers in clinical trials. Unlike previously described BET inhibitors that induced BRD4 accumulation, BPI-23314 serendipitously decreased BRD4 protein in MV-4-11 cells and in tumors from MV-4-11 xenografts. The feature of target-protein degradation differentiates BPI-23314 from the other BET inhibitors, renders it good in vivo efficacy, and suggests a lower risk of drug resistance in future clinical development. In conclusion, our study establishes BPI-23314 as a novel small molecular BET inhibitor with target BRD4 protein degradation property. BPI-23314 has obtained IND approval from Chinese regulatory authority and is planned to enter Phase 1 clinical development in hematologic malignancies in early 2020.
Citation Format: Jing Guo, Yan Xu, Dan Yan, Bo Yu, Weiwei Yu, Haibo Chen, Xiaofeng Xu, Xiangyong Liu, Hong Lan, Lieming Ding, Jiabing Wang. BPI-23314: A novel orally bioavailable small molecular BET inhibitor with target protein degradation activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1751.
Abstract 1755: Prodigiosin inhibits the proliferation and migration of mcf-7 breast cancer cells through the demethylation of mir-200c gene
Authors: Shi Fengqin , Lu Lingeng , LV Peng , Li Ya , Li Hou , Chen Xinyi , Zhu Yong 
Published: September 2020

Abstract
Background: DNA methylation in microRNA (miRNA) host genes is associated with the down-regulation of gene expression in tumorigenesis and progression. Accumulating evidence shows that low levels of miR-200c were correlated with a worse prognosis in breast cancer. MiRNA promoter methylation has been reported as a major cause of miR-200c downregulation. Prodigiosin (PG), red bacterial pigment with a pyrrolylpyrromethene skeleton, has significant antibacterial, antifungal, antimalarial and antitumor activity via the modulation of multiple cell signaling pathways against a variety of human cancer cells. However, there is little information regarding the epigenetic-based effects of Prodigiosin in breast cancer. In this study, we hypothesize that Prodigiosin has anti-proliferative and anti-migration effects on breast cancer cells through the demethylation of miR-200c.
Material and Methods: MCF-10A breast epithelial cells and MCF-7 breast cancer cells were used to investigate the effects of Prodigiosin on the expression and methylation of miR-200c using real time-PCR (RT-qPCR) and methylation-specific PCR (qMSP), respectively. MTS proliferation assay, cell scratch assay and three-dimensional (3D) formation assay were performed to assess the effect of Prodigiosin on the proliferation and migration of MCF-7 breast cancer cells.
Result: MCF-7 breast cancer cells showed significant hypermethylation of miR-200c, and significantly down-regulated miR-200c expression compared to MCF-10A breast epithelial cells. Prodigiosin treatment led to significant inhibition of proliferation and migration, and significantly up-regulated miR-200c expression, whereas the methylation level of miR-200c significantly decreased in MCF-7 breast cancer cells.
Conclusion: Prodigiosin, a secondary metabolite of bacteria, inhibits the proliferation and migration of breast cancer cells, and restores the demethylation status and expression of miR-200c. These findings elucidate that the demethylation of miR-200c may be a molecular mechanism underlying the anti-tumor of Prodigiosin in breast cancer.
Citation Format: Fengqin Shi, Lingeng Lu, Peng LV, Ya Li, Hou Li, Xinyi Chen, Yong Zhu. Prodigiosin inhibits the proliferation and migration of mcf-7 breast cancer cells through the demethylation of mir-200c gene [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1755.
Abstract 1757: Developing sensitive assays to facilitate hit identification of RNA modifying enzymes
Authors: Tomlinson Chris , Lawrence Rachel , Best Stuart , Boden Grace , Alanine Thomas , Wasp James , Smith Bethany , Wilkie Ross , Thomson Stuart , Unitt John , Pollack Scott , Jordan Allan M. 
Published: September 2020

Abstract
N-6-methyladenosine (m6A) is the most abundant RNA chemical modification found in the eukaryotic transcriptome. It is a dynamic and reversible modification which plays a role in RNA function across a wide range of biological processes. Dysregulation of the m6A modification and the readers, writers and erasers involved in these processes have been implicated in the progression of multiple types of cancer and metabolic disease. RNA modifying enzymes are therefore emerging as exciting therapeutic targets.
To facilitate and accelerate drug discovery efforts in this area, we have developed several sensitive and robust assays suitable for identifying and assessing chemical matter against the RNA modifying enzymes, fat mass and obesity associated protein (FTO) and methyltransferase-like 3/14 (METTL3/14). Specifically, a robust Microscale Thermophoresis (MST) assay was developed, validated, and used to screen 100 compounds from the LOPAC for novel human FTO small molecule binders. Five compounds, which displayed reproducible, concentration-dependent binding in the MST screen, were tested for inhibition of human FTO RNA demethylation activity and revealed a single, novel FTO inhibitor. To further profile emerging FTO hit matter, we are also developing sensitive and robust mass spectrometry assays to demonstrate target inhibition and proof of mechanism. Our progress in this area will be reported. Additionally, we have developed a highly sensitive and robust LC-MS/MS assay to monitor the METTL3/14 catalysed conversion of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH). This assay is suitable for identifying either substrate competitive or allosteric METTL3/14 inhibitors.
In summary, our proof of concept studies describe the development of several robust and sensitive assays suitable for hit identification and further characterisation of inhibitors of key RNA modifying enzymes and offer a platform for the discovery and development of novel therapeutics in this emerging area of research.
Citation Format: Chris Tomlinson, Rachel Lawrence, Stuart Best, Grace Boden, Thomas Alanine, James Wasp, Bethany Smith, Ross Wilkie, Stuart Thomson, John Unitt, Scott Pollack, Allan M. Jordan. Developing sensitive assays to facilitate hit identification of RNA modifying enzymes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1757.
Abstract 1759: KDM5 inhibitor regulates growth of early stage and advanced human prostate cancer cells
Authors: Smith Tunde , Chen Zhenbang , Stewart LaMonica V. 
Published: September 2020

Abstract
Prostate cancer (PCa) remains a leading cause of cancer deaths because many patients ultimately develop an incurable castration-resistant form of metastatic PCa. While chromatin alterations are linked to PCa, the role of histone demethylases in the PCa progression has not been fully elucidated. Members of the Jumonji AT-rich interactive domain 1 (JARID1) or lysine demethylase 5 (KDM5) family of lysine demethylases are known for their ability to demethylate H3K4me3. However, the genes encoding these proteins are amplified in metastatic PCa. Literature suggests members of the KDM5 family enhance expression and function of androgen receptor (AR), a protein that drives growth of human PCa cells. The KDM5 family inhibitor 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT) has been suggested as a potential lead compound for cancer therapy since it suppresses proliferation of human breast cancer cells. However, to date no studies have tested the effects of PBIT in PCa. The goal of this study was to characterize the effects of PBIT alone and in combination with a PPARγ agonist, 15-Deoxy-Δ-12,14-prostaglandin J2 (15-dPGJ2) on PCa cells. Presto blue analyses were conducted in AR positive, castration-sensitive LNCaP cells and the castration-resistant PC3 cells expressing little to no AR. Our studies revealed that PBIT treatment decreased the proliferation of both LNCaP and PC3 cells in a dose-dependent manner. Significant decreases in cell proliferation were detected when PBIT concentrations were greater than or equal to 5 μM. In addition, 15-dPGJ2 was able to decrease the proliferation of PCa cells. Importantly, the combination of PBIT and 15-dPGJ2 significantly suppressed the growth of PC3 and LNCaP cells. The anti-proliferative effect of the combined inhibition was at least additive, as the combination index was less than 1. Furthermore, PBIT at concentrations ≥ 5 μM also reduced migration of PC3 cells. Together, our data suggest that PBIT and other KDM5 inhibitors can reduce the proliferation and migration of multiple types of PCa cells. Our findings also provide evidence that the combination of KDM5 family inhibitors and PPARγ agonists might serve as an effective therapy for advanced human PCa.
Citation Format: Tunde Smith, Zhenbang Chen, LaMonica V. Stewart. KDM5 inhibitor regulates growth of early stage and advanced human prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1759.
Abstract 1761: Examination of therapeutic potential of epigenetic modulation by dual HDAC-LSD1 inhibition in murine models of triple negative breast cancer (TNBC)
Authors: Messerli Shanta M. , Hoffman Mariah M. , Zylla Jessica S. , Gnimpieba Etienne , Miskimins Keith W. 
Published: September 2020

Abstract
This study examines the effects of the epigenetic modulator 4SC-202, a dual histone deacetylase (HDAC) /lysine-specific histone demethylase 1A (LSD1) small molecule inhibitor, on tumor growth and metastasis in a mouse model of breast cancer. 4SC-202 differs from clinically available HDAC inhibitors such as Vorinostat (SAHA) by specifically targeting class I HDACs including HDAC1, HDAC2, and HDAC3 and the histone demethylase LSD1. The hypothesis to be examined is that epigenetic modulation via dual inhibition of HDAC1 and LSD1 improves disease control in breast cancer. In vitro data indicates that 4SC-202 is significantly cytotoxic and cytostatic to the highly metastatic murine Triple Negative Breast Cancer (TNBC) murine model 4T1 and the human TNBC cell line MDA-MB-231 and reduces cancer cell migration. In vivo studies conducted in the syngeneic 4T1 model which closely mimics human TNBC in terms of sites of metastasis, show increased necrosis in 4T1 tumors, reduced tumor burden in vivo as compared to Vorinostat treatment, and significantly reduced metastasis. Furthermore, multiple studies in different cell types indicate that the mechanism of action of 4SC-202 may involve effects on cancer stem cells, which are able to self-renew and form metastatic lesions. It has been shown that a marker of cancer stem cells (CSC's) in breast cancer is high aldehyde dehydrogenase (ALDH) activity and that ALDH high cells mediate metastasis. In the 4T1 syngeneic mouse model of breast cancer, inhibition of ALDH activity suppresses stem-like cell properties. Preliminary data suggests 4SC-202 substantially reduces the ALDH high 4T1 cancer stem population. Transcriptome bulk RNA -sequencing analysis from 4T1 tumors reveal changes in metastatic related pathways in 4SC-202 treated tumors, including significant changes to the expression levels of genes implicated in focal adhesion and ECM-receptor interaction pathways. Furthermore, 4SC-202 appears to alter expression of cytokines which serve as chemokines, potentially leading to increased expression of tumor infiltrating lymphocytes. In summary, treatment of a highly metastatic murine model of TNBC with 4SC-202 significantly reduces metastasis, and warrants further preclinical studies in conjunction with standard of care chemotherapy treatment.
Citation Format: Shanta M. Messerli, Mariah M. Hoffman, Jessica S. Zylla, Etienne Gnimpieba, Keith W. Miskimins. Examination of therapeutic potential of epigenetic modulation by dual HDAC-LSD1 inhibition in murine models of triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1761.