bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1787: Statin therapy enhances the efficacy of HER2 directed antibody-drug conjugates in breast cancer
Authors: Liu Bo , Drago Joshua Z. , Rao Yi , Pereira Patricia R. , Safonov Anton , Marra Antonio , Ahmed Mehnaj S. , Modi Shanu , Reis-Filho Jorge S. , Montemurro Filippo , Razavi Pedram , Lewis Jason S. , Chandarlapaty Sarat 
Published: June 2022

Abstract
Antibody-drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (HER2) are a widely successful strategy for the treatment of HER2-positive breast cancer. Despite the demonstrated efficacy, intrinsic and acquired resistance to anti-HER2 ADCs remains a major challenge. The activity of ADCs is dependent upon the internalization of the HER2-ADC complex into specific subcellular compartments permissive for release of the chemotherapeutic payload. Previous studies have demonstrated that statins, a commonly used cholesterol-lowering medication, could increase plasma membrane-bound HER2 and improve trastuzumab efficacy in HER2-positive gastric cancer. In this study, we sought to characterize the impact of statins on the efficacy of HER2 ADCs. We performed in vitro internalization assays with trastuzumab emtansine (T-DM1) labeled with a pH-sensitive pHrodo fluorogenic dye to monitor T-DM1 entering lysosome whereupon payload DM1 is released, and found that combined treatment of T-DM1 and lovastatin potently enhanced T-DM1 internalization of T-DM1 into lysosome in HER2-amplified and HER2-low models. Consistent with the internalization assays, lovastatin increased cell death caused by T-DM1 and sensitized the HER2-low ZR75-1 cells to T-DM1 treatment in vitro. Using HER2-positive xenograft models, we found orally administrated lovastatin promoted T-DM1 uptake in tumors and enhanced T-DM1 efficacy in vivo. To investigate whether these results might be observed in the clinic, we conducted retrospective analyses on a cohort of 164 HER2 positive metastatic breast cancer patients treated at MSKCC who received T-DM1. Among these patients, 21 (12.8%) were taking statins concurrently with T-DM1, and the median progression-free survival in the patients who received statins was 14 months (95% confidence interval, 3.5-24 months) compared to 5.4 months (95% confidence interval, 3.9-7.0 months) in those who had no record of statin use (p=0.1). Overall, our findings demonstrate that statins potentiate the susceptibility of breast cancer cells to anti-HER2 ADCs by modulating HER2 membrane dynamics and HER2-ADC internalization, suggesting statin as a rational therapeutic partner for anti-HER2 ADC in HER2-positive breast cancer, especially those with relatively low HER2 expression.
Citation Format: Bo Liu, Joshua Z. Drago, Yi Rao, Patricia R. Pereira, Anton Safonov, Antonio Marra, Mehnaj S. Ahmed, Shanu Modi, Jorge S. Reis-Filho, Filippo Montemurro, Pedram Razavi, Jason S. Lewis, Sarat Chandarlapaty. Statin therapy enhances the efficacy of HER2 directed antibody-drug conjugates in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1787.
Abstract 1809: Engineered destabilized ARE on the 3UTR of MYC degrades oncogenic c-MYC transcript and protein and induces apoptosis in multiple cancer types
Authors: Awah Chidiebere , Dong Fu , Glemaud Yana , Levine Fayola , Weiser Daniel , Ogunwobi Olorunseun 
Published: June 2022

Abstract
The c-MYC oncogene is overexpressed in more than 18 human cancers, including triple negative breast cancer (TNBC), prostate cancer, and osteosarcoma, yet there is no clinically approved drug that targets this major oncogenic driver. We discovered that the 3’UTR of c-MYC in many cancers is enriched with stabilizing poly U tract sequences that can be destabilized with our novel engineered stabilizing AU Rich Elements (ARE), leading to degradation of c-MYC. We hypothesize that c-MYC destabilizing constructs will degrade c-MYC transcript and proteins across a range of cancers that overexpress this oncogene. We used heterogeneous panels of TNBC, prostate cancer, and osteosarcoma cell lines that are reflective of the heterogeneity of human cancers. We introduced our c-MYC destabilizing construct and assessed cell viability. We then performed immunofluorescence and western blot for assessment of c-MYC protein expression. Vector constructs were used as controls. Introduction of destabilizing elements achieved the degradation of both c-MYC transcript and proteins within four days, as well as a subsequent loss in cell viability. We observed that treated cells disintegrated from their nucleus, leading to increased active caspase 3/7 and cell death. Taken together, we have developed a novel technology that reliably targets and degrades the c-MYC oncogene across a range of highly aggressive and difficult to treat cancers
Citation Format: Chidiebere Awah, Fu Dong, Yana Glemaud, Fayola Levine, Daniel Weiser, Olorunseun Ogunwobi. Engineered destabilized ARE on the 3UTR of MYC degrades oncogenic c-MYC transcript and protein and induces apoptosis in multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1809.
Abstract 1821: SPTBN1 Is a potential target to prevent progression of steatohepatitis to hepatocellular carcinoma
Authors: Yang Xiaochun , Rao Shuyun , Xiang Xiyan , Ohshiro Kazufumi , Latham Patricia , Shetty Kirti , Mishra Lopa 
Published: June 2022

Abstract
Background: Nonalcoholic steatohepatitis (NASH) is a risk factor for the development of hepatocellular carcinoma (HCC). β-spectrin, encoded by SPTBN1, is associated with HCC. The goal of this study was to evaluate the hepatocyte-specific roles of SPTBN1 in NASH and HCC using mouse models.
Methods: We investigated the effect of knocking out Sptbn1 specifically in the liver in mice (LSKO mice). We examined the effect of diets that promote NASH—a high-fat diet (HFD) or Western diet (WD)— and the outcomes of HCC induced by diethylnitrosamine (DEN). Based on the phenotypes of these mice, we examined the therapeutic effects of knocking down Sptbn1 using siRNA.
Results: We found LSKO mice were protected from HFD-induced obesity and NASH. Control mice administered siRNA targeting Sptbn1 were protected from developing NASH when placed on a HFD, and NASH phenotypes triggered by WD were reduced by administration of siRNA targeting Sptbn1. LSKO mice appeared to be protected from HFD-induced HCC: One of four HFD control mice developed liver tumors, but none of the three LSKO mice did. HFD-induced HCC is rare in mice, therefore we evaluated DEN-induced HCC. LSKO mice subjected to DEN with or without WD had less severe cancer than did wild-type mice. Compared to the HCC in the control mice, the number of liver tumors in the LSKO mice was lower, the size of the tumors was smaller, and the tumors were less proliferative based on KI67 staining intensity. Furthermore, overall liver pathology was reduced.
Conclusions: These data suggest that SPTBN1 is a potential target for therapeutic intervention to treat NASH and prevent progression to HCC. Because other injected siRNA therapies are approved to treat liver diseases, a siRNA-based therapy targeting SPTBN1 could translate into clinical trials.
Citation Format: Xiaochun Yang, Shuyun Rao, Xiyan Xiang, Kazufumi Ohshiro, Patricia Latham, Kirti Shetty, Lopa Mishra. SPTBN1 Is a potential target to prevent progression of steatohepatitis to hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1821.
Abstract 1824: EZH2 inhibition induces blast differentiation in acute myeloid leukemia
Authors: Fobare Sydney , Elgamal Ola A. , Stahl Emily H. , Mehmood Abeera , Truxall Jean , Johnson Mariah L. , Abdul-Aziz Amina , Byrd John C. , Hertlein Erin 
Published: June 2022

Abstract
Enhancer of zeste homolog 2 (EZH2) is a part of the polycomb repressive complex and catalyzes the trimethylation of lysine 27 on histone H3 (H3K27me3). EZH2 inhibition has a complex role in the pathogenesis of acute myeloid leukemia (AML), in that it has been shown to be either a tumor suppressor or an oncogene depending on the stage of AML development and the genes that EZH2 is regulating during each stage. Unlike follicular and diffuse large B-cell lymphoma where EZH2 mutations result in gain of function, EZH2 mutations are typically loss of function in myeloid diseases. However, we hypothesized that in AML patients without EZH2 mutations, loss of EZH2 function may produce a phenotype that would allow for therapeutic targeting without influencing normal hematopoiesis.
We used EPZ011989 (EPZ), an EZH2 inhibitor tool compound, to inhibit H3K27me3 in our studies. We started by treating the MOLM-13 AML cell line with EPZ and confirmed a decrease in H3K27me3. This reduction in H3K27me3 resulted in a slight decrease in metabolic activity via MTS assays as well as decreased colony formation in methocult. These studies were followed up with EPZ inhibition in primary AML samples in vitro. We found that EZH2 inhibition resulted in decreased self-renewal of primary AML samples but not of CD34+ bone marrow cells from normal donors. Furthermore, we found that after 7-day treatment with EPZ, primary AML samples undergo moderate differentiation as suggested by an increase in CD11b surface expression via flow cytometry. These results are further supported by the morphological changes seen after 14-days of EPZ treatment in vitro. Based on these results, we hypothesize that EZH2 inhibition in primary AML samples promotes the differentiation of AML blasts. Furthermore, our preliminary data suggests that daily treatment with 150 mg/kg of EPZ results in a survival advantage and reduced disease burden in the MOLM-13-luciferase murine xenograft model.
Despite loss of function EZH2 mutations portending poor outcomes in myeloid malignancies, we demonstrate that pharmacologic EZH2 inhibition reduces AML blast stemness and promotes differentiation into mature myeloid cells. In contrast, no change in normal CD34+ stem cells occurs with EZH2 inhibition, offering the opportunity to selectively target myeloid leukemia.
Citation Format: Sydney Fobare, Ola A. Elgamal, Emily H. Stahl, Abeera Mehmood, Jean Truxall, Mariah L. Johnson, Amina Abdul-Aziz, John C. Byrd, Erin Hertlein. EZH2 inhibition induces blast differentiation in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1824.
Abstract 1825: Romidepsin therapy results in p53 mediated apoptosis in hepatoblastoma
Authors: Espinoza Andres F. , Whitlock Richard , Srivastava Rohit , Patel Roma , Govindu Sai , Shah Aayushi , Larson Samuel , Woodfield Sarah , Vasudevan Sanjeev 
Published: June 2022

Abstract
Purpose: Relapsed and treatment refractory hepatoblastoma (HB) has a survival rate less than 50% due to limited treatment options. We have previously shown that HB and treatment refractory HB has upregulation of class I histone deacetylase (HDAC) genes (HDAC1-4) through microarray, confirmed by RT-PCR. The highest consistent upregulation noted was with HDAC 2 and 3. Given this upregulation, we tested established and treatment refractory HB cell lines with HDAC 2/3 inhibitor, Romidepsin. We sought to characterize Romidepsin efficacy and mechanism of action.
Methods: Romidepsin was tested with cytotoxic assays (MTT). Tumor derived cell lines were treated with Romidepsin and evaluated for gene expression of p53 pathway via qRT-PCR. Immunoblotting assays were used to assess changes in expression of Acetyl-p53 at time points of 0, 4, 8, and 24 hours after 0.01 µM concentrated Romidepsin treatment. Evaluation of the specific cell death pathway involved was performed via cell viability assays using 0.01 µM concentration of Romidepsin in combination with cell death reversal agents including Z-VAD for apoptosis, 3-Methyladenine for autophagy, Necrostatin-1 for necroptosis, and Ferrostatin-1 for ferroptosis at 48 hours.
Results: Romidepsin (IC50 of 0.001-0.02 µM) showed strong in vitro effects for viability. HB cell lines treated with HDAC inhibitor had increased p21 and PUMA expression on RT-PCR, most notably at the 24-hour mark (p = &lt; 0.05). Acetyl p-53 was noted to increase in HUH-6 and Hep G2 throughout the 24 hours of treatment on western blots, while Hep T1 was noted to have no changes in expression. All cell lines showed the highest level of cell death reversal with ZVAD in cell viability assay after Romidepsin treatment. Hep T1 showed the highest cell death reversal with Romidepsin: relative cell viability of 52% (±5%) versus 95% (±2%) in ZVAD/Romidepsin.
Conclusions: Romidepsin demonstrates strong in vitro efficacy and suggest HDAC 2/3 inhibition may act through p53 mediated mechanism, notably acetylated p53. Cell death via apoptosis is further supported by cell death reversal with ZVAD/Romidepsin treatment in HB cell lines.
Citation Format: Andres F. Espinoza, Richard Whitlock, Rohit Srivastava, Roma Patel, Sai Govindu, Aayushi Shah, Samuel Larson, Sarah Woodfield, Sanjeev Vasudevan. Romidepsin therapy results in p53 mediated apoptosis in hepatoblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1825.
Abstract 1831: 9-ING-41, a glycogen synthase kinase 3B inhibitor targets TP53 in pediatric brain tumors ATRT and ETMR
Authors: Haw Jason L. , Moore Elizabeth M. , McKinney Kimberly , Dykema Karl , Nagulapally Abhinav , Steuerwald Nury , Sholler Giselle S. 
Published: June 2022

Abstract
Purpose: The study aims to determine the activity of the blood brain barrier permeable glycogen synthase kinase 3B (GSK3B) inhibitor, 9-ING-41, in pediatric brain tumors: embryonal tumor with multilayered rosettes (ETMR) and atypical rhabdoid tumor (ATRT).
Methods: ETMR cell line, BT183, was grown in ultralow attachment flasks and ATRT cell lines: ATRT-7316-2187, ATRT-787197, and CHLA02 were grown in suspension flasks. Cells were treated with 9-ING-41 at dose range (0-20µM). After 24 and 48 hours of 9-ING-41 cells were analyzed by western blot. After 72 hours of 9-ING-41 cell viability was assessed with Cell Titer Glo 2.0 and IC50s were analyzed by GraphPad. RNA seq was performed on cells after 12, 24, and 48 hours of 9-ING-41 treatment. Total RNA was isolated with miRNeasy Mini Kit. RNA integrity was evaluated by an Agilent 2100 Bioanalyzer profile. rRNA was selectively depleted by employing RiboZero Globin. Next generation sequencing libraries were prepared using an Illumina TruSeq Stranded Total RNA kits. Read mapping was performed using STAR in BaseSpace. DESeq2 was used for normalization and differential expression analysis. Ingenuity Pathway Analysis was performed.
Results: The IC50s of 9-ING-41 in the cell lines BT183, CHLA02-ATRT, ATRT-787197, and ATRT-2187 are 145.5nM, 481.2nM, 503.1nM, and 528.3nM, respectively. In BT183 cells treated with 150nM 9-ING-41 for 48 hours, XIAP decreased significantly by 55% and cleaved caspase 3 increased significantly by 29-fold, quantified by densitometry. In addition, western blot showed a decrease in LIN28A and an increase in TP53 protein levels. RNA-seq data show an increase in the p53 signaling pathway in the ETMR BT183 cell line with z-scores of 2.53 and 3 (p=3.73x10-13 and 2.35x10-14) after 12 and 24 hours of 150nM 9-ING-41, respectively. In ATRT-787197 cells p53 signaling increased with z-scores of 1.0 and 2.236 (p=2.62x10-8 and 2.89x10-5) after 24 and 48 hours of 400nM 9-ING-41, respectively. RNA seq data also show the ability of 9-ING-41 to significantly increase the expression of CDK inhibitor, CDKN1A, and pro-apoptotic genes BBC3, DRAM1, and BAX in ETMR and ATRT while significantly decreasing stemness associated genes: SMO and GLI1 in ETMR.
Conclusions: 9-ING-41 decreases ETMR and ATRT cell viability at clinically relevant concentrations and these doses increase the p53 pathway and induce apoptosis while reducing the expression of stemness associated genes.
Citation Format: Jason L. Haw, Elizabeth M. Moore, Kimberly McKinney, Karl Dykema, Abhinav Nagulapally, Nury Steuerwald, Giselle S. Sholler. 9-ING-41, a glycogen synthase kinase 3B inhibitor targets TP53 in pediatric brain tumors ATRT and ETMR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1831.
Abstract 1842: Drug repurposing screen reveals glioblastoma cell line susceptibility to statins
Authors: Harwood Dylan S. , Michaelsen Signe R. , Kristensen Bjarne W. 
Published: June 2022

Abstract
Background: The standard therapy for glioblastoma patients is tumor resection followed by radiotherapy and temozolomide chemotherapy. Although glioblastoma has been extensively molecularly profiled along with other cancers, this knowledge has not yet been translated into improved survival outcomes. We used a bioinformatics approach to identify potential novel therapeutic strategies for glioblastoma. Objectives: Comprehensive online datasets which have assessed up to 1376 cancer cell lines in multiple ways were interrogated to identify potential drug candidates for glioblastoma.
Methods: Datasets included were from the cancer cell line encyclopedia (mRNA expression), the Achillies project (cell viability following Crispr-Cas9 knockout) and PRISM (drug treatment). A t-test comparing cell viability of glioblastoma cell lines versus other cancers was used to identify potential drug candidates, followed by the use of multiple statistical tools to investigate potential mechanism of action and status of biomarkers.
Results: Fluvastatin and pitavastatin were amongst the drugs with the most significant effects against glioblastoma cell lines while also being FDA approved. These effects were found in both glioblastoma cells and other cancer types with a mesenchymal-like expression phenotype. The anti-cancer properties of statins have previously been attributed to the inhibition of HMG-Coa reductase. Here, we found their effects correlated with the gene knockout of UBIAD1, which participates in non-mitochondrial ubiquinone and menaquinone-4 synthesis. We tested the effects of statins on patient-derived glioblastoma cell lines with a mesenchymal (n = 2) and non-mesenchymal phenotype (n=2). Mesenchymal-like glioblastoma cells lines were found to be particularly susceptible to multiple statins.
Conclusion: Statins appeared to be especially effective against glioblastoma lines and the effect could be linked to the direct or indirect inhibition of UBIAD1. In vitro validation of this finding is ongoing.
Citation Format: Dylan S. Harwood, Signe R. Michaelsen, Bjarne W. Kristensen. Drug repurposing screen reveals glioblastoma cell line susceptibility to statins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1842.
Abstract 1852: G protein-coupled estrogen receptor-1 agonist LNS8801 induces mitotic arrest and cell death in uveal melanoma cells
Authors: Ambrosini Grazia , Natale Christopher A. , Schwartz Gary K. 
Published: June 2022

Abstract
Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults. Nearly 50% of the patients develop hepatic metastasis, and when this occurs the 1-year survival rate is 12 months. While the primary tumor can be treated with radiotherapy and surgery, current treatments for metastatic disease have shown limited clinical activity in UM patients and there is an urgent need for new effective therapies. Recent reports have shown that male patients have more metastases than female patients, and the time from the diagnosis until development of metastases was shorter, suggesting a potential role of female hormones in disease progression. The G-protein-coupled estrogen receptor-1 (GPER) has distinct functions from those of the classic estrogen receptors ERα/β and its activation with a specific agonist has tumor-suppressive roles in several cancers. Here, we demonstrate that the novel clinical GPER agonist, LNS8801 (Linnaeus Therapeutics), has potent anticancer activities in UM cells including inhibition of cell migration and cell proliferation. LNS8801 treatment induced a G2/M cell cycle arrest due to disruption of tubulin polymerization and defective mitotic spindle formation. There was a time-dependent increase of mitotic proteins, such as phosphorylated aurora-A, aurora-B and histone-3, while c-Myc and phospho-Rb were downregulated. The drug treatment also induced significant cell death, as detected by caspase 3/7 activation and PARP cleavage. Finally, LNS8801 inhibited tumor growth in a UM xenograft model in vivo. In conclusion, our studies suggest that GPER agonists may be a novel treatment for uveal melanoma, and clinical trials with the GPER agonist LNS8801 are warranted and currently underway.
Citation Format: Grazia Ambrosini, Christopher A. Natale, Gary K. Schwartz. G protein-coupled estrogen receptor-1 agonist LNS8801 induces mitotic arrest and cell death in uveal melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1852.