bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4025: New candidate therapy for BAP1-mutant cancer identified using novel screen
Authors: OWENS DAWN A. , Kuznetsov Jeffim N. , Lopez Andy , Kurtenbach Stefan , Bilbao Daniel , Roberts Evan R. , Volmar Claude-Henry , Wahlestedt Claes R. , Brothers Shaun P. , Harbour J. William 
Published: September 2020

Abstract
Inactivation of the oncogene BAP1 is associated with poor prognosis in many cancers, including uveal melanoma (UM). Therapies for mediating the detrimental effects of BAP1 mutations have yet to be developed. Previously, we found that BAP1 depletion in Xenopus causes a striking developmental phenotype and a global dysregulation of differentiation markers across the genetic landscape. This was caused by impaired promoter assembly at commitment genes, marked by decreased H3K27ac levels. Inhibition of HDAC4 protein rescues the affected BAP1-depleted phenotype and genetic regulations, further emphasizing the role of H3K27ac in BAP1 function. Pairing these findings with a lab-devised multitiered screening process, we identified an epigenetic compound that successfully reverses the detrimental effects of the BAP1 deficient phenotype back to phenotypically normal conditions. This multitiered screening process tests prospective compounds for the ability to mediate transcriptional aberrations caused by BAP1 loss in UM cells (phase 1), rescue the BAP1 loss phenotype in Xenopus (phase 2), and provide significant inhibition of UM tumor growth in a mouse model (phase 3). These findings reveal a new application for a promising epigenetic compound as a therapeutic and reversing agent for BAP1 mutant UM. Furthermore, our streamlined process for the testing of promising therapeutic agents can accelerate the testing of such agents and getting them to clinical trials in a timely manner.
Citation Format: DAWN A. OWENS, Jeffim N. Kuznetsov, Andy Lopez, Stefan Kurtenbach, Daniel Bilbao, Evan R. Roberts, Claude-Henry Volmar, Claes R. Wahlestedt, Shaun P. Brothers, J. William Harbour. New candidate therapy for BAP1-mutant cancer identified using novel screen [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 4025.
Abstract 4082: Hsp90B protects MAST1 from CHIP-mediated ubiquitination and degradation providing cisplatin resistance
Authors: Pan Chaoyun , Li Jie , Boese Austin , Kang Sumin 
Published: September 2020

Abstract
Microtubule-associated serine/threonine kinase 1 (MAST1) plays a key role in cisplatin resistance of human cancers. However, the mechanism underlying MAST1 regulation remains elusive. We identified the hsp90B as a direct MAST1 binding partner essential for its stabilization via a proteomics screen. Targeting hsp90B in cancer cells sensitizes cisplatin treatment mainly through MAST1 destabilization. Mechanistically, hsp90B protects MAST1 from ubiquitination at lysine 317 and 545 by the E3 ubiquitin ligase CHIP and prevents proteasomal degradation. The role of the hsp90B-MAST1-CHIP signaling axis in cisplatin resistance was clinically validated in cancer patients. Furthermore, a combination of hsp90 inhibitor and MAST1 inhibitor lestaurtinib further inhibited MAST1 activity and consequently potentiated the cisplatin effect in a patient-derived xenograft model. Our study not only reveals the mechanism of MAST1 regulation in tumors but also demonstrates a promising combinatorial therapy to overcome cisplatin resistance in human cancers.
Citation Format: Chaoyun Pan, Jie Li, Austin Boese, Sumin Kang. Hsp90B protects MAST1 from CHIP-mediated ubiquitination and degradation providing cisplatin resistance [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 4082.
Abstract 4093: Drug combinations that can overcome resistance to PARP inhibitor therapy for BRCA1-associated breast cancer
Authors: Moustafa Dina Mohamed Abd El Aziz , Elwahed Maha Abd , Said Hanaa El , Parvin Jeffrey 
Published: September 2020

Abstract
Triple negative breast cancer (TNBC) represents approximately 10–15% of all breast cancers and has a poor outcome as it lacks a receptor target for therapy. Poly (ADP-ribose) polymerases inhibitors (PARPi) drugs have demonstrated some effectiveness in treating BRCA1 or BRCA2 mutated breast and ovarian cancers but resistance to PARPi is common. Published results found that resistance to Olaparib, a PARPi, can be due to downregulation of EMI1 and the consequent upregulation of the RAD51 recombinase. Using a tissue culture-based cell viability assay, we extended those observations to another PARPi and to other chemotherapy drugs that affect DNA repair or the cell cycle. As we expected, EMI1 downregulation resulted in resistance to another PARPi drug, Talazoparib. EMI1 downregulation also led to resistance to other cytotoxic drugs, Cisplatin and CHK1 inhibitor. Surprisingly, EMI1 downregulation also led to resistance to a MEK inhibitor, though this inhibitor blocks cells in G1 phase of the cell cycle and would not be expected to be sensitive to EMI1 levels. Notably, increasing the RAD51 protein expression can mimic the EMI1 downregulation and lead to resistance to different PARPis and the other cytotoxic drugs. This result suggests that the key downstream effect of EMI1 downregulation is increasing the concentration of RAD51 protein in the cell. We found that combining CHK1 inhibitor with Olaparib results in cell death in a dose specific manner. This combination therapy may be a means to overcome the PARPi resistance in BRCA1-deficient TNBC cells.
Citation Format: Dina Mohamed Abd El Aziz Moustafa, Maha Abd Elwahed, Hanaa El Said, Jeffrey Parvin. Drug combinations that can overcome resistance to PARP inhibitor therapy for BRCA1-associated breast cancer [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 4093.
Abstract 4113: Discriminatory 11-plex assay designed to monitor estrogen receptor mutations using a novel, melt-analysis capable digital PCR platform
Authors: Bernier Jennifer N. , Takach Johanna E. , Wang Tiffany , Gallagher Steve , Lin Robert , Zayac Andrew , Hung Paul , Lesho Matthew , Whitman Douglas 
Published: September 2020

Abstract
In a large fraction of ER+/HER2- metastatic breast cancer (MBC) patients, treatment with aromatase inhibitors fails due to emerging resistance. A key mechanism of this resistance is associated with a limited set of missense mutations in the gene encoding for the estrogen receptor (ESR1). These mutations are primarily found in the ligand binding domain of the protein. They result in a constitutively active estrogen receptor, are infrequently found in primary tumors (&lt;5%) and instead likely coincide with the emergence of an endocrine resistant phenotype. The occurrence of ESR1 mutations following treatment has varied from study to study depending on patient selection and method of detection, but prevalence may be as high as 50%. Because these patients require second line therapies as soon as possible, ESR1 mutations are an area of intense focus in research and clinical trials for ER+/HER2- breast cancer. Studies utilizing droplet digital PCR (ddPCR) assays have correlated an increase of ESR1 mutations in patient liquid biopsy samples with therapeutic resistance approximately 8 months prior to conventional methods, however the number of individual mutations evaluated in these studies was limited due to an inability to accurately and sensitively identify more than one individual mutated SNP allele within a single reaction. We have developed a multiplex digital PCR assay that utilizes melt-based probes to detect and discriminate between 10 unique, clinically relevant ESR1 mutations in circulating tumor DNA (ctDNA) samples while simultaneously quantifying total cell-free DNA (cfDNA). Designed for use with an innovative, array-based dPCR system, the assay requires a hands-on time of only 10-15 minutes and a total run time of 2.5 hours. This assay will allow breast cancer researchers to further refine our understanding of the role ESR1 mutations play in personalized treatment strategies for MBC.
Citation Format: Jennifer N. Bernier, Johanna E. Takach, Tiffany Wang, Steve Gallagher, Robert Lin, Andrew Zayac, Paul Hung, Matthew Lesho, Douglas Whitman. Discriminatory 11-plex assay designed to monitor estrogen receptor mutations using a novel, melt-analysis capable digital PCR platform [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 4113.
Abstract 4134: Characterization of ATRX loss combined with IDH1 R132H mutation in gliomas
Authors: Garbarino Jennifer , Bindra Ranjit , Jensen Ryan 
Published: September 2020

Abstract
Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) is mutated frequently in gliomas and is a potential therapeutic target. ATRX functions as a histone chaperone that helps incorporate histone variant H3.3 into the genome. There is some evidence of its involvement in both nonhomologous-end-joining (NHEJ) and replication stress, but a distinct role for ATRX in DNA repair has not been determined. Our lab has found that another common mutation in gliomas in the isocitrate dehydrogenase (IDH1) gene, leads to deficiency in homologous recombination (HR). We hypothesize that modelling these common mutations in glioma cell lines will to confer sensitivity to combinations of DNA repair inhibitor and damaging agents. To test this, we have created multiple cell lines with a CRISPR knockout of ATRX as well as lines that overexpress the IDH1 R132H in the presence of doxycycline. This will allow comparison of the double mutation and each mutation individually in different glioma cell lines for their DNA repair capacity. Currently, we have found a retention of H2AX foci in these cells after hydroxyurea treatment. A luciferase reporter based DNA repair assay has shown a decrease in HR capacity and no change in NHEJ in ATRX KO cells compared to WT. Additionally, we have begun screening DNA repair inhibitors and DNA damaging agents to identify compounds that specifically target ATRX KO cells or the double mutant cell lines. These preliminary screens have shown sensitivity to Chk1 inhibitors and temozolomide, which is currently being validated. We have also performed a focused DNA repair CRISPR screen to assess which DNA repair genes cause sensitivity or resistance ATRX KO cells. We infected both WT and ATRX KO cells with our pooled CRISPR library and harvested genomic DNA at multiple time points. Next generation sequencing was then used to identify sgRNAs that dropped out of the population compared to control guides. Sensitive hits from these screens were underrepresented in the ATRX KO population compared to WT and resistant hits were overrepresented in ATRX KO. These hits are the in the process of being validated. This work is continuing to expand on the hypothesis that ATRX is an important targetable mutation in low and high grade gliomas. Further understanding its mechanism of action as well as its action in combination with IDH1 R132H will help understand these cancers and lead to more targeted treatments for patients.
Citation Format: Jennifer Garbarino, Ranjit Bindra, Ryan Jensen. Characterization of ATRX loss combined with IDH1 R132H mutation in gliomas [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 4134.
Abstract 4155: ARID1A loss leads to chemotherapy resistance and is associated with a poor clinic outcome for patients with non-small cell lung cancer
Authors: Yang Linlin , Shen Changxian , Mo Xiaokui , Williams Terence M. 
Published: September 2020

Abstract
Purpose: ARID1A (AT-rich interactive domain 1A) is a member of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, and plays important roles in the regulation of gene transcription and DNA damage responses. ARID1A mutations occur frequently in non-small cell lung cancer (NSCLC), but the functions of ARID1A loss in the initiation, progression and maintenance of NSCLC remains largely unknown. This study aimed to investigate the clinical, pathological, and functional significance of ARID1A in NSCLC.
Experimental design: We first analyzed the prognostic value of ARID1A using a gene-expression microarray from the Director's Challenge Lung Study. Kaplan-Meier method and Log-rank tests were used to estimate the correlation between ARID1A expression and overall survival (OS). Univariate and multivariate Cox regression models were used to investigate the relationship between ARID1A and other clinical covariates. We further established stable ARID1A knockdown H1299 and H358 cell lines, and ARID1A exogenously expressing H460 and A549 cell lines. We performed functional assays to study the effects of ARID1A on proliferation, migration, invasion, cell cycle progression, sensitivity to chemotherapy, and in vivo tumor growth.
Results: In the Director's Challenge Study, decreased expression of ARID1A was associated with lymph node dissemination, higher T-stage (T3/T4), and worse survival compared with high expression in patients in the whole group (n=440) and subgroup who received surgery alone and no adjuvant therapy (n=328). ARID1A ablation by shRNA suppressed cell proliferation, promoted cell mobility, increased G2/M phase cell cycle distribution, and protected NSCLC cells from chemotherapy; whereas overexpression of ARID1A showed the opposite biological effects. Consistent with in vitro findings, in vivo tumor xenografts demonstrated ARID1A depletion led to reductions in cell growth but resistance of NSCLC to chemotherapy.
Conclusions: Our results suggest that loss of ARID1A suppresses NSCLC cell growth perhaps by inducing G2/M arrest, but promotes cell migration/invasion, and protect cells from chemotherapy. Further study of ARID1A is needed to better define its roles in the initiation and progression of NSCLC and response to chemotherapy.
Citation Format: Linlin Yang, Changxian Shen, Xiaokui Mo, Terence M. Williams. ARID1A loss leads to chemotherapy resistance and is associated with a poor clinic outcome for patients with non-small cell lung cancer [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 4155.
Abstract 416: Regulation of osteosarcoma cell metastasis by FGFR and mTOR signaling
Authors: Banu Arshiya , Zandueta Carolina , Lecanda Fernando , Grigoriadis Agamemnon E. 
Published: September 2020

Abstract
Osteosarcoma (OS) is the most common primary malignancy of the skeleton, occurring primarily in children and adolescents. Metastatic disease is the single most important prognostic factor with survival dropping to 15-20% in patients with lung metastases. We have recently demonstrated that high FGFR1 signaling in an oncogene-induced murine model of OS as well as in human OS samples contributes to the pathogenesis and metastasis of OS. Significantly, xenograft studies showed that genetic or pharmacological inhibition of FGFR1 decreased lung metastasis.
We have identified the mTOR signaling pathway as a cooperating pathway with FGFR signaling in OS cells. Stimulation of murine and human OS cell lines with FGF2 showed an increase in both MAPK and pAkt/mTOR signaling and mTOR target genes that was inhibited by the FGFR inhibitor, PD173074. Colony growth in soft agar showed that inhibition of mTOR blocked FGF2-stimulated colony growth of OS cells and shRNA silencing of mTOR prevented FGF2-stimulated cell migration in wound/scratch assays.
To confirm pathway cooperativity in vivo, we performed xenograft studies. Silencing of mTOR in FGFR1-expressing OS cells reduced tumor formation on a chick chorioallantoic membrane, with reduced pHistone-H3 expression. Orthotopic injection of OS cells demonstrated that small molecule inhibition of both FGFR1 and mTOR signaling (AZD4547 and AZD8055, respectively), showed greater inhibition of size and diameter of lung metastatic nodules than each inhibitor alone. This was associated with a decrease in the number of Ki67+ cells in lung metastases of FGFR/mTOR inhibitor-treated mice, whereas no changes in activated caspase-3 were detected. In a complementary in vivo model, tail vein injections of OS cells showed that combined FGFR/mTOR inhibition reduced cell seeding in the lungs, suggesting that FGFR/mTOR signaling are driving lung colonization independently of the primary tumor. Finally, preliminary studies indicate that long term growth of OS cells in the lung following tail vein injection may reveal a potential for OS cells to acquire chemoresistance to mTOR inhibition. The mechanisms are not yet known but are independent of the primary tumour.
Taken together, our data suggest that combinatorial treatment significantly decreased lung metastasis of OS cells from primary xenografts. Ongoing analysis of activated FGFR and mTOR pathways in patient-derived tissue microarrays will enable patient stratification that will be useful in the clinical setting to exploit this as a potential anti-metastatic therapy in OS.
Citation Format: Arshiya Banu, Carolina Zandueta, Fernando Lecanda, Agamemnon E. Grigoriadis. Regulation of osteosarcoma cell metastasis by FGFR and mTOR signaling [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 416.
Abstract 4178: ETH-155008, a dual inhibitor of CDK and Pim in preclinical treatment of human B-cell lymphoma xenografts
Authors: Liu Changnian , Sun Zuopeng , Xu Chunping , Zhang Pan , Ji Bin , Zhang James , Liu Laura , Yu Chengzhi 
Published: September 2020

Abstract
Non-Hodgkin lymphomas (NHLs) are the most common hematologic malignancies. The treatment of lymphoma presents a challenge in clinical oncology. Despite significant therapeutic efficacy achieved with combination of chemotherapy and new targeted agents, a large number of patients eventually relapse. Cyclin-dependent kinases (CDKs) are therapeutic targets frequently deregulated in various cancers including solid tumors and hematopoietic malignances. It was also reported that Moloney murine leukemia virus (PIM) kinases are overexpressed in several hematopoietic and solid tumors, especially in B-cell lymphomas. We evaluated the inhibition of kinases' activities and cell proliferation in vitro, and antitumor activities in vivo of ETH-155008, a dual inhibitor of CDK4/6 and PIM in preclinical treatment of human B-cell lymphoma xenografts. ETH-155008 was found to have strong inhibitory activities against key target enzymes with IC50s for CDK4/D1 at 0.8nM, CDK6/D1 at 1.4nM, PIM-1 at 13.3 nM, and PIM-3 at 0.9 nM. ETH-155008 showed to have highly potent antiproliferative activities against cultured human B-cell lymphoma cells of WSU-DLCL2 (diffuse large B-cell lymphoma) and JeKo-1 (mantle cell lymphoma) with IC50s at 1.7nM and 20 nM, respectively. The in vivo antitumor activities of ETH-155008 were evaluated and compared with abemaciclib (CDK4/6 inhibitor) and Imbruvica (Bruton tyrosine kinase inhibitor) in the treatment of the two lymphoma models, respectively. Treatment with ETH-155008 (40 mg/kg/daily x 14-21 days) almost completely eradicated the tumor xenografts and some of the tumor-bearing mice were cured; while as control drugs abemaciclib produced a tumor growth inhibition (TGI) of 56-60% and ibrutinib with a TGI of 60-67% in the two xenograft models. ETH-155008 treatment showed very little toxicity (only 2-4% body weight loss) which were well below the maximum tolerated dose. ETH-155008 represents a novel dual inhibitor that may yet fulfill the promise of effective B-cell lymphoma therapy through dual targeting of CDK4/6 and PIM3. These preclinical results supported the safety and efficacy observed in the preclinical studies and worthy of further clinical evaluation.
Citation Format: Changnian Liu, Zuopeng Sun, Chunping Xu, Pan Zhang, Bin Ji, James Zhang, Laura Liu, Chengzhi Yu. ETH-155008, a dual inhibitor of CDK and Pim in preclinical treatment of human B-cell lymphoma xenografts [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 4178.
Abstract 4184: Genetic and pharmacological disruption of survivin suppressed primary and metastatic tumor growth by attenuating TGFB pathway in ovarian cancer
Authors: Yue Junming 
Published: September 2020

Abstract
Introduction: Survivin, a member of the inhibitor of apoptosis family, is upregulated in multiple cancers including ovarian cancer, but is rarely detectable in normal tissues. Therefore, it is a potential drug target. However, targeting survivin is still challenge and small molecule inhibitors failed in clinical trials. It's very important to understand how survivin contributes to tumor development. In this study, we investigated the role of survivin in ovarian cancer using ovarian cancer cell lines in vitro and mouse models in vivo and examined how survivin contributes to ovarian primary ovarian tumor growth and metastasis by examining epithelial to mesenchymal transition (EMT).
Methods: To define the role of survivin in EMT in ovarian cancer cells, we established survivin knockout cell lines using lentiviral CRISPR/Cas9 nickase and pharmacologically inhibited survivin with a novel inhibitor MX106. We examined EMT markers, migration and invasion assays in survivin disrupted ovarian cancer cells using Transwell plates. We also assessed primary ovarian tumor growth and metastasis in an orthotopic ovarian cancer mouse models through intrabursal injecting survivin KO cell line and also treatment using MX106.
Findings: We found that disruption of survivin expression inhibited EMT by attenuating the TGFβ pathway in ovarian cancer cells. Cell proliferation, migration, and invasion were significantly inhibited in survivin knockout or MX106 treatment in SKOV3 and OVCAR3 cell lines compared to control cells. Inhibition of survivin sensitized cell responses to paclitaxel treatment and overcame chemoresistance in vitro. Lentiviral CRISPR/Cas9 mediated survivin knockout or MX106 treatment efficiently inhibited primary ovarian tumor growth and metastasis in orthotopic ovarian cancer mouse models.
Conclusions: Our data demonstrate that inhibition of survivin using either genetic knockout or a novel inhibitor MX106 suppresses primary ovarian tumor growth and metastasis by attenuating TGFβ pathway. MX106, as a novel survivin inhibitor effectively overcame chemoresistance compared to commercial YM155, which provides a novel approach for ovarian cancer therapy.
Citation Format: Junming Yue. Genetic and pharmacological disruption of survivin suppressed primary and metastatic tumor growth by attenuating TGFB pathway in ovarian cancer [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 4184.