bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1256: Validation of Ubiquitin specific peptidases 37 as a prognostic and diagnostic marker in osteosarcoma
Authors: Singh Mayank , Batra Atul , Bakhshi Sameer , Summers Matthew 
Published: August 2019

Abstract
Osteosarcoma has been a challenge for the oncologist because even after surgical removal of tumors 80 percent patients go on to develop metastasis to the Lung. Systematic development of Drug has been literally on a standstill in osteosarcoma. The emergence of Adjuvant therapy after surgery for localized osteosarcoma has increased the long term survival in patients under age 40 by 60 to 70 percent however for patients who go on to develop metastasis the prognosis is poor as there are limited therapeutic options. Protein ubiquitination and deubiquitylation plays an important role in controlling protein stability. Initial studies by us points to a model in which Ubiquitin specific peptidase 37 regulates cell cycle progression. Our data indicates that USP37 expression correlates with transformation by preventing degradation of different oncoproteins. It was found that in osteosarcoma cell lines USP37 is elevated which gives survival advantage to these cells while its depletion leads to enhanced cell death in response to genotoxic stress. USP37 depletion results in reduced resolution of DNA damage foci like gamma H2AX and 53BP1 and increase in no of collapsed replication fork which indicate the reduced ability of cells to carry out constitutive DNA replication. Physically USP37 interacted with proteins involved in DNA damage repair and effected their stability. We tried to correlate our data with archived patient osteosarcoma samples by analyzing if USP37 levels corelate with patient prognosis at our center which will be further discussed. The current data adds a new dimension to this newly explored deubiquitinates and merits development of targeting strategies to explore its therapeutic potential in osteosarcoma.
Citation Format: Mayank Singh, Atul Batra, Sameer Bakhshi, Matthew Summers. Validation of Ubiquitin specific peptidases 37 as a prognostic and diagnostic marker in osteosarcoma [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 1256.
Abstract 1258: Pooled-analysis of response markers in cancer cell lines treated with tumor treating fields
Authors: Shahaf Gitit Lavi , Giladi Moshe , Schneiderman Rosa S. , Gotlieb Karnit , Zeevi Einav , Porat Yaara , Munster Mijal , Weinberg Uri , Kirson Eilon D. , Palti Yoram 
Published: August 2019

Abstract
Low intensity, intermediate frequency alternating electric fields (TTFields) exert an inhibitory effect on numerous cancer cell lines with some variability in the response. The goal of the present study is to compare characteristics of cell lines based on their response pattern to TTFields and to identify response markers. Forty-five different human cancerous cell lines were treated for 72 hours with TTFields at optimal cell-specific frequency at the same nominal intensity (1.7 V/cm). Cytotoxicity and clonogenic potential were determined. Functional analysis of differentially expressed genes and mutations associated with response to TTFields was performed based on the Cancer Cell Line Encyclopedia (CCLE) database. Sensitivity to TTFields was compared with pharmacological profiling (CCLE). The cytotoxic response to TTFields was found to be distributed around an average of 50% with (ranging between 14% and 86% reductions in cell counts). The clonogenic effect varied between no effect and 88% reduction in the number of colonies. Increased sensitivity to: Lapatinib, PHA-665752 and PLX-4720 was common in the group of cell lines which were more highly responsive to TTFields. Functional analysis of cell line gene expression and mutation data revealed enriched pathways related to DNA damage repair response, cell migration, hypoxia signaling and oxidative stress. This analysis of cancerous cell line response to TTFields define the optimal frequency to be applied for each cell line and demonstrates the broad effectiveness of TTFields in cells. The role of the specific mutations associated with TTFields response should be further explored in additional studies. Pharmacological profiling may offer a rational for combining specific agents with TTFields.
Citation Format: Gitit Lavi Shahaf, Moshe Giladi, Rosa S. Schneiderman, Karnit Gotlieb, Einav Zeevi, Yaara Porat, Mijal Munster, Uri Weinberg, Eilon D. Kirson, Yoram Palti. Pooled-analysis of response markers in cancer cell lines treated with tumor treating fields [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 1258.
Abstract 1260: Inhibition of DOG1, or TMEM16A, results in antitumoral effects in gastrointestinal stromal tumors (GIST) in vitro
Authors: Fröbom Robin , Berglund Erik , Bränström Robert 
Published: August 2019

Abstract
DOG1/TMEM16A, over-expressed in &gt;95% of all GISTs, is a calcium-activated chloride channel that has gained attention as a promising drug target due to its involvement in several tumor-physiological processes. Two well-established human GIST cell lines (GIST-T1 and GIST882) were used to study DOG1 inhibitors effect on viability, colony formation, and cell cycle. In this study, we show that specific DOG1/TMEM16A-inhibitors (T16inh-A01 and CaCCinh-A01) decrease chloride currents, and reduces cell viability in GIST cells. However, only CaCCinh-A01 changes the distribution of the cell cycle in GIST cells, putting them into G1 cell cycle arrest, and increases sub-G1 phase population in GIST882 cells. CaCCinh-A01 strongly reduces the colony forming ability of the cells, whereas limited effect by T16inh-A01. Conclusions: DOG1/TMEM16A inhibition has antitumoral effects in GIST cells in vitro, and could potentially serve as a target for GIST therapy. CaCCinh-A01 seems to be the more potent inhibitor, presumably due to its effect not only on chloride currents but also on DOG1/TMEM16A expression.
Citation Format: Robin Fröbom, Erik Berglund, Robert Bränström. Inhibition of DOG1, or TMEM16A, results in antitumoral effects in gastrointestinal stromal tumors (GIST) in vitro [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 1260.
Abstract 1262: Relationship between RAS, BRAF, PIK3CA and location of primary tumor in urothelial carcinoma
Authors: Kim Young Saing , Lee Sang-Cheol , Hwang In Gyu , Lee Su Jin , Park Se Hoon 
Published: August 2019

Abstract
Purpose: In urothelial carcinoma (UC), somatic mutations in RAS, BRAF, and PIK3CA genes are suggested for prognostic markers as well as for therapeutic targets. Studies have reported that upper tract (renal pelvis and ureter) and bladder UC differ in factors including prognosis and genetic features.
Methods: We investigated the difference in clinicopathological features and oncogenic mutations (RAS, BRAF, and PIK3CA) according to the location of primary disease. In a prospective biomarker study in patients with metastatic or unresectable UC, tumor DNA was analyzed for mutations in KRAS, NRAS, HRAS, BRAF, and PIK3CAusing Ampliseq v2 platform. We further stratified the frequency of the mutations by the location of primary tumor.
Results: Among a total of 210 patients, those with upper tract UC and bladder UC were 90 and 120 patients, respectively. Missense mutations in KRAS, NRAS, HRAS, BRAF, and PIK3CA were present in 9 (4.3%), 1 (0.5%), 18 (8.6%), 4 (1.9%), and 32 (15.2%) patients, respectively. PIK3CA mutations were detected in 16 patients with upper tract UC (17.8%) and 16 patients with bladder UC (13.3%). Likewise, HRAS mutations were detected more frequently in upper tract UC (10/90, 11.1%) than bladder UC (8/120, 6.7%). In metastatic UC setting, PIK3CA or HRAS mutations were not associated with different overall survival.
Conclusions: PIK3CA and HRAS mutations were more frequently observed in patients with upper tract UC compared to those with bladder UC. The different genetic features need to be studied by further studies.
Note: This abstract was not presented at the meeting.
Citation Format: Young Saing Kim, Sang-Cheol Lee, In Gyu Hwang, Su Jin Lee, Se Hoon Park. Relationship between RAS, BRAF, PIK3CA and location of primary tumor in urothelial carcinoma [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 1262.
Abstract 1266: Co-expression of P-glycoprotein and ABCG2 in a cell line model reveals both independent and cooperative transporter function
Authors: Robinson Andrea , Robey Robert , Gottesman Michael 
Published: August 2019

Abstract
Although overexpression of multiple ATP-binding cassette transporters has been reported in clinical samples, few studies have examined how expression of multiple transporters might confer resistance to chemotherapy drugs. We therefore examined how P-glycoprotein (P-gp, encoded by the ABCB1 gene) and ABCG2 contribute to drug resistance in a cell line model. HEK-293 cells were transfected with vector encoding full-length ABCB1, ABCG2, or a vector containing both genes under the control of a separate promoter. Cells transfected to express both transporters (B1/G2 cells) expressed high levels of both transporters and were able to transport both the P-gp-specific substrate rhodamine 123 and the ABCG2 specific substrate pheophorbide a when examined by flow cytometry. B1/G2 cells were also cross-resistant to the P-gp substrate doxorubicin, the ABCG2 substrate topotecan as well as mitoxantrone, a substrate of both transporters. The checkpoint inhibitor prexasertib was also found to be a substrate of both P-gp and ABCG2. When B1/G2 cells were incubated with both rhodamine 123 and pheophorbide a, transport of both compounds was observed, suggesting that P-gp and ABCG2 can function independently to transport substrates. P-gp and ABCG2 were also found to function cooperatively to transport the common fluorescent substrates mitoxantrone and BODIPY®-prazosin, as it was necessary to inhibit both transporters to prevent efflux from B1/G2 cells. This was also true in 3-day cytotoxicity assays with mitoxantrone and prexasertib. Thus, P-gp and ABCG2 can independently and cooperatively confer resistance to substrates, underscoring the need to inhibit multiple transporters when they are coexpressed.
Citation Format: Andrea Robinson, Robert Robey, Michael Gottesman. Co-expression of P-glycoprotein and ABCG2 in a cell line model reveals both independent and cooperative transporter function [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 1266.
Abstract 1277: Honokiol, a natural product, overcomes acquired resistance of EGFR mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib
Authors: ZANG Hongjing , Fan Songqing , Arbiser Jack , Owonikoko Taofeek K. , Ramalingam Suresh S. , Sun Shi-Yong 
Published: August 2019

Abstract
Osimertinib (AZD9291) is a FDA-approved EGFR inhibitor for treating non-small cell lung cancer (NSCLC) patients with activating EGFR mutations (first-line) or those who have become resistant to 1st generation EGFR inhibitors through the T790M mutation (second-line). The development of acquired resistance to osimertinib limits the long-term benefits of patients, and effective treatment options are urgently needed. We have identified that honokiol, a natural product with potential antitumor activity, may be used to overcome osimertinib resistance. In several osimertinib-resistant cell lines including HCC827/AR, PC-9/AR, PC-9/GR/AR and PC-9/3M (with EGFR 19del, T790M and C797S mutations), the combination of honokiol and osimertinib had synergistic effects on decreasing the survival of these cell lines. The combination inhibited cell colony formation and growth, and augmented induction of apoptosis of resistant cells. This combination enhanced reduction of Mcl-1, a critical mechanism by which osimertinib induces apoptosis in sensitive EGFR mutant NSCLC cells; this effect is likely due to enhanced Mcl-1 degradation since Mcl-1 was degraded much faster in cells exposed to the combination of honokiol and osimertinib than in DMSO-treated control cells. Moreover enforced overexpression of ectopic Mcl-1 abolished the enhanced effect of honokiol and osimertinib combination on induction of apoptosis, supporting a critical role of Mcl-1 reduction in inducing apoptosis of the osimertinib-resistant cells by this combination. Our findings warrant further study of this combination for overcoming osimertinib-resistance in vivo and potentially in the clinic. (This work was supported by the NIH/NCI R01 CA223220 to SYS and Winship lung cancer pilot award to SYS).
Citation Format: Hongjing ZANG, Songqing Fan, Jack Arbiser, Taofeek K. Owonikoko, Suresh S. Ramalingam, Shi-Yong Sun. Honokiol, a natural product, overcomes acquired resistance of EGFR mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib [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 1277.
Abstract 1280: Positive PD-L1 expression is associated with unfavorable clinical outcome in EGFR-mutated lung adenocarcinomas treated with EGFR-TKIs
Authors: Lee Seung Hyeun , Park Myung Jae , Chang Boksoon 
Published: August 2019

Abstract
Objectives: Clinical implication of programmed death ligand 1 (PD-L1) expression in oncogene-addicted non-small cell lung cancer treated with tyrosine kinase inhibitors (TKIs) is largely unknown. The objective of this study was to determine the frequency of PD-L1 expression and the clinical outcome according to PD-L1 expression in lung adenocarcinomas harboring EGFR mutation and treated with EGFR-TKIs.
Methods: We retrospectively evaluated PD-L1 expression using 22C3 pharmDx assay in lung adenocarcinoma patients with EGFR mutations at two referral hospitals between January 2017 and June 2018. Samples were obtained from surgically resected tumors, small biopsy, or cytologic cell blocks.
Results: Of all 71 patients analyzed, 44 (58.7%) had PD-L1 tumor proportion score (TPS) of &lt; 1%, 23 (30.7%) had PD-L1 TPS of 1%-49%, and 8 (10.7%) had PD-L1 TPS of ≥ 50%. Of the 37 patients treated with first-line EGFR-TKIs, PD-L1 TPS ≥ 1% was associated with a significantly decreased response rate, compared with PD-L1 TPS &lt; 1% (45.7% vs. 67.3%, p=0.005). Furthermore, PD-L1 TPS ≥ 1% was associated with a significantly shorter median progression free survival, compared with PD-L1 TPS &lt; 1% (9.3 months vs. 14.2 months, p = 0.024). Multivariate analysis showed that PD-L1 TPS ≥1% is independently associated with shorter PFS (hazard ratio 1.32, p=0.012).
Conclusion: PD-L1 was positive in approximately 40% of patients with EGFR-mutated lung adenocarcinoma. Postive PD-L1 expression may be associated with unfavorable clinical outcome to EGFR-TKIs among those patients group.
Citation Format: Seung Hyeun Lee, Myung Jae Park, Boksoon Chang. Positive PD-L1 expression is associated with unfavorable clinical outcome in EGFR-mutated lung adenocarcinomas treated with EGFR-TKIs [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 1280.
Abstract 1285A: Erythropoietin can cancelchemo-resistances viadown regulation of ABC transporters
Authors: Matsui Hirofumi , Kurokawa Hiromi 
Published: August 2019

Abstract
Introduction: Erythropoietin (EPO) is a glycoprotein cytokine which stimulates red blood cell production (erythropoiesis) in the bone marrow. The receptor of it (EPOR) was reported to exist on the cancer cellular membrane: more than 85% cancer cell expresses EPOR. Several reports suggested to play an important role for cancer cellular growth, however, the role of EPOR in cancer cells is not confirmed. The authors have studied the cancer cellular porphyrin accumulation, metabolism and excretion to clear the pathogenetic mechanism which involved the high concentration of porphyrins. The authors found that reactive oxygen species (ROS) accelerate both the cancer cellular porphyrin accumulation and the effect of photodynamic therapy. However, we cannot confirm which substrate is a key of signal transduction. EPO has been known used to be up-regulated at the metabolic acidosis via the stabilization of HIF-1α, a nuclear factor. Since HIF-1α can be stabilized by not only acidosis but also the high concentration of nitric oxide (NO), NO rich cancer cells may involve EPOR. Moreover, the purpose of EPO-EPOR system is likely to survive the hypoxic condition, it may keep intracellular heme/ porphyrins. The authors’ hypothesis is EPO-EPOR system in cancer cells may down-regulate ABCG2 which excretes heme/ porphyrins, and several anti-cancer drugs. Moreover, if so, the excretion of several anti-cancer chemo reagents should be inhibited to involve more effective chemotherapy.
Methods: To prove these possibilities, the authors carry out following experiments with gastric and colorectal cancer cells. The existence of EPOR, the amount of ABC transporters (B1, C5, G2) after the recombinant EPO (rEPO) exposure (dose dependency and time dependency) were analyzed by western blotting. Cytotoxicity of anti-cancer drugs with or without rEPO was measured with the Cell Counting Kit-8.
Result: (1) EPOR existed in each cell line used in this study. (2) rEPO treatment involved down regulation of ABC transporters (B1, C5, G2) in dose dependently. (3) ABCG2 expression decreased until 24 hours after rEPO treatment. However, its expression re-increased 48 hours after treatment. (4) The 24 hours pretreatment of EPO significantly increased the effect of doxorubicin, paclitaxel, irrinotecan, cisplatin, 5-FU and oxaliplatin even in chemo-resistant cells.
Conclusions: rEPO accelerates the effect of anti-cancer drugs via the down regulation of ABC transporters.
Citation Format: Hirofumi Matsui, Hiromi Kurokawa. Erythropoietin can cancelchemo-resistances viadown regulation of ABC transporters [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 1285A.
Abstract 1300: Novel thyrointegrin αvβ3 antagonist in the treatment of glioblastoma multiforme
Authors: Mousa Shaker A. , Sudha Thangirala , Godugu Kavitha , Rajabi Mehdi , Sell Stewart , Davis Paul J. 
Published: August 2019

Abstract
Background: The proliferative and pro-angiogenic actions mediated by L-thyroxine, pro-inflammatory and all known growth factors in glioblastoma multiforme (GBM) are initiated at cell surface thyrointegrin αvβ3 receptors for thyroid hormone on the extracellular domain of integrin αvβ3. Thyrointegrin αvβ3 receptors are over-expressed on cancer and rapidly dividing blood vessel cells, but quiescent on normal cells. A macromolecule Polyethylene glycol-conjugated bi-TriAzole Tetraiodothyroacetic acid (P-bi-TAT) acts with high affinity (Ki 3.1 nM) and specificity for the thyrointegrin αvβ3 receptors without any significant nuclear translocation.
Methods: In the present studies, three primary human GBM cells and U87 glioma cell line were implanted orthotopically or subcutaneously (s.c.) into nude mice that were treated daily for up to 21 days with P-bi-TAT at different doses. Additionally, preclinical Pharmacokinetic and Safety assessments were carried out in multiple species.
Results: Pharmacokinetic profiles indicated once-a-day dosing, and safety assessment studies demonstrated high safety and tolerability at 100-fold over the anticipated human equivalent dose. Fluorescence labeled P-bi-TAT administered s.c. demonstrated high biodistribution to GBM tumor in the brain that was comparable to peripherally implanted tumor. P-bi-TAT administered daily for 10-21 days s.c. at 0.3-10 mg/kg resulted in a dose-dependent suppression of GBM tumor growth and viability monitored with IVIS imaging (p &lt;0.001). Histopathological analysis of tumors revealed 95% loss of the vascularity of treated tumors at 10 days (p &lt;0.001) along with extensive cellular necrosis and apoptosis, without intratumoral hemorrhage. GBM tumors had a 97% volume loss and maximal loss of GBM cell viability during a subsequent 22 days off-treatment period (p &lt; 0.001). Genomic micro-array studies with human primary GBM revealed that over 30 pathways relevant to the progression of GBM are modulated by P-bi-TAT.
Conclusions: P-bi-TAT is a promising lead clinical candidate effective in the treatment of human GBM.
Citation Format: Shaker A. Mousa, Thangirala Sudha, Kavitha Godugu, Mehdi Rajabi, Stewart Sell, Paul J. Davis. Novel thyrointegrin αvβ3 antagonist in the treatment of glioblastoma multiforme [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 1300.