bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1151: Inclusion of cholesterol and A549 lipid extract in CLENs improved cellular uptake in adenocarcinoma non-small cell lung cancer target cells
Authors: Langlois Maxime , Kao Guo-Yun , Lasker Diana 
Published: September 2020

Abstract
Purpose:The purpose of this investigation was to determine the optimal amount of cholesterol and A549-derived lipid extract (LE) included in the initial design and development of A-549-cell membrane lipid extracted nanoliposomes (A549-CLENs) for cell targeting studies.
Methods and Materials:A549 (ATCC® CCL-185™), used as a positive control and NCI-H1703 (ATCC® CRL-5889™), used as a negative control, and respective growth media were purchased from ATCC (Manassas, VA). A549-GFP (green fluorescent protein) cell line was purchased from AntiCancer, Inc. DOPC, DOTAP, cholesterol, and DSPE-PEG5000 were obtained from Avanti Polar Lipids (Alabastar, AL). Cellular membrane lipids of A549 cells were extracted by modified Bligh & Dyer method. CLENs were fluorescently labeled with rhodamine-B. Particle sizes and zeta potentials were performed using ZetaPALS (Brookhaven Instruments Corporation, Holtsville, NY, USA). For cellular uptake studies cells were seeded at 2.0 x 104 cells in a 48-well plate followed by incubation for 24 hours. A fluorescence microplate reader and/or fluorescence microscopy were used to evaluate cellular uptake as a function of relative amount of cholesterol and A549-lipid extract inclusion in CLENs.
Results:In general, an increase in the inclusion of cholesterol reduced the particle size of CLENs. Amount of 10 mol% of cholesterol content in CLENs demonstrated the smallest mean size diameters and a zeta potential value recorded at 243 ± 4.4 nm and 1 ± 2.61 mV, respectively. The finding correlated also with a relatively high degree of cellular uptake of the preparation type for part I of the physicochemical characterization studies. We next maintained 10 mol% cholesterol content consistent in all future preparations and increased the total A-549 lipid extract material at the expense of DOPC. In general, the mean diameter and zeta potential for A549-CLENs were 246 ± 3.8 nm and 20.4 ± 0.84 mV, respectively. Approximately 10-15 mol% of A-549 lipid extract inclusion resulted in a consistently high degree of overall cellular uptake by GFP-A549 and A549 target cells compared to control and the non-target cell population, NCI-H1703.
Conclusion: Preparation of A549-CLENs consisting of DOPC/ DOTAP/ Chol/ LE/PEG (65/10/10/10/5) established the greatest increase in cellular uptake and overall selectivity. Future studies will consider antibody conjugation and development of tumor-specific biomarkers for serodiagnostic detection and lung cancer treatment.
Citation Format: Maxime Langlois, Guo-Yun Kao, Diana Lasker. Inclusion of cholesterol and A549 lipid extract in CLENs improved cellular uptake in adenocarcinoma non-small cell lung cancer target 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 1151.
Abstract 1237: Biological effects of a FRα-targeting antibody-drug conjugate, IMGN853 (mirvetuximab soravtansine) in high-grade serous ovarian cancer
Authors: Chelariu-Raicu Anca , Stur Elaine , Ivan Cristina , Coleman Robert L. , Sood Anil K. , Yunfei Wen 
Published: September 2020

Abstract
Objective: Autophagic cell death is an important mechanism induced by blocking folate receptor (FRα) in inhibiting tumor growth. Here, our objective is to examine the biological effects of IMGN853 (mirvetuximab soravtansine) in preclinical models of ovarian cancer and to identify potential combination therapies.
Methods: In vitro, immunoblotting, assays for cell viability, proliferation and cell cycle by fluorescence-activated cell sorting (FACS) were performed in an array of high grade serous carcinoma (HGSC) cell lines. Autophagy flux and activities of autophagy factors were also determined. In vivo, metastasis mouse models were used for testing the therapeutic efficacy of IMGN853 monotherapy or in combination with olaparib or cisplatin. Potential synergy with these drugs was assessed using in vitro assays. The resulting tumors were subjected to immunohistochemistry and reverse phase protein arrays (RPPA).
Results: Data from the Cancer Genome Atlas Data (TCGA) revealed that FRα copy-number alterations was significantly correlated with shorter disease-free survival in patients with HGSC. Autophagy marker LC3 was upregulated following monotherapy with IMGN853 as well as in combination of IMGN853 with olaparib or cisplatin in HGSC cell lines such as OVCA8 and OVCA432, which express high-level of FRα. Experiments using metastatic HGSC models showed that IMGN853 monotherapy reduced tumor growth (30% change); the combination of IMGN853 and olaparib was superior to olaparib monotherapy (24% change; p 0.0033). Integrated analysis on RPPA revealed increased expression of ABL1 and PEA15 in the groups treated with IMGN853 monotherapy or in combination with olaparib. We further found reduced FRα expression and increased caspase 3 expression in IMGN853 groups compared with control.
Conclusion: Our results point to sustained autophagy in FRα positive cells as a mechanism of effect of IMGN853. These findings could have implications for clinical development of anti-FRα therapies, especially in combination with other drugs such as olaparib.
Citation Format: Anca Chelariu-Raicu, Elaine Stur, Cristina Ivan, Robert L. Coleman, Anil K. Sood, Wen Yunfei. Biological effects of a FRα-targeting antibody-drug conjugate, IMGN853 (mirvetuximab soravtansine) in high-grade serous 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 1237.
Abstract 124: Recycling endosomes in mature epithelia restrain tumorigenic signaling
Authors: Goswami Sayantani 
Published: September 2020

Abstract
The effects of polarized membrane trafficking in mature epithelial tissue on cell growth and cancer progression have not been fully explored in vivo. A majority of colorectal cancers have reduced and mislocalized Rab11, a small GTPase dedicated to trafficking of recycling endosomes. Patients with low Rab11 protein expression have poor survival rates. Using genetic models across species, we show that intact recycling endosome function restrains aberrant epithelial growth elicited by APC or RAS mutations. Loss of Rab11 protein led to epithelial dysplasia in early animal development and synergized with oncogenic pathways to accelerate tumor progression initiated by carcinogen, genetic mutation, or aging. Transcriptomic analysis uncovered an immediate expansion of the intestinal stem cell pool along with cell-autonomous Yki/Yap activation following disruption of Rab11a-mediated recycling endosomes. Intestinal tumors lacking Rab11a traffic exhibited marked elevation of nuclear Yap, upd3/IL6-Stat3, and amphiregulin-MAPK signaling, while suppression of Yki/Yap or upd3/IL6 reduced gut epithelial dysplasia and hyperplasia. Examination of Rab11a function in enteroids or cultured cell lines suggested that this endosome unit is required for suppression of the Yap pathway by Hippo kinases. Thus, recycling endosomes in mature epithelia constitute key tumor suppressors, loss of which accelerates carcinogenesis. Statement of significance: Recycling endosome traffic in mature epithelia constitutes a novel tumor suppressing mechanism.
Citation Format: Sayantani Goswami. Recycling endosomes in mature epithelia restrain tumorigenic 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 124.
Abstract 126: Dasatinib attenuates Src pathway signaling and combined with veliparib and carboplatin potently inhibits tumor growth in PTEN-null TNBC model
Authors: Sun Yuliang , Lin Xiaoqian , Aske Jennifer , Williams Casey , Abramovitz Mark , Leyland-Jones Brian 
Published: September 2020

Abstract
Background: The combination of a poly ADP ribose polymerase (PARP) inhibitor with a DNA-damaging agent has shown promise in treating triple-negative breast cancer (TNBC); but not all patients respond to this combination. The Src protein kinase modulates multiple cancer cell properties and plays a key role in tumorigenic processes. However, Src inhibitors as single agents have shown limited effects in solid tumors. In this study, we examined the antitumor effects of the Src inhibitor dasatinib, the PARP inhibitor veliparib, and the DNA-damaging agent carboplatin in PTEN-null TNBC cells in vitro and tumors in vivo to try to identify the combination with the most clinical potential. Methods: The PTEN-null TNBC cell line, MDA-MB-468, was used in this study. For in vitro studies, proliferation, cellular apoptosis, and 3D on-top clonogenic growth were measured, tube formation assays and western blot analysis were performed. For in vivo studies, a xenograft model was used to examine treatment responses, and immunohistochemical analysis was performed. Results: Interestingly, treatment with the combination of veliparib plus carboplatin led to an increase in Src phosphorylation of MDA-MB-468 cells. Importantly, addition of dasatinib attenuated Src overexpression induced by veliparib plus carboplatin and further increased the activation of caspase 3 and PARP, thereby enhancing the antitumor efficacy of veliparib plus carboplatin. In an MDA-MB-468 xenograft model, the triple combination of dasatinib with veliparib plus carboplatin showed greater tumor growth inhibitory effects compared with single agents or double combinations. No systemic toxicity was observed in mice treated with the triple combination. Conclusion: Here, we provide novel evidence that veliparib combined with carboplatin drives Src activation in the preclinical model tested. Moreover, we provide provocative in vitro and in vivo data highlighting the potential for increasing therapeutic efficacy by combining dasatinib with veliparib and carboplatin in PTEN-null TNBC.
Citation Format: Yuliang Sun, Xiaoqian Lin, Jennifer Aske, Casey Williams, Mark Abramovitz, Brian Leyland-Jones. Dasatinib attenuates Src pathway signaling and combined with veliparib and carboplatin potently inhibits tumor growth in PTEN-null TNBC 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 126.
Abstract 1316: Molecular features of complete response to neoadjuvant anti-androgen therapy in high risk localized prostate cancer
Authors: Tewari Alok , Cheung Alexander T. , Conway Jake , Park Jihye , Wankowicz Stephanie , Lis Rosina T. , Zhang Zhenwei , AlDubayan Saud , McKay Rana R. , Taplin Mary-Ellen , Van Allen Eliezer M. 
Published: September 2020

Abstract
Though often curable, high-risk localized prostate cancer has a significant chance of recurring either biochemically, locoregionally, or as distant metastatic disease. Efforts are ongoing to evaluate neoadjuvant strategies to reduce this risk of recurrence. Our recent clinical trial showed that intense androgen deprivation with enzalutamide, leuprolide, and abiraterone acetate with prednisone (ELAP) induced pathologic complete response or minimal residual disease (&lt; 5mm) at prostatectomy in 30% of trial patients (exceptional responders). Though previous studies have identified the pathological and genomic heterogeneity of localized prostate cancer, the impact of this heterogeneity on treatment response is unknown. To address this, we performed multi-region whole-exome and whole transcriptome sequencing on tumor and normal prostate regions from 15 exceptional responders and 15 non-responders treated with intensive androgen deprivation prior to prostatectomy. Overall, we found heterogeneous somatic mutation patterns with strong evidence of intra-tumoral heterogeneity and no association between mutation frequency and response. However, when subsetting patients by treatment response, SPOP mutation and SPOPL copy number loss were only observed in exceptional responders, while TP53 mutations were only observed in the non-responders. We observed expression signature differences between exceptional responders and non-responders, with exceptional responders having an increase in Androgen Receptor related gene signatures. Though underpowered to identify statistically significant genomic correlates of response to neoadjuvant ADT, our findings may inform future studies to identify clinically relevant features of high-risk localized prostate cancers to stratify therapies to reduce the risk of disease recurrence.
Citation Format: Alok Tewari, Alexander T. Cheung, Jake Conway, Jihye Park, Stephanie Wankowicz, Rosina T. Lis, Zhenwei Zhang, Saud AlDubayan, Rana R. McKay, Mary-Ellen Taplin, Eliezer M. Van Allen. Molecular features of complete response to neoadjuvant anti-androgen therapy in high risk localized prostate 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 1316.
Abstract 1317: RET aberrations in Chinese solid tumor patients: Next-generation sequencing of 10194 patients
Authors: Zhou Chengzhi , Zhang Junhang , Shen Zhuojian , Wang Hongbiao , Li Yun , Wang Minghui , Fu Qin , Zhang Lin , Liu Angen 
Published: September 2020

Abstract
Purpose: RET is an emerging oncogenic target showing promise in phase I/II clinical trials, but the comprehensive genomic landscape of RET aberrations across multiple cancers has had limited exploration.
Experimental Design: We interrogated the molecular portfolio of 10194 patients with diverse cancers for the presence of RET aberrations using targeted next-generation sequencing (NGS) of 450 genes panel (OrigiMed, Shanghai).
Results: Among various cancer types, RET aberrations were identified in 234 cases (2.3%, 234/10 194), with mutations being the most common alteration (62.4%, 146/234), followed by fusions (19.2%, 45/234), amplifications (13.2%, 31/234), and rearrangements (5.1%, 12/234). The proportion of RET mutations in papillary thyroid carcinoma, lung adenocarcinoma, colorectal adenocarcinoma, small cell lung cancer, and other subtypes was 28.6%, 4.2%, 3.6%, 3.0%, and 16.5% respectively. Most patients had coexisting aberrations in addition to RET anomalies (73.5%, 172/234), with the most common being in TP53-associated genes (40.2%, 94/234), the Wnt signaling pathway (39.3%, 92/234), the HR signaling pathway (19.2%, 45/234), the PI3K signaling pathway (17.5%, 41/234), and MAPK effectors (16.2%, 38/234). All 172 patients harboring coexisting aberrations had distinct genomic portfolios.
Conclusions: This study revealed RET aberrations in 2.3% of Chinese solid tumor patients. RET aberrations were detected more in papillary thyroid carcinoma, lung adenocarcinoma, colorectal adenocarcinoma, and small cell lung cancer. Most cases harbored actionable, albeit distinct, coexisting alterations, all of which may potentially contribute to more effective treatment options in the future.
Citation Format: Chengzhi Zhou, Junhang Zhang, Zhuojian Shen, Hongbiao Wang, Yun Li, Minghui Wang, Qin Fu, Lin Zhang, Angen Liu. RET aberrations in Chinese solid tumor patients: Next-generation sequencing of 10194 patients [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 1317.
Abstract 1386: 5-FU-induces PD-L1 in the absence of p53 via ATM dependent activation of STAT3
Authors: Sessler Tamas , Falcone Fiammetta , Gallagher Peter , Wright Timothy , Savage Kienan , Longley Daniel B. , McDade Simon S. 
Published: September 2020

Abstract
Background: 5-Fluorouracil (5-FU) is an antimetabolite DNA damaging chemotherapeutics that forms the backbone for treatment of colorectal cancer (CRC) and currently it is the most commonly used anti-cancer drug. Despite the central role played by p53 in regulating DNA-damage response, its role in regulating response to 5-FU remains unclear.
Methods: To better understand how p53 status differentially affects response to 5-FU, we conducted a detailed phenotypic analysis of the effects of 5FU alone or in combination with Oxaliplatin on cell cycle, DNA damage, cell death, DNA repair and consequent signaling across a panel of p53 isogenic, null and mutant CRC cell lines.
Results: This revealed that while 5-FU induce both p53 dependent and independent cell death, the effects on cell cycle are profoundly different, with p53 deficient cells accumulating in S-phase with prolongated double strand breaks. This is not observed in p53 proficient cells, which are protected from these effects by induction of the p53 target gene p21/CDKN1A limiting cell cycle and enforcing suppression of cell cycle genes. Notably in both p53 or p21 deficient cells 5-FU results in sustained DNA damage-signaling through ATR and ATM in p53 deficient cells which preferentially arrest in S-phase. Importantly, these cells exhibit significant induction of cell surface expression of programmed death ligand-1 (PD-L1), which is enhanced by ATR inhibition concomitant with increased ATM activation. Further analysis indicates that transcriptional induction of PD-L1 is mediated through STAT3 in an interferon independent manner.
Conclusion: This work adds significantly to our understanding of how p53 status impacts 5FU induced cell cycle arrest and response in CRC patients and have important implications for understanding 5-FU response, particularly in future combinations with immune checkpoint inhibitors.
Citation Format: Tamas Sessler, Fiammetta Falcone, Peter Gallagher, Timothy Wright, Kienan Savage, Daniel B. Longley, Simon S. McDade. 5-FU-induces PD-L1 in the absence of p53 via ATM dependent activation of STAT3 [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 1386.
Abstract 1388: Loss of TGFβ signaling increases alternative end-joining and could sensitize high-grade serous ovarian cancer to PARP inhibitors
Authors: Guix Ines , Liu Qi , Palomero Luis , Moore Jade , Pujana Miquel Angel , Barcellos-Hoff Mary Helen 
Published: September 2020

Abstract
Defective DNA damage repair (DDR) is an important therapeutic target in high-grade serous ovarian cancer (HGSOC). This is exemplified by the efficacy of platinum analogues in this disease, as well as the advent of PARP inhibitors that exhibit synthetic lethality when applied to BRCA-mutated tumors. We recently found that loss of transforming growth factor β (TGFβ) signaling in head and neck squamous cell carcinoma causes dysregulation of BRCA1 and hence defective homologous recombination, which pushes cells to rely on error-prone alternative end-joining (alt-EJ) for DDR (Liu et al. Clin Ca Res 2018). To examine this link in ovarian cancer, here we interrogated the transcriptomes from 562 HGSOC patients from The Cancer Genome Atlas Consortium (TCGA) using a 50-gene signature of chronic TGFβ signaling and a 30-gene signature of alt-EJ competency.
Our study unveiled a highly significant (p&lt;0.00001) inverse correlation between TGFβ and alt-EJ in HGSOC. Alt-EJ is error prone, thus we examined the fraction of the genome altered as a function of TGFβ/alt-EJ; the TGFβ/alt-EJ pathway index score was negatively associated with the fraction of genome altered (Pearson correlation coefficient: -0.3288887; P-value = 2.9e-15), with tumors with low TGFβ/high alt-EJ exhibiting more genomic alterations. Alt-EJ increases tumor cell sensitivity to radiation and chemotherapy. Patients with low TGFβ/high alt-EJ profile were associated with an overall survival advantage (p=0.02) and a disease-free survival advantage (p=0.03). Consistent with this, patients with low TGFβ/high alt-EJ profile showed a significantly better response to primary treatment with cisplatin (p=0.038).
These data support combinations of TGFβ inhibitors that could boost response to chemotherapy in HGSOC. Because PARP enzymes are key to alt-EJ, which sensitizes cells to PARP inhibition (ibid), these data suggest a novel means to identify patients that will likely be responsive to PARP inhibitors independently of BRCA mutational status.
Citation Format: Ines Guix, Qi Liu, Luis Palomero, Jade Moore, Miquel Angel Pujana, Mary Helen Barcellos-Hoff. Loss of TGFβ signaling increases alternative end-joining and could sensitize high-grade serous ovarian cancer to PARP inhibitors [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 1388.
Abstract 1407: MicroRNA-18a targeting inhibits the tumor growth of cisplatin-resistant ovarian cancer
Authors: Quiñones-Díaz Blanca Iris , Reyes-González Jeyshka M. , Valiyeva Fatma , Vivas-Mejía Pablo E. 
Published: September 2020

Abstract
Platinum-based therapy remains as the front-line treatment for ovarian cancer. However, despite initial response to treatment, most patients develop platinum resistance and eventually succumb to the malignancy. In an attempt to identify novel targets in cisplatin-resistant ovarian cancer, we studied the role of the microRNA-18a-5p (miR-18a) in cisplatin-resistant ovarian cancer. miR-18a is part of the vastly researched miR-17-92 cluster. Although most members of this cluster have been associated with pro-tumorigenic roles in several cancers, recent findings suggest that miR-18a plays a tumor-suppressive role in ovarian cancer. However, the specific role of miR-18a in platinum resistance has yet to be elucidated. In this study, Real-Time PCR analysis was performed to measure the levels of miR-18a in several ovarian cancer cell lines. We found miR-18a downregulation in cisplatin-resistant ovarian cancer cells relative to their sensitive counterparts. Therefore, we assessed the effect of miR-18a upregulation by oligonucleotide microRNA mimics (OMM) in tumor growth using a xenograft mouse model of cisplatin-resistant ovarian cancer. As ovarian tumors have been shown to overexpress the Folate Receptor α (FRα), we used nanoliposomes conjugated to folic acid as vehicles to deliver the OMMs. Following intraperitoneal injections of OMM-loaded liposomes (twice per week for three weeks), there was a significant decrease in tumor weight of miR-18a-OMM treated mice in comparison to the control-OMM group. Moreover, immunohistochemical analysis was performed on the mice tumor tissues to assess the levels of cell proliferation and angiogenesis markers (ki67 and CD31, respectively). Our study suggests that miR-18a halts cisplatin-resistant ovarian cancer tumor progression.
This work was supported by the RCMI grant: U54 MD007600, UPR Comprehensive Cancer Center and NIGMS-RISE R25-GM061838.
Citation Format: Blanca Iris Quiñones-Díaz, Jeyshka M. Reyes-González, Fatma Valiyeva, Pablo E. Vivas-Mejía. MicroRNA-18a targeting inhibits the tumor growth of cisplatin-resistant 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 1407.