bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1903: PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Ká inhibitors in breast cancer
Authors: Costa Carlotta , Wang Ye , Ly Amy , Hosono Yasuyuki , Murchie Ellen , Walmsley Charlotte S. , Huynh Tiffany , Healy Christopher , Peterson Rachel , Yanase Shogo , Jakubik Charles T. , Henderson Laura E. , Damon Leah J. , Timonina Daria , Sanidas Ioannis , Pinto Christopher J. , Mino-Kenudson Mari , Stone James , Dyson Nicholas J. , Ellisen Leif W. , Bardia Aditya , Ebi Hiromichi , Benes Cyril H. , Engelman Jeffrey A. , Juric Dejan 
Published: September 2020

Abstract
The combination of CDK4/6 inhibitors with anti-estrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells ablation of PTEN, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Since PTEN loss also causes resistance to PI3Kα-inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment sequencing strategies.
Citation Format: Carlotta Costa, Ye Wang, Amy Ly, Yasuyuki Hosono, Ellen Murchie, Charlotte S. Walmsley, Tiffany Huynh, Christopher Healy, Rachel Peterson, Shogo Yanase, Charles T. Jakubik, Laura E. Henderson, Leah J. Damon, Daria Timonina, Ioannis Sanidas, Christopher J. Pinto, Mari Mino-Kenudson, James Stone, Nicholas J. Dyson, Leif W. Ellisen, Aditya Bardia, Hiromichi Ebi, Cyril H. Benes, Jeffrey A. Engelman, Dejan Juric. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Ká inhibitors in 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 1903.
Abstract 1924: Genetic analysis of responses to eribulin versus vinorelbine and paclitaxel in 100 cancer cell lines from the cancer cell line Encyclopedia (CCLE)
Authors: Sachdev Pallavi , Ronen Roy , Dutkowski Janusz , Littlefield Bruce A. 
Published: September 2020

Abstract
Background: Eribulin mesylate, a synthetic analog of the marine sponge natural product halichondrin B, is a microtubule dynamics inhibitor that acts via both cytotoxic antimitotic mechanisms as well as non-cytotoxic effects on tumor vasculature, tumor phenotype and the tumor microenvironment. Eribulin is approved in the US for treatment of certain patients with advanced breast cancer or liposarcoma. Here we examined in vitro antiproliferative responses to eribulin versus vinorelbine and paclitaxel in 100 human cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE), followed by analysis of CCLE baseline gene expression data with the goal of assessing overlapping and non-overlapping pathways and genes associated with drug response and resistance.
Methods: In vitro proliferation assays were conducted on 100 CCLE cell lines. Cancer types represented by ≥5 cell lines include breast, lung, blood, colorectum, ovary, pancreas, skin and kidney. Comparative systems-level analyses of genes, networks and pathways associated with drug response and/or resistance were performed to identify gene and pathway-level determinants of drug response that were either unique to eribulin or shared with vinorelbine and/or paclitaxel.
Results: We evaluated genes and molecular pathways driving sensitivity to eribulin versus vinorelbine and paclitaxel in a panel of 100 CCLE cell lines and identified key molecular determinants of response and resistance unique to eribulin. Pathway expression analysis revealed key pathways significantly associated with response to eribulin, including those associated with oxidative stress-induced senescence, histone deacetylation, DNA methylation and Notch signaling. The oxidative stress-induced senescence pathway was significantly enriched for genes whose pretreatment/basal mRNA expression levels were positively associated with response to eribulin but not vinorelbine or paclitaxel. Expression levels of various tubulin isoforms were also identified as positively correlated with eribulin response. Higher and lower pretreatment expression of E-cadherin and N-cadherin, respectively, were also found in cell lines sensitive to eribulin treatment.
Conclusion: Pretreatment gene expression analysis demonstrated key gene sets and molecular pathways that may drive response and resistance to eribulin and may differentiate this drug from vinorelbine and paclitaxel. Detailed analysis will be presented at the meeting.
Citation Format: Pallavi Sachdev, Roy Ronen, Janusz Dutkowski, Bruce A. Littlefield. Genetic analysis of responses to eribulin versus vinorelbine and paclitaxel in 100 cancer cell lines from the cancer cell line Encyclopedia (CCLE) [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 1924.
Abstract 1932: Effect of the C677T MTHFR polymorphism on toxicity in patients with colon adenocarcinoma treated with fluoropyrimidine based chemotherapy
Authors: Ramos-Esquivel Allan , Valle-Cano Marta 
Published: September 2020

Abstract
Background: Fluoropyrimidines (5FU and capecitabine) are the backbone of treatment for metastatic colorectal cancer. Their mechanism of action mainly consists on the inhibition of tymidylate synthase in a reaction where the 5,10-methylenetetrahydrofolate (MTHF) acts as a cofactor. This cofactor is highly regulated by the MTHF reductase (MTHFR) activity. It has been previously shown that C677T and A1298C polymorphisms of MTHFR are associated with a low activity of this enzyme, which can result in a higher therapeutical activity and toxicity from these compounds. The aim of this study was to assess the relationship between C677T and A1298 MTHFR polymorphisms and adverse events in first-line patients treated with fluoropyrimidine-based chemotherapy for stage IV colorectal adenocarcinoma. (NCT registration number: 03852290)
Methods: Patients with metastatic colorectal cancer were prospectively recruited in the San Juan de Dios Hospital (San José, Costa Rica). First line therapy consisted in any fluoropyrimidine used alone or in combination with oxaliplatin and/or irinotecan +/- bevacizumab, panitumumab or cetuximab. Germline DNA extraction was done from blood samples to determine the C677T (rs1801133) and A1298C (rs18011131) polymorphisms of MTHFR. Patients were followed by their treating physician every 12 weeks in order to assess the response and tolerability of their treatment. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 4.0.
Results: A total of fifty patients were enrolled. C677T MTHFR genotypic frequencies were distributed as follows: CC (30%), CT(50%), and TT (20%). The C allele frequency was 55%, following the Hardy-Weinberg equilibrium (HWE) (p=0.91). A1298C MTHFR genotypic frequencies were: AA (70%), AC (26%), and CC (4%). The A allele frequency was 80%, also following the HWE (p=0.58). MTHF 677 TT genotype was associated to high risk of grade III or IV anaemia (p=0.004), neutropenia (p&lt;0.001), thrombocytopenia (p=0.001), neuropathy (p=0.03), diarrhea (p=0.015), and hand-foot syndrome (p=0.045). There was no statistically significant association between the A1298 MTHFR polymorphism and side effects.
Conclusion: The MTHF 677 TT genotype can potentially predict toxicity in a subset of Hispanic patients treated with fluoropyrimidine-based therapy for metastatic colorectal cancer.
Citation Format: Allan Ramos-Esquivel, Marta Valle-Cano. Effect of the C677T MTHFR polymorphism on toxicity in patients with colon adenocarcinoma treated with fluoropyrimidine based chemotherapy [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 1932.
Abstract 206: The landscape of oncogenic gene fusions in Chinese colorectal cancer patients
Authors: Lu Zhenhai , Song Rongfeng , Li Kunsong , Cheng Ying , Wang Wenjing , Wang Weifeng 
Published: September 2020

Abstract
Background: Oncogenic gene fusions have been reported in patients with colorectal cancer (CRC) as promising actionable targets, but recognition of rare molecular subgroups is a challenge for precision oncology. We aimed to comprehensively characterize the clinical, pathological, and molecular landscape of Chinese CRC patients with oncogenic gene fusions.
Methods: A total of 1226 patients with CRC underwent genomic testing between Aug. 2017 and Sep. 2019 using a tissue-based next-generation sequencing (NGS) assay. All the coding exons of 450 cancer-related genes and selected introns were captured by the custom hybridization capture panel. Microsatellite instability (MSI) and tumor mutational burden (TMB) were assessed in all patients.
Results: Oncogenic gene fusions were found in 1.6% (20/1226) of Chinese CRC tumors, which was higher than that in the western population (0.68%, R. Madison, ESMO 2018 Congress). The most frequently detected fusions were NTRK1 (N = 5, 25%), BRAF (N = 5, 25%), ALK (N = 3, 15%), NTRK3 (N = 2, 10%), and RET (N = 2, 10%). FGFR1, ROS1, and EGFR fusions each occurred in one patient. Compared with patients without fusions, those with fusions were older (median age 69 vs 59 years, respectively, P=0.009), had right-sided CRC (75.0% vs 27.4%, respectively, P&lt;0.001), MSI-high (45.0% vs 8.7%, respectively, P&lt;0.001), and a higher TMB (median TMB of 9.8 vs 5.6 muts/mb, respectively). All MSI-high patients with fusions were TMB-high with a median value of 73.5 muts/Mb (range 51.8-180.3). The most frequently co-mutated genes in fusion cases were TP53 (70%), APC (60%), KMT2D (50%), ACVR2A (45%), RNF43 (45%), and TGFBR2 (40%). KRAS, NRAS, BRAF, POLE, and mismatch repair gene mutations were all mutually exclusive with oncogenic gene fusions. One patient harboring an EGFR-SEPT14 fusion, who had been heavily treated for right colon cancer metastasis, achieved a partial response to erlotinib.
Conclusions: This study revealed that oncogenic gene fusions were found in 1.6% of Chinese CRC patients by using a tissue-based NGS assay. As oncogenic gene fusions are mutually exclusive with common oncogenic mutations, using NGS to detect fusions as actionable targets or resistance mechanisms has notable implications for precision therapy.
Citation Format: Zhenhai Lu, Rongfeng Song, Kunsong Li, Ying Cheng, Wenjing Wang, Weifeng Wang. The landscape of oncogenic gene fusions in Chinese colorectal cancer 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 206.
Abstract 2081: Intestinal estrogen receptor beta suppresses colon inflammation and tumorigenesis in both sexes
Authors: Hases Linnea , Indukuri Rajitha , Birgersson Madeleine , Nguyen-Vu Trang , Lozano Rodrigo , Saxena Ashish , Hartman Johan , Frasor Jonna , Gustafsson Jan-Åke , Katajisto Pekka , Archer Amena , Williams Cecilia 
Published: September 2020

Abstract
Estrogen has been shown to protect women against colorectal cancer (CRC). In this study, using tissue-specific knockout mice, we characterize the role for intestinal estrogen receptor beta (ERβ) and, for the first time, demonstrate a direct preventive role against colitis-induced colon tumors in both sexes. By inducing colitis and CRC using azoxymethane and dextran sodium sulfate in intestine-specific ERβ knockout mice, we observe an increase in colon ulceration in addition to an enhanced development of neoplasms, with increased number of tumors in males and increased tumor size in females. We identify a local increase in TNFα expression and deregulation of NFκB targets. We note that males exhibit especially strong effects following intestinal ERβ knockout. The protection by intestinal ERβ against TNFα-induced damage is corroborated using ex vivo organoid culture, where we observe that activation of ERβ protects against TNFα-induced epithelial cell damage. Further, we characterize an underlying mechanism of action, using CRC cell lines with re-introduced ERβ, where ERβ binds to cis-regulatory chromatin areas of key NFκB regulators BCL3, BIRC3 and ATF3, and thereby modulates TNFα-induced signaling. With these results we define a clear role for intestinal ERβ and demonstrate an underlying mechanism, strongly supporting the notion that selective activation of intestinal ERβ has potential to prevent CRC in both sexes.
Citation Format: Linnea Hases, Rajitha Indukuri, Madeleine Birgersson, Trang Nguyen-Vu, Rodrigo Lozano, Ashish Saxena, Johan Hartman, Jonna Frasor, Jan-Åke Gustafsson, Pekka Katajisto, Amena Archer, Cecilia Williams. Intestinal estrogen receptor beta suppresses colon inflammation and tumorigenesis in both sexes [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 2081.
Abstract 2083: Alternative splicing regulation by the androgen receptor in prostate cancer cells
Authors: Germain Lucas , Lafront Camille , Beaudette Jolyane , Poluri Raghavendra Tejo Karthik , Weidmann Cindy , Audet-Walsh Etienne 
Published: September 2020

Abstract
The androgen receptor (AR) is a transcription factor that drives prostate cancer (PCa) by modulating the expression of thousands of genes to promote proliferation and survival and to reprogram metabolism. However, how AR activation affects alternative splicing is mostly unknown. Our objective was to define its role in the transcriptome-wide regulation of alternative splicing. Three human PCa models–LNCaP, LAPC4, and 22Rv1 cells–were treated with and without androgens, and RNA was purified for deep-sequencing analyses (RNA-seq). Several bio-informatic tools were then used to study alternative splicing. We demonstrate that in the absence of androgens, alternative splicing complexity is similar among AR-positive PCa cells, with 48% of all transcripts having various levels of alternative splicing. We also describe splicing differences among cell lines, such as specific splicing of AR, REST, TSC2, and CTBP1. Interestingly, AR activation changed the alternative splicing of thousands of transcripts in all the cell lines tested. Overlap between AR-sensitive alternative splicing events revealed that genes linked to PCa metabolism are major targets for this specific modulation. These genes encode metabolic enzymes such as the prostate-specific membrane antigen (FOLH1), malate dehydrogenase 1 (MDH1), and malic enzyme 2 (ME2). Enzymatic assays revealed that AR alters their activities without changing their total gene expression levels, demonstrating that AR-driven regulation of alternative splicing has a direct effect on cancer cell metabolism. Overall, our study presents a comprehensive analysis of PCa cell transcriptome and its modulation by AR, revealing cell metabolism as a key target for AR-dependent regulation of alternative splicing.
Citation Format: Lucas Germain, Camille Lafront, Jolyane Beaudette, Raghavendra Tejo Karthik Poluri, Cindy Weidmann, Etienne Audet-Walsh. Alternative splicing regulation by the androgen receptor in 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 2083.
Abstract 2097: AI powered platform to identify primary prostate cancer patients with high risk of recurrence
Authors: Huang Wei , Jain Parag , Randhawa Raman , Jaiswal Bijay , Hubbard Samuel , Basu Hirak , Roy Rajat 
Published: September 2020

Abstract
Background: To-date, there is no approved adjuvant therapy for primary prostate cancer (PCa). Long time of recurrence and a lack of a strong biomarker predicting recurrence after the first line of therapy is prohibitory to short clinical trials within a reasonable time. Artificial intelligence (AI) offers a unique opportunity for extracting critical morphological features from PCa tissues as prognostic marker that have evaded human eyes. We have built a AI-based platform to analyze H&E stained histological images of PCa. Our platform can accurately detect, grade and quantify PCa in patient tissue images. Here, we show how this platform can identify morphometric features that indicate biochemical recurrence within 3 years after radical prostatectomy (RP).
Methods: Our dataset comprised of a cohort of 169 PCa patients who underwent RP. Whole slide H&E images (WSI) of their tissue sections were scanned at 40x magnification. corresponding pathologic parameters such as Gleason grade, tumor volume, TNM staging, margin status and post-treatment follow-up data were also obtained. Among the 169 patients, 89 patients recurred within 3 years of RP.
Our platform technology involved two different deep CNN (Convolutional Neural Network) architectures. The platform first divided each WSI into multiple tiles. Each tile was analyzed using a CNN that graded the tile and generated a high dimensional vector to provide a mathematical equivalent of the morphology. The combination of high dimensional vectors across the WSI was then fed into a second CNN that generated a morphological score. The clinical parameters were combined with the morphologic score using a logistic classifier to predict outcome.
Results: Thus far, we have obtained 84% AUC (Area under the Curve) for the ROC (Receiver operating characteristics) curve, using 10-fold cross-validation. In contrast, the most predictive clinical covariate was the T stage with 71% AUC.
Conclusion: Our AI based platform can identify high risk PCa patients early for tumor progression post RP and may be selected for more cost effective and much shorter Clinical Trials necessary to develop adjuvant therapy.
Citation Format: Wei Huang, Parag Jain, Raman Randhawa, Bijay Jaiswal, Samuel Hubbard, Hirak Basu, Rajat Roy. AI powered platform to identify primary prostate cancer patients with high risk of recurrence [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 2097.
Abstract 2145: Ex vivo phenotyping and potency monitoring of CD19 CAR T cells with a combined flow cytometry and impedance-based real time cell analysis workflow
Authors: Zhao Li , Lei Ming , Ye Peifang , Lu Yan , Ji Xiaoping , Yan Yu , Jachimowicz Lauren , Guenther Garret , Li Nancy 
Published: September 2020

Abstract
Immunotherapy harnesses the immune system to attack cancer cells. While immunotherapy holds tremendous promise for cancer treatment, significant challenges remain in clinical translation. Further development is still required to expand treatment to more cancers and minimize adverse effects. T-cell differentiation and exhaustion influence the establishment and persistence of CAR-expressing T cells. Evaluation of the potency of CAR T cells is essential for effective immunotherapies. Here, we study the potency of CAR-T cells using a combined impendence-based Real-Time Cell Analysis (RTCA) and flow cytometry cell analysis workflow for ex vivo cytolytic potency monitoring of CD19 CAR T cells (CART19). CART19 cell killing of CD19 expressing HEK-293 cells with different E:T (Effector to Target) ratio was monitored by the xCELLigience RTCA system. Concurrently, T cell cytokine production was measured on the NovoCyte Quanteon. This workflow provides a thorough examination of CART cell function, RTCA data demonstrates that CART19 killing is highly potent as well as being antigen-specific and dose-dependent. In conjunction, more cytokine was produced with higher numbers of effector CART19 cells. It was also observed that CART19 cells express stem memory cell (TSCM) markers, expressing activation and exhaustion markers after expansion. Co-culture with HEK-293-CD19 also results in increased expression of CD25, decreased expression of CD127 and upregulation of exhaustion markers, PD-1, TIM-3, and LAG-3. In summary, this study demonstrates the combination of RTCA and flow cytometry cell analysis is a powerful workflow for immunotherapy research and can be employed for QC in CAR T cell manufacturing.
Citation Format: Li Zhao, Ming Lei, Peifang Ye, Yan Lu, Xiaoping Ji, Yu Yan, Lauren Jachimowicz, Garret Guenther, Nancy Li. Ex vivo phenotyping and potency monitoring of CD19 CAR T cells with a combined flow cytometry and impedance-based real time cell analysis workflow [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 2145.
Abstract 2159: IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signaling pathway in malignant melanoma
Authors: Yang Jilong 
Published: September 2020

Abstract
Immunotherapy targeting the PD-1/PD-L1 receptor in melanoma patients has achieved great success. Although many studies have addressed the underlying mechanisms involved in the blockade of PD-1/PD-L1 and the consequent modulation of the immune system, the mechanisms of PD-L1 upregulation and reliable biomarkers to predict the efficacy of anti-PD-1/PD-L1 therapy remain unknown. The present study demonstrates the correlation between IGFBP2 and PD-L1, reveals a novel immune-associated tumour function of IGFBP2 in facilitating nuclear accumulation of EGFR and activation of the EGFR/STAT3/PD-L1 signalling pathway in melanoma cells. Our results also suggest that combined IGFBP2 and PD-L1 expression have the potential to predict the efficacy of anti-PD-1 treatment for malignant melanoma; because the combination of high IGFBP2 and PD-L1 expression characterizes melanoma patients with worse overall survival and is associated with a better immune ecosystem. These characteristics have been confirmed by both in vitro and in vivo data. So, IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signalling pathway and its function as a PD-L1 regulator might suggest novel therapeutic approach for melanoma.
Citation Format: Jilong Yang. IGFBP2 regulates PD-L1 expression by activating the EGFR-STAT3 signaling pathway in malignant melanoma [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 2159.