bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3113: Regulation of TOR complex 1 by the BRAFV600EMutant determines response and development of resistance to MEK inhibition by trametinib in glioma models
Authors: Li Fuyang 
Published: August 2019

Abstract
Pediatric Low-Grade glioma (PLGG) is the most common brain tumor in children. Current treatment protocols, particularly those involving high dose radiation therapy are associated with neurocognitive and neuroendocrine dysfunction. Genomic studies have revealed that PLGG are characterized by activation of the MAPK cascade. Recently, the value of selumetinib, an allosteric inhibitor of MEK1/2 has been demonstrated in PLGG. However, drug resistance will inevitably limit the efficacy. Trametinib is a more potent MEK1/2 inhibitor with better brain penetration than selumetinib. Here we have attempted to identify the mechanism/s of the resistance to trametinib that PLGG developes, and to explore combination treatments that may retard or prevent emergence of trametinib resistance in animal models.
In BT-40 (childhood anaplastic astrocytoma with BRAFV600E mutation) xenografts, trametinib caused complete tumor regressions, followed by tumor regrowth at the end of treatment. Trametinib treatment rapidly induced pSTAT3(Y705), that was blocked by the JAK1/2 inhibitor, ruxolitinib. Agaist BT-40 xenografts, ruxolitinib slightly enhanced the antitumor response to trametinib. The combination of trametinib with rapamycin was more active in each xenograft line than either single agent alone and in both subcutaneous and intracranial BT-40 models. In BT-40 xenografts, resistance to trametinib was consistently induced within 3 or 4 6-week cycles of treatment similar to that for the trametinib + ruxolitinib combination. In contrast, resistance to combined trametinib and rapamycin was not developed. Rapamycin prevented emergence of trametinib resistance, but did not reverse resistance to trametinib, once acquired. Inhibition of MAPK signaling by trametinib was similar in parental and trametinib-resistant BT-40 xenografts, however, trametinib reistant tumor cells failed to undergo apoptosis. Cells freshly isolated from trametinib resistant BT-40 xenografts had a higher apoptotic threshhold, whereas cells isolated from BT-40 xenografts after 3 cycles of trametinib + rapamycin, remained equally sensitive to parental BT-40 cells, as determined by BH3 profiling. This study reveals a potential new therapeutic use of rapamycin, preventing emergence of resistance to trametinib. Potentially, addition of rapamycin to MEK inhibitor therapy children with BRAF-driven low-grade glioma may be of value.
Citation Format: Fuyang Li. Regulation of TOR complex 1 by the BRAFV600EMutant determines response and development of resistance to MEK inhibition by trametinib in glioma models [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 3113.
Abstract 3120: The novel MEK inhibitor binimetinib decreases cell growth and induces apoptosis in AT/RT
Authors: Shahab Shubin , Rubens Jeffrey , Eberhart Charles , Raabe Eric 
Published: August 2019

Abstract
Atypical teratoid/rhabdoid tumors are a class of malignant CNS tumors disproportionately affecting children with limited therapeutic options. Our group has previously demonstrated that the MAP kinase pathway is altered in a large proportion of these tumors and the MEK inhibitor selumetinib decreases cell growth and promotes apoptosis of AT/RT cells. One of the major drawbacks of selumetinib is its poor blood-brain barrier penetration. Binimetinib is a novel MEK inhibitor currently in pediatric phase II clinical trials for low grade glioma that is thought to have improved brain penetration. Here we demonstrate nanomolar levels of binimetinib successfully decreases cell proliferation and induces apoptosis (2-3 fold induction of cleaved Parp) in AT/RT cell lines, suggesting binimetinib could offer a potential avenue for treating these deadly tumors.
Citation Format: Shubin Shahab, Jeffrey Rubens, Charles Eberhart, Eric Raabe. The novel MEK inhibitor binimetinib decreases cell growth and induces apoptosis in AT/RT [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 3120.
Abstract 3145: Detection of premature aging among adolescent and young adult osteosarcoma and Ewings sarcoma survivors
Authors: Baker Laurence H. , Reinke Denise , Boonstra Philip , Antalis Erin Peregrine 
Published: August 2019

Abstract
BACKGROUND Bone sarcoma survivors are at high risk for multiple chronic diseases at a young age, which can be characterized as premature aging. Bone sarcoma survivors have the highest cumulative incidence of multiple serious chronic conditions according to analysis of the Childhood Cancer Survivor Study 1. Cardiovascular biomarkers can be used to detect CAD, and enable early intervention in asymptomatic patients.
METHODS
Patients are seen annually at the Sarcoma Survivorship Clinic at the University of Michigan and includes high risk patients over the age of 18 who are at least two years free of disease after treatment completion. Clinical data includes: Blood Pressure, BMI, lipid profile, high sensitivity C-Reactive Protein, and imaging.
RESULTS
30% of patients aged 18-39 exhibit elevations in the cardiovascular biomarker hsCRP, in addition to the traditional biologic markers of elevated lipids, hypertension, and BMI at their most recent clinic visit (Table 1). A subset of patients independently evaluated by 2 nuclear cardiologists also show evidence of coronary artery calcifications (CAC), which is considered pathognomonic of CAD. 40% have been diagnosed with 2 or more of the following chronic diseases: dyslipidemia, obesity, renal insufficiency, anxiety and/or depression, pulmonary disease, cardiovascular disease, thyroid dysfunction, hypertension, liver disease, and anemia.
CONCLUSION
The overall cardiac risk profile among high risk bone sarcoma survivors is characteristic of premature aging. Examining the underlying mechanism of premature aging is essential in this population. Proposed investigation includes alteration of immune pathway as effected by diet, the microbiome, metabolomics, and cellular senescence.
REFERENCES:
1. Gibson TM et al: Temporal patterns in the risk of chronic health conditions in survivors of childhood cancer diagnosed 1970-99: a report from the Childhood Cancer Survivor Study cohort. The Lancet Oncology 2045:1-12, 2018
Characteristics of bone sarcoma survivors, aged 18-39 (n=20)Chronic Disease Diagnosis%1502253+15Cardiovascular biomarkershsCRP ≥ 2.030BMI ≥ 3015Cholesterol ≥ 200 mg/dL12Hypertension ≥130/8015Glucose ≥ 100 mg/dL20CAC&gt;015
Citation Format: Laurence H. Baker, Denise Reinke, Philip Boonstra, Erin Peregrine Antalis. Detection of premature aging among adolescent and young adult osteosarcoma and Ewings sarcoma survivors [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 3145.
Abstract 3146: MFG-E8: A novel prognostic marker for gastric cancer
Authors: Ge Sai , Gao Jing , Shen Lin 
Published: August 2019

Abstract
Gastric cancer is one of the leading causes of cancer-related death all over the world. Milk fat globule-epidermal growth factor (EGF)-factor VIII (MFG-E8) was found to be highly unregulated in a variety of cancers, could induce phagocytosis of apoptotic cells and a significant factor in immune systems. However, its prognostic potential has not been evaluated in gastric cancer (GC). In our former proteomic study, MFG-E8 was found significantly overexpressed in gastric cancer tissues comparing with paired non-cancerous gastric tissues. This study aimed to analyze the association between the expression of MFG-E8 in GC tissues and clinical outcomes in GC patients. In this study, 3 independent cohorts (GSE15460, n = 192; TCGA, n = 380 and ACRG, n = 300) were used to assess MFG-E8 as a biomarker, Kaplan-Meier survival analysis showed that its overexpression was associated with poor prognosis of GC with good discriminative ability in 3 independent cohorts (GSE15460, P &lt;0.001; TCGA, P &lt;0.001 and ACRG, P &lt;0.001). Multivariate analysis further confirmed its prognostic significance (GSE15460, P =0.028; TCGA, P &lt;0.001 and ACRG, P =0.012). These results suggest MFG-E8 may become a potential prognostic factor for GC.
Note: This abstract was not presented at the meeting.
Citation Format: Sai Ge, Jing Gao, Lin Shen. MFG-E8: A novel prognostic marker for gastric cancer [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 3146.
Abstract 3147: A novel next generation sequencing strategy for detecting microsatellite instability in colorectal and gastric cancer
Authors: Li Wenyun , Pi Fengmei , Liang Xiaoxia , Cao Taiyuan , Lin Yiheng , Zhai Xiaohui , Huang Mengli , Qin Hao , Gao Chan , Cai Shangli , Wu Xianrui , Xiao Jian , Lan Ping 
Published: August 2019

Abstract
Background: Microsatellite instability (MSI) has become a critical predictive and prognostic biomarker in multiple cancers. The mainstream MSI-detecting techniques, immunohistochemistry (IHC) and polymerase chain reaction (PCR), may have trouble profiling an expanded panel if tissue samples are not available in adequate quantity, depriving patients of treatment options, especially for those with advanced disease. Next generation sequencing, in contrast, allows for massively parallel examination of numerous targets in one single test. In this work, we developed a novel NGS-based assay to detect MSI in colorectal and gastric cancer (CRC/GC) and clinically validated its performance in comparison with IHC and PCR.
Methods: Surgical or biopsy specimens collected from 104 CRC and 15 GC patients were examined for MSI status using IHC, PCR and NGS employing a novel algorithm. The concordance rates between the three techniques were assessed using z-test.
Results: Of the 119 patients enrolled, 53.8% had metastases. IHC tests identified deficient MMR protein expression in 40 (33.6%) cases (dMMR), seven of which were microsatellite stable (MSS) using both PCR and NGS. A discrepancy was also observed for one MMR-proficient (pMMR) case where NGS and IHC consistently produced negative results (pMMR/MSS), while PCR reported a MSI-high (MSI-H) status. The NGS method demonstrated 97.1% (33/34) sensitivity and 100% (85/85) specificity compared to PCR,and 82.5% (33/40) sensitivity and 100% (79/79) specificity compared to IHC. The concordance rate was 99.1% between NGS and PCR, and 94.1% between NGS and IHC. Of the 33 dMMR/MSI-H patients, 30.3% harbored germline defects, suggestive of Lynch Syndrome. In addition, in line with previous reports, the dMMR/MSI-H subset showed a significantly higher median tumor mutational burden (TMB) than the pMMR/MSS patients (P=0.0039).
Conclusion: Our NGS-based approach is reliable and robust for MSI status determination in CRC/GC.
Citation Format: Wenyun Li, Fengmei Pi, Xiaoxia Liang, Taiyuan Cao, Yiheng Lin, Xiaohui Zhai, Mengli Huang, Hao Qin, Chan Gao, Shangli Cai, Xianrui Wu, Jian Xiao, Ping Lan. A novel next generation sequencing strategy for detecting microsatellite instability in colorectal and gastric cancer [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 3147.
Abstract 3149: Prognostic impact of PD-L1 expression in correlation with neutrophil-to-lymphocyte ratio in squamous cell carcinoma of the lung
Authors: Yoneda Kazue , Kuwata Taiji , Mori Masataka , Kanayama Masatoshi , Hirai Ayako , Tashima Yuko , Imanishi Naoko , Kuroda Koji , Ichiki Yoshinobu , Tanaka Fumihiro 
Published: August 2019

Abstract
Aim: To investigate the prognostic impact of programmed death-ligand 1 (PD-L1) expression on tumor cells in correlation with neutrophil-to-lymphocyte ratio (NLR) in early-stage squamous cell carcinoma of the lung, as PD-L1 is a potent regulator of cancer immunity and NLR is a potential surrogate of immune status.
Patients and methods: Eighty-three patients with completely resected pathologic stage I lung squamous cell carcinoma were retrospectively reviewed. Tumoral PD-L1 expression was evaluated with immunohistochemistry, and its prognostic impact was analyzed in correlation with NLR.
Results: Forty-three patients (51.8%) had tumor with positive PD-L1 expression (percentage of tumor cells expressing PD-L1, ≥1%). There was no significant correlation between PD-L1 expression and NLR. PD-L1-positivity failed to provide a significant prognostic impact (overall survival [OS] rate at 5 years, 70.1% in PD-L1-negative patients versus 53.0% in PD-L1-positive patients; P=0.117). Among NLR-low (&lt;2.2) patients, however, PD-L1-positivity was significantly correlated with a poor prognosis (OS rate at 5 years, 86.0% in PD-L1-negative patients versus 46.1% in PD-L1-positive patients; P=0.020). In contrast, among NLR-high (≥2.2) patients, PD-L1-positivity provided no prognostic impact (P=0.680). When NLR status and tumoral PD-L1 status were combined, “NLR-low and tumoral PD-L1-negative” was a significant and independent factor to predict a favorable recurrence-free survival (hazard ratio, 0.237 [95% confidence interval, 0.083 to 0.674]; P=0.007) and OS (hazard ratio, 0.260 [95% confidence interval, 0.091 to 0.745]; P=0.012).
Conclusions: The prognostic impact of PD-L1 expression on tumor cells was distinct according to NLR. “NLR-low and tumoral PD-L1-negative” patients showed a favorable prognosis.
Citation Format: Kazue Yoneda, Taiji Kuwata, Masataka Mori, Masatoshi Kanayama, Ayako Hirai, Yuko Tashima, Naoko Imanishi, Koji Kuroda, Yoshinobu Ichiki, Fumihiro Tanaka. Prognostic impact of PD-L1 expression in correlation with neutrophil-to-lymphocyte ratio in squamous cell carcinoma of the lung [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 3149.
Abstract 315: Identification of distinct and targetable mechanisms of acquired resistance to CDK4/6 inhibitors
Authors: Parsons Stephen 
Published: August 2019

Abstract
Recently, three CDK4/6 inhibitors were approved by FDA and became effective treatments for ER+ breast cancer patients. However, most if not all patients eventually progress on treatment . To identify mechanisms associated with acquired resistance to CDK4/6 inhibitors, we derived 15 CDK4/6i-resistant variants from human cancer cell lines highly sensitive to CDK4/6 inhibition with abemaciclib or palbociclib. Transcriptome and proteomic profiling of the derivatives revealed four general classes of alteration: decreased RB1, increased CCNE1 or CCNE2, increased ERK phosphorylation, and increased Aurora-A expression. A drug screen was employed to identify drugs or abemaciclib-drug combinations that could suppress growth of the resistant variants. Inhibitors of Aurora-A, Chk1 and the Ras-MAPK pathway were effective for the treatment of the respective classes of resistant derivative. Importantly, Rb loss, Aurora-A amplifications and Ras mutations were all observed as recurrent alterations in biopsies from ER+ breast cancer patients after progression on CDK4/6 inhibitors (1,2). Together these data demonstrate that cancer cells can escape from suppression by CDK4/6 drugs via multiple mechanisms and suggest clinically available therapeutic strategies to treat different classes of resistance.
1. S Wander et al, AACR, 2018
2. R Condorelli et al, Annals of Oncology, vol 29, issue 3, 640-645, 2017
Citation Format: Stephen Parsons. Identification of distinct and targetable mechanisms of acquired resistance to CDK4/6 inhibitors [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 315.
Abstract 3150: Impact of interleukin-1 alpha and EGFR expression on recurrence and survival outcomes in head and neck squamous cell carcinomas
Authors: Simons Andrean L. , Rajan Anand , Gibson-Corley Katherine , Ofori-Amanfo Georgina , Eyck Patrick Ten , Espinosa-Cotton Madelyn , Schmitz Sandra , Coppock Joseph , Sperry Steven 
Published: August 2019

Abstract
Interleukin-1 alpha (IL-1α) is a pleiotropic cytokine involved in inflammation and immune response and is upregulated in many solid tumors including head and neck squamous cell carcinomas (HNSCCs). Although IL-1α expression is generally associated with poor prognosis, the implications of the subcellular localization of IL-1α expression in patient outcomes are poorly understood. This study is aimed at investigating the clinical relevance of immunohistochemical IL-1α expression in HNSCCs. Tissue microarrays (TMAs) containing human papillomavirus (HPV)-positive and HPV-negative HNSCCs were analyzed for IL-1α and epidermal growth factor receptor (EGFR) expression by immunohistochemistry. Nuclear and cytoplasmic IL-1α and EGFR expression scores were correlated with clinicopathological parameters and patient outcomes. IL-1α expression was observed in the nuclear and/or cytoplasm compartments in 98% of evaluable tumors and 78% of tumors expressed IL-1α in both compartments. A higher percentage of tumors with combined high nuclear and moderate cytoplasmic IL-1α expression were observed in HPV-negative tumors compared to HPV-positive tumors. In HPV-negative tumors a combined EGFR-negative and high nuclear IL-1α expression profile was associated with a low risk of tumor recurrence and favorable overall survival compared to all other EGFR/IL-1α expression profiles. Lastly, a higher frequency of tumors with combined high nuclear and moderate cytoplasmic IL-1α expression was observed in cetuximab monotherapy responders compared to non-responders. Altogether, IL-1α in combination with EGFR expression may be a strong indicator of risk of recurrence in HPV-negative HNSCCs and warrants further study as a tissue biomarker for predicting HNSCC patient outcomes.
Citation Format: Andrean L. Simons, Anand Rajan, Katherine Gibson-Corley, Georgina Ofori-Amanfo, Patrick Ten Eyck, Madelyn Espinosa-Cotton, Sandra Schmitz, Joseph Coppock, Steven Sperry. Impact of interleukin-1 alpha and EGFR expression on recurrence and survival outcomes in head and neck squamous cell carcinomas [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 3150.
Abstract 3152: A tumor suppressor-regulated cell cycle derived gene signature is prognostic of recurrence risk in prostate cancer
Authors: Corbin Joshua M. , Georgescu Constantin , Thibivilliers Sandra , Webb Zachary , Zhao Yan , Koster Jan , Fung Kar-Ming , Asch Adam , Wren Jonathan , Ruiz-Echevarria Maria 
Published: August 2019

Abstract
Prostate cancer (PCa) is a complex heterogeneous disease, with the majority of cases remaining indolent and 10% of cases progressing to lethality. While some of this clinical heterogeneity can be explained by traditional clinicopathological factors, molecular profiling studies signal an extraordinary genomic variability, which may lead to diverse clinical outcomes. The identification of molecular subclasses of PCa has the potential to guide the prediction of clinical outcomes, the discovery and design of innovative prognostic biomarkers, and the development of novel therapeutics. To this end, we investigated genes associated with TMEFF2, an androgen-regulated tumor suppressor gene with exceptionally heterogeneous expression in PCa. Low levels of TMEFF2 mRNA significantly (p&lt;0.0001) correlate with reduced disease-free survival (DFS) in patients from the Memorial Sloan Kettering Cancer Center (MSKCC) dataset. Using RNA interference, we identified a panel of 11 TMEFF2 regulated cell cycle related genes (TMCC11), with strong prognostic value. TMCC11 expression stratified radical prostatectomy (RP) patients on the risk of recurrence, served as an independent indicator of poor prognosis, and improved the prognostic value of standard clinicopathological markers in four geographically different patient cohorts (n= 834 samples). The prognostic ability of TMCC11 panel exceeded previously published oncogenic gene signatures (p=0.00017). This study provides evidence that the TMCC11 gene signature is a robust prognostic marker for PCa, reveals the value of using highly heterogeneously expressed genes, like TMEFF2, as guides to discover prognostic indicators, and suggests the possibility that low TMEFF2 expression marks a distinct subclass of PCa.
Citation Format: Joshua M. Corbin, Constantin Georgescu, Sandra Thibivilliers, Zachary Webb, Yan Zhao, Jan Koster, Kar-Ming Fung, Adam Asch, Jonathan Wren, Maria Ruiz-Echevarria. A tumor suppressor-regulated cell cycle derived gene signature is prognostic of recurrence risk in prostate cancer [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 3152.