bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3051: A potent pyrimidinone Axl inhibitor DW17401
Authors: Zhang Hefeng , Peng Xia , Ji Yinchun , Dai Yang , Shen Yanyan , Ai Jing , Duan Wenhu 
Published: September 2020

Abstract
Aberrant signaling of Axl frequently occurs in many cancer types. Axl activation has been identified as a key trigger in epithelial to mesenchymal transition (EMT), which accounts for acquired drug resistance to many tyrosine kinase inhibitor therapies. It also has been revealed that Axl signaling is associated with immunosuppression. Therefore, Axl inhibitors may present a promising strategy for cancer therapeutics. We have designed and synthesized a series of pyrimidinone Axl inhibitors, and DW17401 was identified as a highly potent, orally available inhibitor against Axl, with IC50 values of 0.9 nM. DW17401 exhibited significant inhibitory effect against Axl driven cell proliferation, with an IC50 value of less than 0.02 nM for BaF3/TEL-AXL cell line. Oral dosing of DW17401 25 mg/kg (QD) resulted in complete tumor regressions in subcutaneous transplanted model of BaF3/TEL-AXL in nude mice. In addition, DW17401 could also inhibited c-Met kinase and c-Met-mediated tumor cell proliferation and growth with high potency, indicated it therapeutic potential in MET aberrant cancer. Of note, DW17401 presented favorable pharmacokinetic parameters on SD rat with a half-life time of 13.8 h and a plasma exposure value of 32647 ng.h/mL (p.o. at 3 mg/kg). All these data indicated that DW17401 was an effective promising Axl inhibitor for cancer treatment.
Citation Format: Hefeng Zhang, Xia Peng, Yinchun Ji, Yang Dai, Yanyan Shen, Jing Ai, Wenhu Duan. A potent pyrimidinone Axl inhibitor DW17401 [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 3051.
Abstract 3071: VERU-111, a novel orally bioavailable tubulin inhibitor, overcomes taxane resistance in metastatic triple-negative breast cancer
Authors: Deng Shanshan , Krutilina Raisa I. , Parke Deanna N. , Chen Hao , Miller Duane D. , Seagroves Tiffany N. , Li Wei 
Published: September 2020

Abstract
Triple-negative breast cancer (TNBC) has aggressive clinical features strongly associated with poorer overall prognosis and higher mortality rates relative to other molecular subtypes. FDA-approved drugs, such as paclitaxel, are effective in treating TNBC. Yet, treatment failure is commonly observed due to the development of acquired chemoresistance, which remains a clinical challenge for TNBC therapy. We have shown that orally administered VERU-111 inhibits MDA-MB-231 xenograft growth with similar efficacy to paclitaxel, but without acute toxicity, and represses metastases originating from the mammary fat pad. To better understand the effect of VERU-111 on taxane-resistant TNBC, we generated a panel of paclitaxel-resistant TNBC sublines (MDA-MB-231/TxR, MDA-MB-468/TxR, SUM159/TxR and Hs578T/TxR) by gradually exposing paclitaxel to parental lines. MTS assays were used to confirm the chemoresistance of each subline to paclitaxel. VERU-111 maintained its potency against all four taxane-resistant sublines. We further investigated the underlying mechanisms of VERU-111 action and found that it inhibited taxane-resistant TNBC cell proliferation by inducing mitotic arrest and apoptosis via disruption of microtubule stability. In vivo, relative to paclitaxel, VERU-111 significantly inhibited tumor growth in an orthotopic MDA-MB-231/TxR model and reduced lung metastases originating from the mammary fat pad. VERU-111 induced tumor necrosis, anti-angiogenesis and apoptosis in both taxane-sensitive and taxane-resistant TNBC models in vivo. In addition to the MDA-MB-231/TxR model, we also tested the efficacy of VERU-111 in a multidrug-resistant PDX model, HCI-10. VERU-111 significantly inhibited HCI-10 primary tumor growth and suppressed the growth of lymph node metastases present prior to therapy and suppressed lung, liver and kidney metastases at the endpoint. In contrast, paclitaxel had no efficacy to repress tumor growth or metastasis in this model, and in fact, stimulated liver metastasis. Taken together, our data demonstrate that VERU-111 is a new generation of oral tubulin inhibitor that potently inhibits the growth of taxane-sensitive and taxane-resistant TNBC. Therefore, VERU-111 therapy is a promising strategy for the treatment of metastatic TNBC patients, including those patients who progress on taxanes.
Citation Format: Shanshan Deng, Raisa I. Krutilina, Deanna N. Parke, Hao Chen, Duane D. Miller, Tiffany N. Seagroves, Wei Li. VERU-111, a novel orally bioavailable tubulin inhibitor, overcomes taxane resistance in metastatic triple-negative 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 3071.
Abstract 3126: Serum miR-4687-3p as the diagnostic biomarker for NSCLC
Authors: Liu Man , Ouyang Jun , Si Qiufang , Wang Yulin , Yang Ting , Zhang Xue , Jiang Di , Zhang Jianying , Dai Liping 
Published: September 2020

Abstract
Objective: The lack of useful biomarker contributes to the increased morbidity and mortality of non-small cell lung cancer (NSCLC) partly. However, biomarkers in blood have become increasingly appreciated in diagnosis of NSCLC. This study, we aimed to identify serum miRNAs for diagnosing NSCLC.
Methods: Microarray were used to detect 2549 miRNAs in serum from NSCLC patients (n=10) and healthy individuals (n=10) and gain differentially expressed miRNAs. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assay were applied to validate the expression of selected miRNAs in validation set consisting of sera from 60 participants. Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy of the chosen miRNAs. Tissue expression of the selected miRNA was analyzed based on TCGA database. Subsequently, the target gene of the miRNAs were predicted by TargetScan and Gene ontology (GO) and KEGG pathway enrichment analysis tested by R (clusterProfiler package). The effect of miR-4687-3p on proliferation, invasion, and metastasis of lung cancer cells were investigated through CCK-8 and Transwell assay.
Results: We identified serum miR-4687-3p that provided a high diagnostic accuracy of NSCLC (AUC=0.69, 95%CI: 0.543-0.815) in validation data set. According to TCGA database, we also found that the tissue miR-4687-3p level were significantly higher in NSCLC tissues than normal tissues (p&lt;0.05). GO and KEGG pathway enrichment analysis showed that postsynaptic specialization and TGF-β signaling pathway were significantly enriched. Up-regulated miR-4687-3p by miR-4687-3p mimic could promote the proliferation, invasion, and metastasis of the NSCLC cells, compared with mimic negative control. Meanwhile, applying miR-4687-3p inhibitor could suppressed the proliferation, invasion, and metastasis of the NSCLC cells.
Conclusion: Our study on the first reported that serum miR-4687-3p levels may have clinical potentials as a novel non-invasive diagnostic biomarker for NSCLC patients.
Key words: NSCLC, miR-4687-3p, microarray, bioinformatics, biomarker
Citation Format: Man Liu, Jun Ouyang, Qiufang Si, Yulin Wang, Ting Yang, Xue Zhang, Di Jiang, Jianying Zhang, Liping Dai. Serum miR-4687-3p as the diagnostic biomarker for NSCLC [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 3126.
Abstract 3127: To investigate the role of BRAF V600E co-occurring mutations in Langerhans cell histiocytosis (LCH)
Authors: Karmakar Subhradip , Dhar R , Purkayastha K , Seth R , Karmakar S 
Published: September 2020

Abstract
a. Introduction :
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia caused by alterations of several genes in the MAPKinase pathway. The cell of origin is a white blood cell known as a dendritic cell priviously called as histiocyte characterized by a unique cytoplasmic organelle, the Birbeck granule, and the expression of CD1a and class II major histocompatibility complex molecules . The mutations cause these dendritic cells to attract other white blood cells and cause a “lesion” in any organ of the body. LCH has multi-orgnan involvement affecting skin bones, lymph nodes, brain etc. Systemic symptoms may include fever, bone pain, weight loss, jaundice, diabetes insipidus.
b. Description:
LCH is a rare sporadic, non-hereditary and non-malignant disease with unknown etiology characterized with a clonal proliferation of pathologic cells.Recent discovery of recurrent somatic mutations, BRAFV600E in MAPK pathway genes at critical stages of myeloid hematopoietic differentiation in LCH patients supports redefinition of the disease as a myeloproliferative disorder and provides opportunities to develop novel approaches to diagnosis and therapy. In the present proposal, we intend to analyze the BRAFV600E status along with other co-occurring mutations in a cohort of pediatric LCH patients by DNA sequencing in bone marrow samples or Peripheral Blood. Additionally we approach the above unanswered questions by applying an improved machine learning approach for classification and defining an algorithm for disease into different clusters for immediate clinical implication and to address its clinical heterogeneity.
c. Results :
We screened about 5 LCH patients and performed tageted exome seq to asertain the mutational profile of these patients. Sequencing detected BRAF V600E mutation in 3 of 5 samples for a mutation frequency of 60%. IHC based immunofloroscence shows that the intensity of phospho-MEK and phospho-ERK staining shows no significant alterations samples with mutation in BRAF. We are currently investigating mutations in other members of MAK pathways
d. Conclusion :
BRAF-V600E mutations were detected in few of our LCH patients. Neverless seeing the disease heterogeneity, we expect additionall mutations. More studies are needed to investigate mutations in the MAPK pathways that could efffect the course of disease management.We further plan to integrate the clinical and genomic findings to design a predictive model for the disease outcome.
Citation Format: Subhradip Karmakar, R Dhar, K Purkayastha, R Seth, S Karmakar. To investigate the role of BRAF V600E co-occurring mutations in Langerhans cell histiocytosis (LCH) [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 3127.
Abstract 315: Multifaceted functional assessment of checkpoint inhibitor efficacy using 3D tumor spheroids
Authors: Lassahn Katy A. , Appleton Kathryn M. , Elrod Ashley , Carlson Aaron L. , DesRochers Teresa M. 
Published: September 2020

Abstract
Three-dimensional (3D) culture of immortalized cell lines and patient-derived primary cells has been shown to be a more representative in vitro model of tumor biology compared to standard 2D techniques. For immune-oncology, animal models continue to lack the ability to fully recapitulate the human immune system. The use of 3D models to study immunotherapies provides the opportunity to mimic the complex interactions between immune cells and the tumor microenvironment in a fully human system. However, standard well-based assays that measure cell viability prevent the obtainment of useful knowledge on tumor-immune cell interactions and immunotherapy effect on immune cell numbers and viability. To address these limitations, we have developed an in vitro based assay for the visualization and quantitation of T-cell-mediated cell death using fluorescently labeled live tumor cells in a 3D spheroid platform. Enhanced T-cell mediated tumor cell killing using immune checkpoint inhibitors can be detected allowing for real-time evaluation of tumor-specific apoptosis in the presence of cytotoxic T-cells. Moreover, the cytotoxic effects can be inhibited by co-treatment with a blocking anti-CD8 antibody, demonstrating a specific requirement for CD8+ T-cells. In order to detect changes to tumor biology induced by T-cells as well as immune-oncology drug treatments, we monitored dynamic fluctuation of PD-L1 and MHC-I expression using immunofluorescence in the spheroids. Finally, we detected changes in T-cell populations, such as T-cell activation, and changes in CD8+:Treg ratios, induced by tumor spheroids with or without drug treatment using flow cytometry. In summary, we can observe T-cell mediated tumor cell killing and relate drug efficacy back to identified changes in tumor cell and T-cell phenotypes. This multifaceted approach is ideal for the functional evaluation of preclinical I/O agents and for identifying drug combinations as it represents a holistic perspective of drug response.
Citation Format: Katy A. Lassahn, Kathryn M. Appleton, Ashley Elrod, Aaron L. Carlson, Teresa M. DesRochers. Multifaceted functional assessment of checkpoint inhibitor efficacy using 3D tumor spheroids [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 315.
Abstract 3163: Cell-based reporter bioassays for development of Fc-functional and Fc-silent SIRPa/CD47 checkpoint inhibitors
Authors: Mitchell Jonathan , Grailer Jamison , Hartnett Jim , Fan Frank , Cong Mei , Cheng Zhijie Jey 
Published: September 2020

Abstract
CD47, a membrane glycoprotein commonly overexpressed in human cancers, interacts with its cognate receptor SIRPα on myeloid cells to deliver a “don't eat me” signal that inhibits phagocytosis. This SIRPα/CD47 interaction has emerged as a critical and potentially druggable immune checkpoint. Blockade of SIRPα/CD47 interaction promotes phagocytosis of tumor cells in vitro, and SIRPα/CD47 inhibitors exhibit anti-tumor activity, including synergistic activity with other tumor-targeted mAbs (e.g. rituximab), in vivo. These encouraging pre-clinical data have sparked widespread development of SIRPα/CD47 inhibitors and driven a need for robust functional assays to measure the activity of these drug candidates. Biological activity of SIRPα/CD47 inhibitors is typically assessed via in vitro phagocytosis assays based on imaging or flow cytometry. These assays often use primary monocyte-derived macrophages and are inherently prone to donor variability, are low-throughput, and difficult to implement in drug development settings. Additionally, many SIRPα/CD47 inhibitors under development are designed to minimize Fc function to enhance safety and are thus incapable of driving phagocytosis directly. To overcome these limitations, we have developed a pair of reporter-based bioassays for measuring the biological activity of Fc-functional and Fc-silent SIRPα/CD47 inhibitors. These bioassays utilize a SIRPα-positive monocyte effector cell-line that expresses multiple Fc gamma receptors (FcγRs) and an FcγR-responsive NanoLuc luciferase reporter that is inhibited by SIRPα/CD47 interaction upon co-culture of SIRPα effector cells with CD47-positive target cells. Addition of CD47 inhibitors with Fc functional activity simultaneously disrupts the SIRPα/CD47 interaction and engages FcγRs on the SIRPα effector cells, resulting in NanoLuc reporter activation. To enable testing of Fc-silent inhibitors, we have engineered a second CD47 target cell-line which provides a constitutive activating stimulus to SIRPα effector cells that is restricted by SIRPα/CD47 interaction. Addition of Fc-silent SIRPα/CD47 blockers releases inhibition by SIRPα/CD47, resulting in NanoLuc reporter activation. These newly developed reporter bioassays provide a robust, high-throughput platform to facilitate discovery and development of diverse SIRPα/CD47 checkpoint inhibitors.
Citation Format: Jonathan Mitchell, Jamison Grailer, Jim Hartnett, Frank Fan, Mei Cong, Zhijie Jey Cheng. Cell-based reporter bioassays for development of Fc-functional and Fc-silent SIRPa/CD47 checkpoint 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 3163.
Abstract 3173: Predictive biomarker evaluation for the anti-cancer imipridone ONC201
Authors: Morrow Sara , Prabhu Varun Vijay , Allen Joshua E. , Oster Wolfgang 
Published: September 2020

Abstract
Small molecule imipridone ONC201 is a selective, mixed competitive and non-competitive antagonist of dopamine receptor D2 (DRD2), a GPCR that is overexpressed in a broad range of malignancies (Madhukar et al, Nature Communications, 2019). ONC201 was recently found to also act as an allosteric agonist of the mitochondrial protease ClpP that degrades members of the electron transport chain and other mitochondrial substrates (Ishizawa et al, Cancer Cell 2019). ONC201 is currently being tested in several Phase II clinical trials with evidence of clinical activity in DRD2-dysregulated tumor types, including high-grade glioma, endometrial cancer, mantle cell lymphoma and adrenal tumors. Previously, we reported that DRD2 and DRD5 expression correlates with ONC201 efficacy in the NCI60 and GDSC panels (&gt;1000 cancer cell lines) (Prabhu et al, Clinical Cancer Research, 2019). In this study, we explored additional predictive biomarkers of response for ONC201, including ClpP and known downstream effects of ONC201 across the NCI60 and GDSC cancer cell line panels. Elevated ClpP expression emerged as a top predictive biomarker for ONC201 anti-cancer efficacy (low IC50) in the NCI60 and GDSC (p = 0.0066 and p = 0.00071, respectively) panels. Upregulation of HIF1 expression is known to drive cancer cells toward glycolysis; conversely, its loss shunts cellular energetics toward oxidative phosphorylation as the primary mechanism of ATP generation (Clark et al, Cell, 2019) that is inhibited by ONC201 via ClpP activation. Accordingly, decreased HIF1a expression correlated with increased anti-cancer efficacy in the NCI60 (p = 0.058) and GDSC (p = 0.0021) panels. ONC201 is known to cause downstream activation of the integrated stress response pathway, triggering induction of ATF4 (Ishizawa et al, Science signaling, 2016). High baseline ATF4 expression correlated with lower ONC201 IC50s in the GDSC panel (p = 0.027). Proteasomal degradation of c-myc by ONC201 has been reported in association with DRD2 antagonism and inhibition of oxidative phosphorylation in GBM (Ishida et al Clinical Cancer Research, 2018). High c-myc expression correlated with lower ONC201 IC50s in the GDSC panel (p = 2.5e-6). Ongoing studies are investigating biomarker combinations and identifying tumor types that are enriched for these predictive biomarkers. In conclusion, a series of target and downstream signaling biomarkers can be used to predict innate ONC201 tumor cell sensitivity that may provide guidance for patient and tumor type selection in future ONC201 clinical trials.
Citation Format: Sara Morrow, Varun Vijay Prabhu, Joshua E. Allen, Wolfgang Oster. Predictive biomarker evaluation for the anti-cancer imipridone ONC201 [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 3173.
Abstract 3177: Panel-derived tumor mutational burden (TMB) is associated with the response to the immune checkpoint inhibitors (ICIs) in urothelial cancers
Authors: Hsieh Yi-Lin , Yu Pei-Ning , Jan Yi-Hua , Lai Meng-Shao , Wang Woei-Fuh , Zhuo De-Wei , Chen Shu-Jen , Cheng Jen-Hao , Tan Kien Thiam , Su Yu-Li 
Published: September 2020

Abstract
Background: Tumor mutational burden (TMB) has been emerging as a relatively new biomarker that is independent of PDL1 for the prediction of response to the immune checkpoint inhibitor (ICI) treatment. A recent study has shown that whole exome sequencing (WES)-derived TMB correlates well with panel-derived TMB that is estimated using targeted sequencing. Here, we evaluate the correlation between panel-derived TMB with response to ICI treatment in urothelial cancers.
Methods: FFPE tumor tissues from 30 patients with urothelial cancers who had previously received ICI as monotherapies or combination with chemotherapies at Chang Gung Memorial Hospital were retrospectively underwent targeted next-generation sequencing (ACTOncoTM) for the identification of nonsynonymous variants across 440 cancer- associated genes. Tumor mutational burden (TMB) was calculated by using the sequenced regions of ACTOncoTM to estimate the number of somatic nonsynonymous mutations per megabase of all protein-coding genes. The TMB calculation predicted somatic variants and applied a machine learning model with a cancer hotspot correction. RECIST criteria were used to categorize tumor response to the treatment.
Results: Patients were defined as responders (CR/PR) and non-responders (SD/PD) according to the RECIST evaluation. In the cohort receiving ICI monotherapy, the responders (CR/PR, n=8) had significantly higher TMB than non-responders (SD/PD, n=15) (Median 16.2 muts/Mb vs. 6.5 muts/Mb, p=0.0035). One patient with moderate TMB (11.0 muts/Mb) who exhibited disease progression following ICI therapy harbored biallelic JAK2 inactivation. Three high-TMB tumors exhibited mutational signature of aristolochic acid exposure.
Conclusions: Although the cohort size is small, this study showed that panel-derived TMB can serve as an independent predictive biomarker to identify urothelial cancer patients for immune checkpoint inhibitor therapy.
Citation Format: Yi-Lin Hsieh, Pei-Ning Yu, Yi-Hua Jan, Meng-Shao Lai, Woei-Fuh Wang, De-Wei Zhuo, Shu-Jen Chen, Jen-Hao Cheng, Kien Thiam Tan, Yu-Li Su. Panel-derived tumor mutational burden (TMB) is associated with the response to the immune checkpoint inhibitors (ICIs) in urothelial cancers [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 3177.