bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1042: Preclinical pharmacokinetic and metabolic characterization of the next generation oral SERD AZD9833
Authors: Gangl Eric T. , Markandu Roshini , Sharma Pradeep , Sykes Andy , Pop-Damkov Petar , Gutierrez Pablo Morentin , Scott James S. , McGinnity Dermot F. , Fretland Adrian J. , Klinowska Teresa 
Published: September 2020

Abstract
AZD9833 is a potent, orally delivered, non-steroidal selective estrogen receptor degrader (SERD) that both antagonizes and degrades ERα. It is currently in clinical testing for the treatment of ER+ metastatic breast cancer (SERENA-1; NCT03616587). While ER is a clinically validated target, sustained inhibition of the target via oral delivery has proven an elusive goal. Despite intensive research, no oral SERD options are currently approved. Poor pharmacokinetic (PK) properties and/or short half-life (t ½) are often underlying features that limit oral SERD candidates from once or twice daily dose regimens. AZD9833 is a clinical stage next generation oral SERD that may overcome these challenges.
The pre-clinical PK properties of AZD9833 are consistent with once daily oral dosing in patients and are reported herein. AZD9833 is a low molecular weight (&lt;500 Da), low lipophilicity (logD &lt;3) base with good permeability characteristics. High volume of distribution (6-13 L/kg) and high bioavailability were observed in preclinical species. The in vitro hepatic metabolic clearance (CLint) for AZD9833 varied across species and were found to be nonlinear as a function of concentration. This nonlinear behaviour most strongly manifested in dog where in vivo bioavailability was &lt;2 or 95 %F depending on dose. To explain these observations, detailed in vitro mechanistic studies were conducted and physiologically based PK (PBPK) models were created. Cytochrome P450 phenotyping studies suggest dog clearance is mediated by CYP2D15 whereas CYP3A is the dominant P450 isoform responsible for clearance in human. In vitro CLint vs. concentration studies exhibited a low Km in dog (0.2 μM) relative to human (2 μM) and other species. To further our understanding, we constructed PBPK models which demonstrated that the dose dependent exposures in dog were predictable. The human model suggests that nonlinear behaviour will manifest well above predicted efficacious doses. Modeling also allowed us to assess the potential for drug-drug interactions with likely co-medications such as CDK 4/6 inhibitors. The PBPK predictions of good human exposure and long t ½ are being explored in the ongoing clinical trial.
Citation Format: Eric T. Gangl, Roshini Markandu, Pradeep Sharma, Andy Sykes, Petar Pop-Damkov, Pablo Morentin Gutierrez, James S. Scott, Dermot F. McGinnity, Adrian J. Fretland, Teresa Klinowska. Preclinical pharmacokinetic and metabolic characterization of the next generation oral SERD AZD9833 [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 1042.
Abstract 1049: Personalized neoantigen/cancer testis antigen nanovaccine (PVAC) in combination with PD-1 monoclonal antibody and/or antiangiogenic treatment in patients with metastatic solid tumors
Authors: Wei Jia , Liu Qin , Qian Hanqing , Shao Jie , Zhu Lijing , Wang Lifeng , Yu Lixia , Sha Huizi , Liu Baorui 
Published: September 2020

Abstract
Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated to drive anti-tumor responses. Nanotechnology has been reported to enhance immune responses of vaccines. Moreover, immunizing patients against such neoantigens, in combination with checkpoint inhibitor (CPI) and/or antiangiogenic drugs may elicit greater anti-tumor responses.
Methods: Patient-specific mutation-containing neoantigens were selected on the basis of tumour-specific mutations whole-exome sequencing (WES) and RNA sequencing. Cancer testis antigens were obtained according to immunohistochemical staining and HLA-binding affinity prediction. Personalized neoantigen/cancer testis antigen nanovaccine (PVAC) is an amphiphiles nanovaccine loaded with personalized vaccine encoding multiple neoantigens designed to induce neoantigen specific T cells responses. Patients will receive PVAC in combination with PD-1 monoclonal antibody and/or antiangiogenic drugs. Primary end points include safety and tolerability.
Results: 9 microsatellite stability (MSS) patients, which had relapsed from standard treatments, are enrolled in this study. 4 patients (1 gastric cancer, 1 liver cancer, 1 cervical carcinoma, 1 soft tissue sarcoma) received PVAC in combination with PD-1 mAb, and another 5 patients (2 gastric cancer, 1 colon cancer, 1 NSCLC, 1 renal carcinoma) received PVAC in combination with PD-1 mAb and antiangiogenic therapy. No DLTs were reported. Five patients developed grade 1 subcutaneous indurations in the injection sites,which collected with nanovaccine. One patient had grade 2 rash caused by antiangiogenic drug. No drug related SAEs have been observed. There are 1 CR, 4 PR, 3 SD and 1 PD. Neoantigen specific T cell responses have been detected by IFN-γ Elispot from PBMCs.
Conclusions: PVAC is safe and well tolerated. Clinical responses have been observed in combination with PD-1 mAb and antiangiogenic drugs and neoantigen-specific T cell response have been observed after vaccination. Clinical trial information: ChiCTR1900022986.
Citation Format: Jia Wei, Qin Liu, Hanqing Qian, Jie Shao, Lijing Zhu, Lifeng Wang, Lixia Yu, Huizi Sha, Baorui Liu. Personalized neoantigen/cancer testis antigen nanovaccine (PVAC) in combination with PD-1 monoclonal antibody and/or antiangiogenic treatment in patients with metastatic solid tumors [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 1049.
Abstract 118: FCHSD2 controls oncogenic ERK1/2 signaling by regulating endocytic trafficking in non-small-cell lung cancer
Authors: Xiao Guan-Yu , Schmid Sandra 
Published: September 2020

Abstract
Non-small-cell lung cancer (NSCLC) is the major cause of cancer deaths. The evolution of transformed NSCLC cells into metastatic tumors is, in part, driven by altered intracellular signaling downstream of receptor tyrosine kinases (RTKs). The surface levels and activity of RTKs are governed mainly through clathrin-mediated endocytosis (CME), endosomal recycling or degradation. We recently discovered that oncogenic signaling downstream of RTKs can reciprocally regulate CME and endocytic trafficking by creating feedback loops and that some of these mechanisms for crosstalk between signaling and endocytosis appear to be specific for, or co-opted by cancer cells to enhance tumor progression. We previously identified that FCHSD2 (FCH/F-BAR and double SH3 domain-containing protein) has a cancer-cell specific function in regulating CME downstream of ERK1/2 in NSCLC cells. It is now critical to further determine its role in RTK trafficking, signaling outcome and NSCLC progression. Here, we report that knockdown of FCHSD2 impacts recycling of the RTKs, EGFR and MET, and switches the RTK trafficking toward late endosome compartments and degradation. Notably, FCHSD2 loss results in active ERK1/2 signaling from late endosome and the nuclear translocation of ERK1/2 leading to upregulated EGFR and MET in NSCLC cells. We further identified the small GTPase, Rab7, as being essential for the FCHSD2 depletion-induced RTK upregulation. Loss of FCHSD2 activity in NSCLC cells leads to enhanced cell proliferation, survival and migration. Correspondingly, the expression level of FCHSD2 is negatively correlated with lung tumor grades and positively correlated with higher lung cancer patient survival rates, suggesting that FCHSD2 negatively affects cancer progression. Our study provides new insight into the molecular nexus for crosstalk between oncogenic signaling and RTK trafficking that can control cancer progression, opening the possibility of novel therapeutic strategies for lung cancer.
Citation Format: Guan-Yu Xiao, Sandra Schmid. FCHSD2 controls oncogenic ERK1/2 signaling by regulating endocytic trafficking in non-small-cell lung 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 118.
Abstract 176: The Evolution of NANOGP8 and its possible roles in tumorigenesis
Authors: Guo Yande 
Published: September 2020

Abstract
Human NANOG gene is located in Chromosome 12p13. It is a transcription factor in embryonic stem cells. There are 11 NANOG pseudogenes in human genome. NANOGP1 is an unprocessed pseudogene that arose through duplication of the chromosomal region containing NANOG before the human-chimpanzee (H/C) divergence and before insertion of the Alu element into the NANOG gene. NANOGP1 remained functional after duplication. NANOGP2 to NANOGP11 are ten processed pseudogenes in the human genome. NANOGP8 is theoretically unique since it has a complete open reading frame and an Alu element in the 3'-UTR which is homologous to that of Nanog. However, the human NANOGP8 is absent from the chimpanzee genome. Genome DNA sequence analysis revealed that NANOGP8 is the most recent of the NANOG pseudogenes and was inserted into chromosome 15 after the H/C divergence. Its transcription factor binding sites in SVA LTR may promote expression of NANOGP8 in cancer cells. This may be the partial reason of the higher genetic predisposition for cancer in humans compared with other primates.
Citation Format: Yande Guo. The Evolution of NANOGP8 and its possible roles in tumorigenesis [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 176.
Abstract 2100: Deep learning can predict microsatellite instability from histology in colorectal cancer across different ethnic groups
Authors: Pressman Isaiah S. , Xu Hongming , Kang Jeonghyun , Cha Yoon Jin , Lee Sung Hak , Hwang Tae Hyun 
Published: September 2020

Abstract
Microsatellite instability (MSI) is known to be an important genomic marker for prediction of a patient's response to immune checkpoint inhibitors across various types of cancer. Conventional methods to measure DNA mismatch repair (MMR) status are pCR-based panel sequencing or immunohistochemical staining based methods. Recently, deep learning has been proposed as an efficient diagnostic tool in this regard, as it can learn to predict MSI directly from H&E stained slides. However, it is thought that deep learning may not generalize effectively beyond the ethnicities present in the training dataset. Therefore, we investigated the impact of ethnic differences on deep learning performance at MSI classification across a range of model architectures and hyperparameters.
A total of 360 WSIs from a subset of the TCGA colorectal cancer (TCGA set) and another 170 WSIs from Gangnam Severance Hospital (Yonsei University College of Medicine, Seoul, Republic of Korea, Gangnam set) were included in this study. 360 H&E stained WSIs from TCGA set were divided into a set of square tiles of size 256x256um (0.5um/pixel) and then color normalized using Macenko normalization. Those tiles were divided into two classes - MSI-H and MSS (Microsatellite stable) based on the patient's MSI status. We trained various models on those tiles using a range of hyperparameters including model architecture, number of trainable layers, learning rate, and learning rate scheduling. The performance of this model was measured using the AUROC in the TCGA set (internal validation) and Gangnam set (external validation).
Our results for ResNet18 - a popular convolutional network architecture - on TCGA and Gangnam test datasets are around 0.79 and 0.76 respectively, with a standard deviation on Gangnam of 0.03. Given good hyperparameters and model architecture, the model's performance on the Gangnam test data was within one standard deviation of its performance on the TCGA test data, despite the fact that said model was trained using only the TCGA data containing few asian patients. The lack of a significant performance difference challenges the notion that there are morphological differences in colorectal cancers between patients of Caucasian and Asian ethnicities that would prevent a deep learning system from generalizing effectively.
Citation Format: Isaiah S. Pressman, Hongming Xu, Jeonghyun Kang, Yoon Jin Cha, Sung Hak Lee, Tae Hyun Hwang. Deep learning can predict microsatellite instability from histology in colorectal cancer across different ethnic groups [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 2100.
Abstract 2137: A high proportion of protein phosphorylation sites identified in CPTAC breast cancer and lung adenocarcinoma may result from direct phosphorylation by CDK1
Authors: Wang Dunrui , Qian Xiaolan , Eng Sarah , Jenkins Lisa , Durkin Marian , Lowy Douglas 
Published: September 2020

Abstract
Cyclin-dependent kinase 1 (CDK1) is a serine/threonine kinase that drives the G2/M phase of the cell cycle, and increased CDK1 kinase activity is a frequent feature of several tumor types. In the current study, we have used the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets to identify potential target phosphorylation sites associated with CDK1 activity in breast and lung adenocarcinoma and to experimentally study some of their biologic effects. Among the global protein phosphorylation sites detected in CPTAC, 80% and 81% of the identified phosphorylation sites in breast cancer and lung adenocarcinoma were found to correlate well with the level of an activating phosphorylation site in CDK1, t161. Positive correlations (r &gt; 0.6) were present in most paired samples of tumor tissue and normal tissue. In addition, 42% and 40% of all phosphorylation sites in both of these tumor types were found to contain the minimum CDK1 consensus motif Ser/Thr-Pro (S/T-P). This result suggests that many of the sites with this motif are directly phosphorylated by CDK1, while most of the sites that lack this sequence are likely to be phosphorylated by other kinases. In both tumor types, increased phosphorylation of proteins in several signaling pathways, including those for glycolysis and the cell cycle, were found to be associated with phosphorylation of CDK1 t161. To study a possible direct effect of CDK1-dependent phosphorylation on a protein involved in cell cycle progression, we selected Epithelial Cell Transforming 2 (ECT2), which is a Rho family-specific GEF (guanine nucleotide exchange factor) with a role in G2/M. In agreement with the proteomic data, mass spectrometry analysis showed elevated ECT2 phosphorylation on T359, S367, T373, S376 and S861 in the G2/M phase that was sensitive to treatment with a CDK1 inhibitor. Biological experiments confirmed that phosphorylation of these sites enhanced the pro-oncogenic and GEF activity of ECT2. Additional experimental mechanistic analysis is needed to demonstrate whether specific phosphorylations are attributable to direct or indirect effects of CDK1.
Citation Format: Dunrui Wang, Xiaolan Qian, Sarah Eng, Lisa Jenkins, Marian Durkin, Douglas Lowy. A high proportion of protein phosphorylation sites identified in CPTAC breast cancer and lung adenocarcinoma may result from direct phosphorylation by CDK1 [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 2137.
Abstract 2220: Non-clinical tumor models reveal broad combination potential of ICOS agonist antibodies
Authors: Waight Jeremy D. , Bi Meixia , Kilian David , Hopson Christopher , Zhang Shu-Yun , Brett Sara , Yadavilli Sapna , Zhang Tianqian , Shi Hong , Hance Kenneth W. , Ballas Marc , Hoos Axel 
Published: September 2020

Abstract
Unprecedented rates of durable clinical responses have been observed for antibody-based therapeutics targeting immune checkpoint proteins such as cytotoxic T lymphocyte antigen-4 (CTLA-4) or programmed death receptor-1 (PD-1). Nonetheless, a significant number of patients fail to respond, highlighting the need for alternative and complementary immunotherapeutic interventions for cancer. Inducible T-cell costimulator (ICOS/CD278) is a CD28 superfamily receptor that is predominantly expressed on effector and cytotoxic T cells shortly after T cell receptor (TCR) activation. In addition to promotion of T cell and B cell collaboration, ICOS signaling (via ICOS ligand [ICOSL] or antibody-based crosslinking) has been shown to improve T cell antitumor activity, survival, durable tumor rejection. To support the clinical development of GSK3359609 (a hIgG4 ICOS agonist antibody) several in vivo combination studies were conducted using a tool anti-mouse ICOS agonist antibody (clone 7E.17G9). Analogous with the Fc-based characteristics of a human IgG4 antibody, the anti-mouse ICOS tool antibody exhibited significant antitumor activity when grafted on a murine IgG1 (or Fc-reduced) backbone. Using an in vivo models of breast cancer (EMT6, BALB/c), the murinized ICOS tool antibody demonstrated potent antitumor activity alone (tumor growth inhibition [TGI] of 40-60%) in combination with immune checkpoint inhibitors (ICI) targeting PD-1 and CTLA-4 (TGI of 100% and 90%, respectively). Antitumor activity was associated with increased total T cell infiltration into the tumor, a higher tumor CD8/Treg cell ratio, and broad increases in T cell activation markers (e.g. CD25, CD69, Granzyme B, perforin, and PD-1). The cancer immunity cycle posits that multiple points of intervention exist for cancer immunotherapy, many of which should be considered in order to identify complementary therapeutic strategies. With this in mind, and consistent with ICI, antitumor activity was observed in combination with innate immune modulators (e.g. TLR4 agonist) and chemo/cytotoxic (e.g. carboplatin and paclitaxel) therapies in different syngeneic tumor models. Altogether these data underscore the broad utility of ICOS agonist antibodies as a reliable combination partner for cancer immunotherapy.
Citation Format: Jeremy D. Waight, Meixia Bi, David Kilian, Christopher Hopson, Shu-Yun Zhang, Sara Brett, Sapna Yadavilli, Tianqian Zhang, Hong Shi, Kenneth W. Hance, Marc Ballas, Axel Hoos. Non-clinical tumor models reveal broad combination potential of ICOS agonist antibodies [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 2220.
Abstract 2589: Dysregulation of RalGAPA2 in hepatocellular carcinoma
Authors: Tian Lu , Chan Lo Kong , HO Daniel Wai Hung , Zhao LuQing , NG Irene Oi Lin 
Published: September 2020

Abstract
RalGTPases are Ras-like G-proteins which cycle between the active GTP-bound and the inactive GDP-bound forms. Elevation of expression and activity of RalGTPase has been demonstrated to play an oncogenic role in human cancers. RalA activity could be positively regulated by RalGEF and negatively regulated by RalGAP. The functional RalGAP complex consists of either one of the catalytic subunits, RalGAPA1 or RalGAPA2, together with the regulatory subunit, RalGAPB. In this study, we aimed to investigate the potential role of RalGAPA2 dysregulation and its functional significance in hepatocellular carcinoma (HCC). By RNA-sequencing analysis in human HCC tissues and cell lines, we found that RalGAPA2 was the predominantly expressed RalGAP catalytic subunit in the liver. To examine the RalGAPA2 expression in HCC, we performed qPCR analysis in paired HCC tissues (n=90), and 37.8% of the HCC samples showed a 2-fold downregulation of RalGAPA2. Clinically, downregulation of RalGAPA2 was significantly correlated with a lower cellular differentiation (P=0.034) and a shorter overall survival rate (P=0.045). Interestingly, HCC tumors showing combined upregulation of RalA and downregulation of RalGAPA2 tended to be associated with more aggressive tumor behaviour, including higher occurrence of venous invasion (P=0.001) and more advanced TNM stage (P=0.007). On the other hand, by targeted-DNA sequencing, RalGAPA2 was identified to be recurrently mutated in 7.4% of the patients in a HBV-associated HCC cohort (n=95). Functionally, CRISPR/Cas9-mediated RalGAPA2 knockout HCC cells showed an enhanced migratory ability when compared to the control cells, underlying an upregulation of RalA activity. In HCC, expression of RalA isoform was found to be specifically upregulated and functionally supporting HCC metastasis. Also, inhibition of RalGAP has been demonstrated to promote RalA activity and enhance cell invasion in several cancer types, including oral squamous cell carcinoma, prostate and bladder cancer. Consistently, the inverse correlation between the RalA activity and RalGAPA2 expression was also observed in a panel of HCC cell lines. Furthermore, HCC cells possessing a higher RalA activity were demonstrated to be more prone to RBC8 treatment, a RalGTPase-specific inhibitor. Taken together, our results suggested that RalGAPA2 might play a potential tumor suppressive role in HCC by negatively regulating RalA activity.
Citation Format: Lu Tian, Lo Kong Chan, Daniel Wai Hung HO, LuQing Zhao, Irene Oi Lin NG. Dysregulation of RalGAPA2 in hepatocellular carcinoma [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 2589.