bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3773: Investigating the tumor-host evolutionary arms race as a possible strategy for cancer therapy
Authors: Hashim Arig A. Ibrahim , Abrahams Dominique , Luddy Kim , Gillies Robert , Richards Christina L. , Brown Joel , Gatenby Robert 
Published: August 2019

Abstract
As first proposed by Cairns and Nowell more than 60 years ago, cancer is a Darwinian process so that cancer progression and resistance to therapy are governed by natural selection and eco-evolutionary dynamics. This creates an “evolutionary arms race” between the cancer cells and the tumor suppressor mechanisms of the host. To mechanistically investigate these dynamics we have conducted an experiment in which we selected for resistance to growth of implanted Lewis lung (mouse) cancer tumor (LL/2-Luc-M38) cells in immuno-deficient (SCID) mice and immuno-competent (C57BL/6). At each round a fixed numbers of LL/2-Luc-M38 cells were implanted in 10 male SCID and 10 male C57BL/6 mice. Tumor growth was measured and the two animals that exhibited the slowest tumor growth were bred and their male progeny were used as host in the subsequent round. After 12 generations, the tumors grew at approximately 1/10th the rate compared their initial generation. We observed that the hosts evolved cancer suppression through two general strategies. The evolved SCID mice suppressed tumor growth via mechanical restriction with increased in collagen deposition in and around the tumor. In contrast BL/6 mice enhance their immunologic response. We investigated the molecular properties of tumor cells growing in the different cohorts suing microarray. We identified genes significantly different in their expression of cancer cells harvested at different days following injection in Wild Type and Evolved SCID and BL/6 mice using Principle component analysis (PCA) method. The genes were functionally classified based on Gene Ontology and the majority was found to be related to integrin binding, cell adhesion molecular binding, and extra cellular matrix (ECM) binding in SCID mice with collagen, type XII, alpha (Col12a1) being the significantly decreased (results validated with RT-PCR (**p=0.009)). However, in BL/6 mice Molecular studies, contrary to expectation, did not show significant changes in expression of immune-related genes. Rather we found a decrease in expression of genes associated with the angiogenesis and ATP production as well as increased expression of genes regulating EMT. Thus, our results highly suggest that the counter adaptive strategies deployed by the cancer cells in response to the host suppressive mechanisms is host dependent and can be a possible target for therapy.
Citation Format: Arig A. Ibrahim Hashim, Dominique Abrahams, Kim Luddy, Robert Gillies, Christina L. Richards, Joel Brown, Robert Gatenby. Investigating the tumor-host evolutionary arms race as a possible strategy for cancer therapy [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 3773.
Abstract 3779: Clonal tracing reveals different mechanisms of resistance to immune checkpoint blockade
Authors: Gu Shengqing , Hu Xihao , Wang Xiaoqing , Jiang Peng , Li Ziyi , Traugh Nicole , Bu Xia , Xing Xiaofang , Freeman Gordon J. , Brown Myles , Liu Xiaole S. 
Published: August 2019

Abstract
Immune checkpoint blockade (ICB) therapy has improved patient survival in a variety of cancers, but its resistance presents a major clinical challenge. It remains unclear whether therapeutic resistance is driven predominantly by refractory clones of cancer cells or by immunosuppressive microenvironment. To address this, we utilized syngeneic transplantation model and performed clonal tracing of cancer cells to monitor the response to ICB. Different cancer clones displayed variable sensitivity to ICB treatment, reflecting intratumoral heterogeneity in therapy response. Furthermore, different recipients manifested distinct resistance mechanisms. ICB-responders developed resistance through selection and expansion of pre-existing ICB-resistant cancer clones, whereas non-responders presented with irresponsive microenvironment rather than dominance of resistant cancer clones. Extrapolation of the tumor-infiltrating immune repertoire revealed that higher IgG and lower IgA strongly correlated with better ICB response. This biomarker was further validated in multiple clinical cohorts. Our approach discriminates different sources of resistance to ICB, and identifies humoral immunity as biomarker of ICB response.
Citation Format: Shengqing Gu, Xihao Hu, Xiaoqing Wang, Peng Jiang, Ziyi Li, Nicole Traugh, Xia Bu, Xiaofang Xing, Gordon J. Freeman, Myles Brown, Xiaole S. Liu. Clonal tracing reveals different mechanisms of resistance to immune checkpoint blockade [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 3779.
Abstract 378: HDAC inhibition enhances MEK antagonist therapy in uveal melanoma through combined blockade of YAP, AKT and RTK signaling
Authors: Faiao-Flores Fernanda , Emmons Michael , Durante Michael , Saha Biswarup , Fang Bin , Koomen John , Chellappan Srikumar , Maria-Engler Silvya , Licht Jonathan , Harbour William , Smalley Keiran 
Published: August 2019

Abstract
Around 85-90% of all uveal melanomas harbor driver mutations in GNAQ or GNA11 leading to constitutive activation of numerous signaling pathways, including the MAPK pathway. MEK inhibitors have been evaluated clinically for metastatic uveal melanoma, but the responses are short-lived and the mechanisms of adaptation are poorly understood. In the current study, we performed RNA-seq and activity-based protein profiling (ABPP) to define the adaptive response of uveal melanoma cells to MEK inhibition and to design more effective combination therapy strategies. These analyses showed that MEK inhibition caused cytoskeleton remodeling driven by cortactin/Rho-GTPases with an increase in YAP activity, which in turn allowed therapeutic escape. Cortactin knockdown decreased YAP activity in response to MEK inhibition, increased cell death in vitro and was associated with tumor shrinkage in vivo. The proteomic data showed that MEK inhibition increased HDAC activity and an increase in global protein deacetylation. Co-targeting of HDACs and MEK was associated with increased apoptosis, decreased survival in 2D and 3D cell culture assays and suppression of YAP signaling. As YAP was unlikely to be the only escape pathway, we performed kinome and RTK arrays and demonstrated MEK inhibition also increases ROR1/2 and IGF-1R phosphorylation, leading to downstream PI3K/AKT signaling. At a signal transduction level, the combination of a pan-HDAC inhibitor (panobinostat) with a MEK inhibitor (trametinib) blocked all of the adaptive signaling pathways we identified, including RTKs, AKT, YAP and cortactin. In vivo xenograft studies revealed the MEK/HDAC inhibitor combination to outperform either agent alone, leading to long-term decrease of tumor growth and the suppression of adaptive PI3K/AKT, cortactin and YAP signaling. These findings identify HDAC inhibitors as a promising combination partner for MEK inhibitors in advanced uveal melanoma that may lead to improved systemic responses.
Citation Format: Fernanda Faiao-Flores, Michael Emmons, Michael Durante, Biswarup Saha, Bin Fang, John Koomen, Srikumar Chellappan, Silvya Maria-Engler, Jonathan Licht, William Harbour, Keiran Smalley. HDAC inhibition enhances MEK antagonist therapy in uveal melanoma through combined blockade of YAP, AKT and RTK signaling [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 378.
Abstract 3788: Sensitive detection of oncoviruses integrated into a comprehensive tumor immuno-genomics platform
Authors: Bartha Gabor , Li Robin , Luo Shujun , West John , Chen Richard 
Published: August 2019

Abstract
Introduction
HPV, HBV, HCV and EBV viruses are causally linked to over 11% of cancers worldwide while KSHV, HTLV and MCV are linked to an additional 1%. As use of immunotherapy expands to a broader variety of cancers, it is important to understand how these oncoviruses may be impacting the overall immune response in patients as part of the tumor and tumor microenvironment. However, typical cancer diagnostic and genomic biomarker assays do not include oncovirus detection.
Methods
To enable detection of these oncoviruses, we have developed ImmunoID NeXT, a novel augmented exome and transcriptome based platform that comprehensively characterizes tumor and tumor microenvironment from a single sample. As part of the platform assay design we developed targeting for the following oncoviruses: HPV, HBV, HCV, EBV, KSHV and HTLV. Furthermore we developed analytics for detecting these viruses from both the DNA and RNA data. To test the ability of the platform to detect these oncoviruses, we identified a set of 11 EBV cell lines from Coriell in which EBV was used as a transformant. We obtained another 23 cell lines from ATCC containing HPV16, HPV18, HPV45, HPV68, HBV, EBV, KSHV, HTLV1 and HTLV2 in which the oncoviruses were known to be in the tumors from which the cell lines were created. We have also started running a series a FFPE tumor samples of unknown status. We extracted DNA and RNA from all these samples, made libraries and sequenced them on a NovaSeq to 30G. High quality read counts were computed for all targeted oncoviruses.
Results
We detected EBV in all the Coriell cell lines in both DNA and RNA indicating strong sensitivity of the platform. Wide dynamic range suggests quantification may be possible as well. In the DNA there was no signal from any other oncovirus indicating high specificity. In the ATCC samples we detected 23 out of 23 oncoviruses expected in both the DNA and RNA. We detected all the different types of oncoviruses that we targeted except for HCV because it wasn’t in any sample. In all but one case the signals were strong. False positive detections appear to be rare. Much less than 1% of the overall exome/transcriptome reads map to oncoviruses in all cases.
Conclusions
Oncovirus detection integrated into an augmented exome and transcriptome assay is sensitive and specific. Oncoviral characterization of the tumor as part of a comprehensive tumor immunogenomics platform can serve and an important additional biomarker for understanding immunotherapy response.
Citation Format: Gabor Bartha, Robin Li, Shujun Luo, John West, Richard Chen. Sensitive detection of oncoviruses integrated into a comprehensive tumor immuno-genomics platform [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 3788.
Abstract 3790: Molecular analysis of HPV genotype in head and neck cancers in a tertiary hospital in Ghana
Authors: Duduyemi Babatunde M. , Yeboah Francis A. , Aboagye Evans 
Published: August 2019

Abstract
Introduction: Human papillomavirus (HPV) has been implicated in head and neck cancers (HNC), and patients now present at a much younger age without a strong alcohol or tobacco history. This work aims to establish the prevalence of HPV in head and neck squamous cell carcinoma (HNSCC) in our center as very minimal work has been done in Ghana in this area.
Method: The study was to detect HPV DNA and genotypes from histologically confirmed HNSCC. Formalin-fixed paraffin embedded (FFPE) tissue blocks and slides of HNSCC cases were retrieved consecutively. Genomic DNA was then prepared from 10μm FFPE tissue section using the Quick-DNATM FFPE kit. A nested multiplex PCR assay that combines degenerate E6/E7 consensus primers and type-specific primer was utilized for the detection of HPV genotypes (16, 18, 31, 33, 35, 45, 51, 52, 56, 58, 59, 6/11, 42, 43 and 44) in three cocktails.
Results: A total of 301 HNSCC cases were extracted from the surgical day book, with male preponderance of 72.1% and a mean age of 54.97 years. The most common site of occurrence was the oral cavity (28.9%), followed by larynx (26.2%). Majority of the samples of patients aged &lt;30 years were poorly differentiated (65.7%). HPV E6/E7 oncogenic DNA was detected in 18% (n=100), with 17 being HPV-16 and 1 both HPV-16 and HPV-18. A higher prevalence of HPV-positive DNA was found in males (83.3%), and there was a trend towards patients older than 56 years likely to have HPV tumours (OR=1.378). Larynx was the commonest site for HPV-positive HNSCC (38.9%), followed by oropharyngeal site (33.3%).
Conclusion: The overall prevalence of HPV DNA (genotypes 16 and 18) in our study was 18%, more common in younger people and mainly male. This suggests that males should be considered in screening and vaccination against HPV to prevent HNSCC.
Citation Format: Babatunde M. Duduyemi, Francis A. Yeboah, Evans Aboagye. Molecular analysis of HPV genotype in head and neck cancers in a tertiary hospital in Ghana [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 3790.
Abstract 380: Tumor suppressor retinoblastoma status as a predictor of ATR inhibitor sensitivity
Authors: Mancusi Caterina , Hartley John , Mittnacht Sibylle 
Published: August 2019

Abstract
Inhibitors of the Ataxia Telangiectasia and Rad3 related protein kinase (ATR) are increasingly entering clinical trials as single agents or in combination with inhibitors of poly (ADP-ribose) polymerases (PARPs), DNA-damaging chemotherapy or radiotherapy. However, and despite promise of broad utility and cancer selectivity, compelling results have remained an exception, underscoring the need to identify responsive patient population and tumour types. Based on in vitro testing in an extended cancer cell line panel we found that deleterious mutation of RB1 is significantly associated with hypersensitivity to multiple clinically relevant ATR inhibitors. Cancer cell lines with deleterious RB1 mutation displayed significantly enhanced cell death following ATR inhibitor treatment compared to a histotype matched cancer cell line groups with RB1 normal status and depletion of RB1 gene in RB1 normal cancer cell lines using siRNA, increased sensitivity to ATR inhibition accompanied by increased cells death. Deletion or deleterious mutation of RB1 is frequent in small cell lung cancers, cancers of neuroendocrine origin, and a considerable portion of triple negative breast and urinary tract cancers, cancers of the nervous system, sarcoma and chronic lymphatic leukemia. The data obtained document a link between RB1 status and ATR inhibitor sensitivity and argue that focus on cancer types with RB1 mutation or 13q14 involvement, where RB1 is encoded, should be considered in the design and analysis of trials involving ATR inhibitors.
Citation Format: Caterina Mancusi, John Hartley, Sibylle Mittnacht. Tumor suppressor retinoblastoma status as a predictor of ATR inhibitor sensitivity [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 380.
Abstract 3802: Interleukin-4 receptor-targeted delivery of Bcl-xL siRNA sensitizes tumors to chemotherapy and inhibits tumor growth
Authors: Lee Soo-Woong , Yoon Jae-Won Yoon , Padmanaban Guruprasath , Park Rang- Woon , Baek Moon-Chang , Kim Dong-Kyu , Kim Won-Jong , Lee Byungheon 
Published: August 2019

Abstract
IL-4 receptor (IL-4R) is commonly up-regulated on tumor cells, and interactions between the receptor and Interleukin-4 (IL-4) can induce the expression of anti-apoptotic proteins, including Bcl-xL. This contributes to tumor cell survival and their resistance to chemotherapy. In this study, we exploited IL-4R-targeted delivery of Bcl-xL siRNA to IL-4R-expressing tumor cells in order to sensitize them to chemotherapy. To target IL-4R, an IL-4R-binding peptide, IL4RPep-1, was attached to branched polyethyleneimine-superparamagnetic iron oxide nanoparticles (BPEI-SPION). These nanoparticles were then complexed with Bcl-xL-targeting siRNA. IL-4R-targeted BPEI-SPION/Bcl-xL siRNA more efficiently reduced Bcl-xL gene expression and enhanced cytotoxicity of doxorubicin in MDA-MB231 breast tumor cells compared to untargeted BPEI-SPION/Bcl-xL siRNA. The siRNA was released from the complexes after 15 h of incubation at pH 5.5 and was stable in the complexes up to 72 h in the serum. The IL-4R-targeted BPEI-SPION/siRNA was internalized by cells through IL-4R, successfully escaped the endosomes, and was dispersed into the cytoplasm. Near-infrared fluorescence and magnetic resonance imaging demonstrated that in vivo tumor homing and accumulation of IL-4R-targeted BPEI-SPION/siRNA were both higher than untargeted BPEI-SPION/siRNA. The IL-4R-targeted BPEI-SPION/Bcl-xL siRNA, in combination with doxorubicin, significantly inhibited tumor growth in mice compared to untargeted BPEI-SPION/Bcl-xL siRNA. These results suggest that the IL-4R-targeted delivery of Bcl-xL siRNA to IL-4R-expressing tumors can sensitize tumors to chemotherapy and enhance the efficacy of anti-tumor therapeutics. Keywords: Bcl-xL, BPEI-SPION, chemotherapy, IL-4R, siRNA
Citation Format: Soo-Woong Lee, Jae-Won Yoon Yoon, Guruprasath Padmanaban, Rang- Woon Park, Moon-Chang Baek, Dong-Kyu Kim, Won-Jong Kim, Byungheon Lee. Interleukin-4 receptor-targeted delivery of Bcl-xL siRNA sensitizes tumors to chemotherapy and inhibits tumor growth [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 3802.
Abstract 3803: Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast cancer
Authors: Liu Yunhua , He Xiaoming , Lu Xiongbin , Zhang Xinna 
Published: August 2019

Abstract
Amplification of chromosome 17q23 is a frequent genomic event that occurs in ~ 11% of human breast cancers. The 17q23 amplification is enriched in HER2+ breast cancers, which is significantly correlated with poor clinical outcomes. Previous studies have identified the oncogenic phosphatase WIP1 gene in the amplicon, which functions as a master inhibitor in DNA damage response. While the possibility of any other protein-coding oncogenes in the WIP1-containing 17q23 amplicon was ruled out, our analysis of human breast cancer genomics uncovered an oncogenic microRNA gene, MIR21, in a majority of the WIP1-containing amplicons. Accordingly, the 17q23 amplification results in aberrant expression of WIP1 and miR-21, which not only promotes breast tumorigenesis, but also leads to resistance to anti-HER2 therapies. Inhibiting WIP1 and miR-21 using small molecular inhibitor against WIP1 (GSK2830371) and anti-miR-21 oligonucleotides selectively inhibits the proliferation, survival and tumorigenic potential of HER2+ breast cancer cells harboring 17q23 amplification. However, the in vivo bioavailability of the two agents in their free form is poor. To overcome the resistance of trastuzumab-based therapies in vivo, we developed pH-sensitive nanoparticles for specific co-delivery of the two agents into breast tumors. The nanoparticles can improve the encapsulation efficiency of anti-miR-21 oligonucleotides but also effectively capture carbon dioxide (CO2) into the nanoparticle to achieve the ‘nano-bomb’ effect for triggered drug release under the reduced pH in tumors. The two agents (inhibitors of miR-21 and WIP1)-laden nanoparticles can be used to efficiently kill trastuzumab-resistant HER2+ breast cancer cells, leading to a profound reduction of the tumor growth in vivo. These results demonstrate the great potential of the combined treatment of WIP1 and miR-21 inhibitors for the HER2+ breast cancers resistant to anti-HER2-based therapies.
Citation Format: Yunhua Liu, Xiaoming He, Xiongbin Lu, Xinna Zhang. Targeting 17q23 amplicon to overcome the resistance to anti-HER2 therapy in HER2+ breast 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 3803.
Abstract 3806: Overcoming drug-tolerant cancer cell subpopulations showing AXL activation and epithelial-mesenchymal transition is critical in conquering ALK-positive lung cancer
Authors: Nakamichi Shinji , Masahiro Seike , Miyanaga Akihiko , Takahashi Akiko , Noro Rintaro , Kubota Kaoru , Gemma Akihiko 
Published: August 2019

Abstract
Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) induce a dramatic response in non-small cell lung cancer (NSCLC) patients with the ALK fusion gene. However, acquired resistance to ALK-TKIs remains an inevitable problem. In this study, we aimed to discover novel therapeutic targets to conquer ALK-positive lung cancer. We established three types of ALK-TKI (crizotinib, alectinib and ceritinib) -resistant H2228 NSCLC cell lines by high exposure and stepwise methods. We found these cells showed a loss of ALK signaling, overexpressed AXL with epithelial-mesenchymal transition (EMT), and had cancer stem cell-like (CSC) properties, suggesting drug-tolerant cancer cell subpopulations. Similarly, we demonstrated that TGF-β1 treated H2228 cells also showed AXL overexpression with EMT features and ALK-TKI resistance. The AXL inhibitor, R428, or HSP90 inhibitor, ganetespib, were effective in reversing ALK-TKI resistance and EMT changes in both ALK-TKI-resistant and TGF-β1-exposed H2228 cells. Tumor volumes of xenograft mice implanted with established H2228-ceritinib-resistant (H2228-CER) cells were significantly reduced after treatment with ganetespib, or ganetespib in combination with ceritinib. Some ALK-positive NSCLC patients with AXL overexpression showed a poorer response to crizotinib therapy than patients with a low expression of AXL. ALK signaling-independent AXL overexpressed in drug-tolerant cancer cell subpopulations with EMT and CSC features may be commonly involved commonly involved in intrinsic and acquired resistance to ALK-TKIs. This suggests AXL and HSP90 inhibitors may be promising therapeutic drugs to overcome drug-tolerant cancer cell subpopulations in ALK-positive NSCLC patients for the reason that ALK-positive NSCLC cells do not live through ALK-TKI therapy.
Citation Format: Shinji Nakamichi, Seike Masahiro, Akihiko Miyanaga, Akiko Takahashi, Rintaro Noro, Kaoru Kubota, Akihiko Gemma. Overcoming drug-tolerant cancer cell subpopulations showing AXL activation and epithelial-mesenchymal transition is critical in conquering ALK-positive lung 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 3806.