bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1055: Evaluation of immune checkpoint inhibitor efficacy in EGFR mutant tumors
Authors: Tang Xuzhen , Yang Li , Qi Hui , Zhai Xianzhi , Wang Fuyang , Qiang Xiangnan , Xu Jie , Qin Xiaoran , Gu Qingyang , Yan Shaoyu , Ji Qunsheng 
Published: August 2019

Abstract
Tyrosine Kinase Inhibitor (TKI) of Epidermal Growth Factor Receptor (EGFR) is a first-line therapy for non-small cell carcinoma lung cancer patients with EGFR mutations, but patients often develop resistance to such a target therapy. Recently several PD-1 and PD-L1 inhibitors were approved for treating NSCLC, however, it remains unclear whether EGFR mutant NSCLC would benefit from PD-1/PD-L1 treatment. PD-1 response in cancer patients is closely associated with oncogenic mutation status, tumor microenvironment, PD-L1 expression and tumor mutation burden (TMB); however, the lack of pre-clinical models limited the investigation of the checkpoint inhibitors in EGFR mutant tumors. Here we use human PBMC reconstitution system for immune-humanization, and established a series of IO-Xenograft models (IO-CDX and IO-PDX) with cancer cell lines (IO-CDX) or patient-derived tissues (IO-PDX) that contain various EGFR mutations, including EGFR 19 del, L858R, T790M, and EGFR over-expression, amplification and fusion. We treated these models with either EGFR TKI (erlotinib, afatinib or osimertinib) or nivolumab, a PD-1 inhibitor. The predictive biomarkers including PD-L1 expression and TMB were analyzed by whole exom sequencing (WES) and FACS for tumor infiltrating lymphocytes (TILs), respectively. We found that 3 TKI-resistant PDX models bearing EGFR T790M mutation exhibited lower TILs than those bearing EGFR wild type or exon 19del mutation. Of the 8 IO-CDX or IO-PDX humanized models we have examined, those exhibiting higher TILs achieved better responses to nivolumab treatment. The 3 most sensitive models are EGFR amplification (wt), EGFR over-expression (wt) and EGFR exon 19del. In contrast, the EGFR T790M model from H1975 cell line was observed with hyper-progressive disease after nivolumab treatment. We will also discuss the contribution of PD-L1 expression and TMB to nivolumab in other models. In summary, these well-established IO-CDX and IO-PDX models can provide a human-resembling immune system for of immune therapeutics and combination with targeted therapies, and help to facilitate the understanding of relationship among tumor microenvironment, driver oncogenic mutations and drug response.
Citation Format: Xuzhen Tang, Li Yang, Hui Qi, Xianzhi Zhai, Fuyang Wang, Xiangnan Qiang, Jie Xu, Xiaoran Qin, Qingyang Gu, Shaoyu Yan, Qunsheng Ji. Evaluation of immune checkpoint inhibitor efficacy in EGFR mutant tumors [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 1055.
Abstract 1072: Development and characterization of patient derived xenograft (PDX) avatars of human cholangiocarcinoma
Authors: Rath Sanhita , Peng Sen , Hartman Lauren , Reid George , Dhruv Harshil , Glaser Shannon , Meng Fanyin , Alpini Gianfranco , Celinski Scott 
Published: August 2019

Abstract
Cholangiocarcinoma (CCA) is a fatal primary malignancy with limited treatment options and a dismal 5year survival rate of &lt;10%. Poor prognosis and early recurrence after surgical treatment warrants further molecular characterization of these tumors to evaluate therapeutic sensitivities and identification of biomarkers for CCA. Although several Next Generation Sequencing (NGS) studies have revealed some targetable genomic aberrations, the lack of preclinical and translational models has severely limited the identification of clinically relevant targeted therapies for CCA. So far, very few putative molecular targets/pathways have been identified using patient-derived xenograft (PDX) models, CCA cell derived xenograft models (CDX) and CCA cell lines, only 4 of which have progressed to preclinical testing for therapeutic value. In this study we describe development and comprehensive characterization of patient derived xenograft models of CCA from freshly resected patient tissue. Patient tumor cells from 8 patients were engrafted subcutaneously in highly immunocompromised NSG (NOD.Cg-PrkdcscidIl2rgtm1Wj) mice for PDX development. Two (CCA-1 and CCA-7) of 8 (25 %) engraftments yielded successful PDX model. The PDX avatar and matched patient tumor samples were genomically characterized at the whole exome and transcriptome level to check the fidelity of PDX models. Exome sequencing analysis of PDX tumors demonstrate higher genomic aberrations as compared to their patient counterparts. Preliminary analysis of transcriptomic profiles from CCA TCGA dataset, long term established intra- and extra-hepatic CCA cell lines (Mz-ChA-1, TFK-1, SG231, CCLP-1, HuCC-T1 and HuH-28), CCA CDX model from Mz-ChA-1 cells and CCA PDX models demonstrate that CCA PDX models more faithfully recapitulate patient tumors as compared to long term established cell lines. In summary, this proof of concept study demonstrates that PDX avatars of CCA could serve as a good model system for preclinical target discovery and validation for a deadly and neglected disease such as CCA.
Citation Format: Sanhita Rath, Sen Peng, Lauren Hartman, George Reid, Harshil Dhruv, Shannon Glaser, Fanyin Meng, Gianfranco Alpini, Scott Celinski. Development and characterization of patient derived xenograft (PDX) avatars of human cholangiocarcinoma [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 1072.
Abstract 1073: Role of CD44 in the transition of ductal carcinoma in situ to invasive breast carcinoma
Authors: Liu Fang , Zhou Jun , Kundu-Roy Tanima , Wahler Joseph , So Jae Young , Lin Yong , Lou You-Rong , Barnard Nicola J. , Matsuura Isao , Suh Nanjoo 
Published: August 2019

Abstract
Ductal carcinoma in situ (DCIS) transition to invasive tumor is an important issue for breast cancer. The human MCF10DCIS.com cell line (abbreviated as MCF10DCIS) is derived from the human MCF10A breast epithelial cell line. The MCF10DCIS xenografts are similar to human high grade comedo DCIS. In the xenograft assay, MCF10DCIS cells form DCIS-like lesion, remain as DCIS-like lesion in the first few weeks, and then progress into invasive carcinoma. Thus, it is an excellent model to study human breast cancer transition from DCIS to invasive carcinoma. To the best of our knowledge, it is also the only cell model for DCIS transition to invasive carcinoma. We investigated the role of CD44 in breast cancer transition from DCIS to invasive carcinoma by knockdown the expression of CD44 in the MCF10DCIS xenograft model. Our results show that knockdown of CD44 expression in the MCF10DCIS cells enhances DCIS transition to invasive carcinoma. Accordingly, a previous study has shown that CD44 expression is lower in invasive human breast tumors compared with DCIS, especially in luminal A subtype. We have also observed that CD44 expression is lower in the invasive carcinomas compared with DCIS. Furthermore, we provide evidence that CD44 plays a role in maintaining the integrity of the myoepithelial layer. Our study uncovered an unexpected role of CD44 in the prevention of DCIS transition to invasive carcinoma. Our findings have important implications for breast cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Fang Liu, Jun Zhou, Tanima Kundu-Roy, Joseph Wahler, Jae Young So, Yong Lin, You-Rong Lou, Nicola J. Barnard, Isao Matsuura, Nanjoo Suh. Role of CD44 in the transition of ductal carcinoma in situ to invasive breast carcinoma [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 1073.
Abstract 1089: Characterization of the immune response to lymph mode metastases
Authors: Jones Dennis , Padera Timothy 
Published: August 2019

Abstract
Metastasis remains the principal cause of cancer mortality. Lymph nodes are the most common site of solid tumor metastases and lymph node status is the most significant prognostic indicator for patient outcome in human solid cancer. Although antitumor T cells are generated in lymph nodes, metastatic cancer cells are able to grow in this seemingly hostile microenvironment. Further, we recently found that lymph nodes are a portal for metastatic progression to distant organs. The challenge is how to treat cancer cells that have spread to lymph nodes or distant organs in order to prevent their growth and ideally eradicate them from the body. Most cancer therapies are developed against the primary tumor growing in its native microenvironment. Our previous work has shown that classical sprouting angiogenesis (as observed in the primary tumor) does not occur in metastatic lymph nodes and is therefore not necessary for metastatic outgrowth. Here, our preliminary data show that cancer cells remodel the blood endothelium in metastatic lymph nodes. Although many blood vessels lack smooth muscle cell coverage, intravenous lectin perfusion reveals a functional blood vasculature within metastatic lymph nodes. However, we measured decreased expression of adhesion molecules on the vasculature in metastatic lymph nodes. Adoptive transfer of lymphocytes revealed impaired lymphocyte migration into mice harboring metastatic lymph nodes compared to naïve lymph nodes. Together, these findings suggest that decreased vascular adhesion molecule expression results in lymphocyte exclusion and impaired host immunosurveillance, leading to the progression of lymph node metastases. Our ongoing work seeks to inform therapeutic strategies that will enhance functional antitumor T cell infiltration into metastatic tumors and prevent their spread to distant organs.
Citation Format: Dennis Jones, Timothy Padera. Characterization of the immune response to lymph mode metastases [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 1089.
Abstract 1091: Comparison of TCR repertoires between cancer tissues and lymph nodes in colorectal cancer patients
Authors: Kiyotani Kazuma , Matsuda Tatsuo , Miyauchi Eisaku , Hsu Yu-Wen , Nagayama Satoshi , Zewde Makda , Park Jae-Hyun , Kato Taigo , Harada Makiko , Suzuki Nobuaki , Nagano Hiroaki , Hazama Shoichi , Nakamura Yusuke 
Published: August 2019

Abstract
Tumor draining lymph nodes (TDLNs) are located in the routes of lymphatic drainage from a primary tumor and have the highest metastasis in various types of solid tumors. TDLNs are considered as a tissue to activate the antitumor immunity, where antigen-specific effector T cells are generated and released to the blood stream. These effector T cells then infiltrate into the tumor site and attack cancer cells. However, T cell receptor (TCR) repertoire in TDLNs has not been well characterized. We performed TCR sequencing of cancer tissues, corresponding normal mucosa tissues and a total of 203 regional lymph nodes, including 67 metastasis-positive lymph nodes from 23 colorectal cancer patients with lymph node metastasis. Metastasis-positive lymph nodes showed a significantly lower TCR diversity and shared TCR clones more frequently with primary tumor tissues compared to metastasis-negative TDLNs. Hierarchical clustering and principal component analyses also supported that TCR repertoires in metastasis-positive TDLNs were more similar to primary tumor tissues than metastasis-negative TDLNs. These finding suggest that cancer-reactive T cell clones might expand in the metastasis-positive TDLNs, although we have not tested their reactivity against cancer cells. We are now examining whether the T cells in TDLNs can recognized autologous cancer cells.
Citation Format: Kazuma Kiyotani, Tatsuo Matsuda, Eisaku Miyauchi, Yu-Wen Hsu, Satoshi Nagayama, Makda Zewde, Jae-Hyun Park, Taigo Kato, Makiko Harada, Nobuaki Suzuki, Hiroaki Nagano, Shoichi Hazama, Yusuke Nakamura. Comparison of TCR repertoires between cancer tissues and lymph nodes in colorectal cancer patients [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 1091.
Abstract 1103: The effects of neo-adjuvant chemotherapy on myeloid cells in high-grade serous ovarian cancer metastases
Authors: Heath Owen M. , Maniati Eleni , Belato Chiara , Gopinathan Ganga , Lecker Laura , Lakhani Anissa , Pegrum Colin , McDermott Jacqueline , Lockley Michelle , Barton Desmond P. , Balkwill Frances 
Published: August 2019

Abstract
Many tumours have abundant macrophage populations. Tumour-associated macrophages (TAMs) frequently have tumour promoting roles and are associated with poor clinical outcome. We hypothesise that targeting TAMs in high-grade serous ovarian cancer (HGSOC) may improve response to chemotherapy.
We have assessed the effects of chemotherapy on TAM populations in human HGSOC obtained pre- and post-chemotherapy as well as in murine HGSOC models harbouring a relevant mutational profile. We find that chemotherapy treatment decreases TAM density within tumour areas. Furthermore, TAMs expressing markers known to associate with disease progression were decreased following chemotherapy. In vivo and in vitro we have demonstrated an up-regulation of inflammasome activation and TLR signalling in live myeloid cells following chemotherapy and have shown that macrophages are killed by chemotherapy at clinically relevant drug concentrations. These observations suggest a mechanism for TAM depletion and highlight chemotherapy induced activation of innate immunity in HGSOC.
The majority of HGSOC patients respond well to first line chemotherapy but will relapse and succumb to treatment resistant disease. We have developed a murine model of HGSOC relapse after first-line chemotherapy, which has the potential to extend translational studies into this clinically important area. We have found that TAMs are re-established in tumours at relapse, suggesting a clinically defined window of opportunity to target TAMs in HGSOC following first-line chemotherapy.
Overall, our results provide a rationale for targeted re-programming of TAMs in HGSOC after chemotherapy.
Citation Format: Owen M. Heath, Eleni Maniati, Chiara Belato, Ganga Gopinathan, Laura Lecker, Anissa Lakhani, Colin Pegrum, Jacqueline McDermott, Michelle Lockley, Desmond P. Barton, Frances Balkwill. The effects of neo-adjuvant chemotherapy on myeloid cells in high-grade serous ovarian cancer metastases [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 1103.
Abstract 1108: Intestine-specific homeobox recruits p300/CBP-associated factor and bromodomain-containing protein 4 to promote epithelial-mesenchymal transition
Authors: Wang Li-Ting , Chiou Shyh-Shin , Hsu Shih-Hsien 
Published: August 2019

Abstract
The epithelial-mesenchymal transition is an important process in the cancer progression, but its occurrence and the regulatory mechanism are not fully understood. Intestine specific homeobox acted both as a proto-oncogene and upstream regulator of EMT markers, by which modulates tumorigenic initiation and progression in lung cancer cells. ISX acetylated by PCAF recruits bromodomain-containing protein 4, to initiate chromatin remodeling, and up-regulated EMT downstream regulators in tumors cells. Ectopic expression of ISX was shown to enhance TWIST1, Snail1 expression by recruiting BRD4 to enhance Pol II dependent transcription, lead in to remodeling of the tumor microenvironment. In NSCLC carcinoma, increased ISX expression was noted correlating with distinct clinical metastatic features and poor prognosis. These results suggest that theISX-BRD4 axis mediates EMT signaling and exerts significant regulatory effects on tumor initiation and metastasis.
Citation Format: Li-Ting Wang, Shyh-Shin Chiou, Shih-Hsien Hsu. Intestine-specific homeobox recruits p300/CBP-associated factor and bromodomain-containing protein 4 to promote epithelial-mesenchymal transition [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 1108.
Abstract 1113: Targeting PRPK function blocks colon cancer metastasis
Authors: Zykova Tatyana , Yao Ke , Shin Seung Ho , Roh Eunmiri , Ma Weiya , Bode Ann M. , Dong Zigang 
Published: August 2019

Abstract
The biological functions of the p53-related protein kinase (PRPK) remain unclear. We have previously demonstrated that PRPK is phosphorylated by the T-LAK cell-originated protein kinase (TOPK) and that phosphorylated PRPK (p-PRPK) promotes colon cancer metastasis. Here, we analyzed colon adenocarcinomas from 87 patients and found that higher expression levels of p-PRPK were associated with later stages of metastatic dissemination (stage III and IV) as compared with earlier stages (stages I and II). Indeed, levels of p-PRPK were higher in metastatic versus malignant human colon adenocarcinomas. Knocking down PRPK expression attenuated colorectal liver and lung metastasis of colon cancer cells in vivo. An in vitro kinase assay indicated that active PRPK does not phosphorylate p53 directly. We found that PRPK phosphorylates survivin, a regulator of colon cancer metastasis. PRPK phosphorylates survivin at Thr34, which is important for survivin stability. Taken together, our data strongly suggest that the PRPK signaling pathway promotes colon cancer metastasis by modulating survivin stability, and that PRPK could be a new prognostic marker for the survival of colon cancer patients. In addition, we identified an FDA-approved bacteriostatic antibiotic, fusidic acid sodium salt (fusidic acid or FA) as an inhibitor of PRPK, and show that FA combined with 5-fluorouracil (5-FU) inhibited PRPK activity and colon cancer metastasis to the lung in mice. We contend that the combination of FA with 5-FU could be an alternative therapeutic strategy to traditional chemotherapy for colon cancer patients with poor prognosis.
Citation Format: Tatyana Zykova, Ke Yao, Seung Ho Shin, Eunmiri Roh, Weiya Ma, Ann M. Bode, Zigang Dong. Targeting PRPK function blocks colon cancer metastasis [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 1113.
Abstract 1114: Upregulation of ALCAM is a marker for non-small-cell lung cancer brain metastases
Authors: Loreth Desiree , Münsterberg Justine , Maire Cecile , Werner Stefan , Gandrass Monja , Bernreuther Christian , Kropidlowski Jolanthe , Westphal Manfred , Steurer Stefan , Lamszus Katrin , Glatzel Markus , Pantel Klaus , Wikman Harriet 
Published: August 2019

Abstract
Non-small-cell lung cancer (NSCLC) is the most common cause of cancer-related death with still a 5-year survival rate of &lt;10%. Every second patient with advanced NSCLC will develop brain metastases and in 50% of those the brain is the only site of tumor relapse (oligo-metastasis). Cancer cells need to have specific properties to access and colonize the brain microenvironment leading to the question which metastatic factors foster brain metastasis formation. Different cell adhesion molecules (CAMs) have been shown to be involved in the process of metastasis in different tumor entities. The activated leukocyte cell adhesion molecule (ALCAM) is a type I transmembrane protein of the immunoglobulin superfamily and involved in the maintenance of cell-cell contacts and has a possible role in the “homing” of metastatic cells in distant organs. ALCAM is also involved in the leukocyte transmigration across the blood-brain barrier. Here we therefore investigated the role of ALCAM in NSCLC brain metastases formation. Our studies on patient material revealed that the ALCAM protein expression in brain metastases (n=71) is significantly increased (50.7% positive, p=0.023) compared to the primary tumor (21.7% positive, n=47). Analysis of matched pairs of primary tumors and brain metastases confirmed this observation, as in 33% a de novo ALCAM expression in the matching brain metastases could be observed. Additionally, patients with a strong ALCAM expression in either their primary tumors or brain metastases showed a significantly shortened overall survival (p=0.017 and p=0.035 respectively). In vitro analysis of the effect of ALCAM knock out in the H460 lung cancer cell line showed no effect on proliferation, migration or colony-forming behavior. However, cell adhesion was severely hampered in the knock out cells. Currently in vivo mice experiments are running. Together these findings indicate an important role for ALCAM in brain metastasis formation.
Citation Format: Desiree Loreth, Justine Münsterberg, Cecile Maire, Stefan Werner, Monja Gandrass, Christian Bernreuther, Jolanthe Kropidlowski, Manfred Westphal, Stefan Steurer, Katrin Lamszus, Markus Glatzel, Klaus Pantel, Harriet Wikman. Upregulation of ALCAM is a marker for non-small-cell lung cancer brain metastases [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 1114.
Abstract 1115: NANOG-AKT signaling increases metastatic capacity via stabilizes HDAC1 protein through Chfr inactivation
Authors: Cho Eunho 
Published: August 2019

Abstract
Histone deacetylases (HDACs), in particular HDAC1, play an important role in tumor development and progression by modifying histone and non-histone proteins. Overexpression of HDAC1, as a cancer marker associated with poor prognosis. Nevertheless, the regulatory molecular mechanisms of HDAC1 expression remain largely unknown. Previously, we validated the correlation between the key pluripotency transcription factor NANOG and HDAC1 in immune-edited tumor cells by identifying that NANOG upregulates HDAC1 expression through its promotor occupancy. In this study, we further elucidated the mechanism that Nanog could regulate the Hdac1 protein level, as well as transcriptional level. Interestingly, we found that Nanog induces phosphorylation of an E3 ubiquitin ligase Chfr through Akt signaling, which results in the inactivation of Chfr. This decreases not only ubiquitinase activity but proteasomal degradation on Hdac1. Furthermore, accumulated Hdac1 on its own gives rise to metastatic capacity in cancer cells. Moreover, inhibition of Akt signaling is significantly effective at reversing HDAC1 mediated metastatic capacity in refractory cancer types. Taken together, we suggest a mechanistic rationale for the application of Akt inhibitors in HDAC1+ cancer treatment.
Citation Format: Eunho Cho. NANOG-AKT signaling increases metastatic capacity via stabilizes HDAC1 protein through Chfr inactivation [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 1115.