bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 399: ctDNA a promising predictive marker for treatment with PD-1 inhibitors in KRAS mutated NSCLC after platinum based chemotherapy
Authors: Hiltermann T.Jeroen.N. , Hijmering-Kappelle Lucie B.M. , Azpurua Maria L. Aguirre , Wekken Anthonie.J. vd , Hiddinga Birgitta.I. , Timens Wim , Groen Harry.J.M. , Schuuring Ed 
Published: August 2019

Abstract
Introduction: Immunotherapy is a breakthrough in non-small cell lung cancer (NSCLC), showing long lasting responses in metastasized disease. However, only a limited number of patients responds to treatment. Selection of patients by known biomarkers (eg PD-L1, TMB) and combining PD-(L)1 inhibitors with other treatments (eg. chemotherapy or CTLA4 inhibitors) enriches the population for responders, however still around 60% do not respond with a durable response. We hypothesized that in KRAS mutant positive advanced NSCLC the detection of changes of ctDNA levels will be a relevant predictive marker in immunotherapy ( and stronger than eg PD-L1 expression in tumor tissue)..
Purpose: To test ctDNA as an early predictive marker for durable response in KRAS mutated lung cancer, in patients treated with PD-1 inhibitors after progression on platinum containing chemotherapy.
Methods: Patients with advanced NSCLC treated with nivolumab with a known KRAS or BRAF mutation from primary biopsy, with disease progression after platinum based chemotherapy are eligible. ctDNA obtained from EDTA plasma at baseline, 1, 2, 4, 6 weeks and thereafter every 12 weeks compared to durable response as primary outcome (ie. benefit from treatment&gt; 6month). Secondary outcomes were tumor response according to RECISTv1.1, progression-free and overall survival. ctDNA was determined and analyzed using a digital droplet PCR assay (Biorad) that was confirmed by a second technique (Idylla). ctDNA was categorized according to its response pattern in time: increasing, decreasing and undetectable KRAS mutant allele frequencies over time.
Results: In this ongoing study 31 patients with a known KRAS and 2 patients with a BRAF mutation participated. 24 (72%) had detectable levels of KRAS (n=22) or BRAF (n=2) in plasma. Concordance between Idylla and ddPCR was good and correlation was high (R2 =0,52). Of first 27 patients ctDNA increasing n=11, decreasing n=10, no change n=6. Data on all included patients will be presented.
Conclusion: Early detection of decreasing KRAS/BRAF mutant alleles in ctDNA predicted durable tumor responses, and increasing levels were associated with early disease progression.
Citation Format: T.Jeroen.N. Hiltermann, Lucie B.M. Hijmering-Kappelle, Maria L. Aguirre Azpurua, Anthonie.J. vd Wekken, Birgitta.I. Hiddinga, Wim Timens, Harry.J.M. Groen, Ed Schuuring. ctDNA a promising predictive marker for treatment with PD-1 inhibitors in KRAS mutated NSCLC after platinum based chemotherapy [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 399.
Abstract 4013: CoA Synthase (COASY): A novel predictive marker and functional protein that mediates radiation resistance via PI3K signaling in rectal cancer
Authors: Ferrandon Sylvain , DeVecchio Jennifer , Duares Leonardo , Chouhan Hanuman , Davenport Jacqueline , Karagkounis Georgios , Orloff Matthew , Liska David , Kalady Matthew F. 
Published: August 2019

Abstract
Purpose: Rectal cancer response to neoadjuvant chemoradiation is prognostic for disease-free and overall survival, with better responders enjoying better outcomes. Understanding the biology underlying better responses to therapy could lead to more personalized treatment approaches. The purpose of this study was to evaluate a newly identified biomarker and explore its mechanism of action.
Experimental Design: Pretreatment human rectal cancer samples underwent DNA microarray analysis and profiles were compared to post-chemoradiation histologic regression scores. A candidate gene, COASY (which encodes for Coenzyme A Synthase), was stably knocked down by shRNA in colorectal cell lines, and the effects on response to radiation were tested in a xenograft model. The biological function of COASY was first assessed by Gene Set Enrichment Assay (GSEA). Its effects on cell death, cell survival, and DNA repair capacity in colorectal cell lines was analyzed. Immunoprecipitation of COASY followed by LC-MS/MS analysis was done to identify COASY partners.
Results: COASY gene expression was overexpressed in rectal cancer compared to normal rectum and was significantly correlated to the tumor regression score. Tumors from cell lines knocked down for COASY had a strong delayed tumor growth, less proliferation, and more apoptosis after irradiation than the control cell line using in vivo xenograft models. In addition, a higher cell death rate after irradiation was observed in vitro in two colorectal cancer cell lines knocked
down for COASY. Mechanistically, a physical interaction between COASY and the PI3K regulatory subunit PI3K-P85α was identified; which led to a modulation of AKT and mTOR phosphorylation after irradiation. Furthermore, there were more residual double DNA strand breaks after irradiation in cell lines knocked down for COASY accompanied by a decrease in DNA-PK and MRE11 protein levels.
Conclusion: COASY serves as a predictive biomarker for rectal cancer response to neoadjuvant chemoradiation and its increased levels correlate with poor response. In addition to its role as a predictive biomarker, COASY has biological relevance leading to increased radiation resistance via the PI3K pathway-dependent increase in DNA repair capacity.
Citation Format: Sylvain Ferrandon, Jennifer DeVecchio, Leonardo Duares, Hanuman Chouhan, Jacqueline Davenport, Georgios Karagkounis, Matthew Orloff, David Liska, Matthew F. Kalady. CoA Synthase (COASY): A novel predictive marker and functional protein that mediates radiation resistance via PI3K signaling in rectal 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 4013.
Abstract 4016: PIK3IP1 regulates prostate cancer cell migration and proliferation and is a noninvasive biomarker of the disease
Authors: Jedinak Andrej , Kaplan Katherine , Loughlin Kevin , Moses Marsha 
Published: August 2019

Abstract
Prostate cancer (PCa) is the second most common epithelial cancer in men after lung cancer. PCa shares similar clinical symptoms with benign prostate hyperplasia (BPH) making it very challenging for physicians to make an accurate diagnosis. Prostate specific antigen (PSA) has been used for several decades to facilitate clinical decision making but unfortunately lacks sensitivity and specificity and cannot effectively distinguish between these two prostate diseases. Therefore, there is a need for new biomarkers that can discriminate between these two diseases with high accuracy. Using a global proteomics approach supported by extensive validation, we have found significantly (P&lt;0.002) elevated levels of Phosphoinositide-3-Kinase Interacting Protein1 (PIK3IP1) in the urine of PCa patients with early disease compared to patients with BPH. These data motivated us to examine the potential role of this protein in prostate cancer development and progression. We began by transiently transfecting multiple prostate cancer cell lines including DU145, PC-3 and LNCaP with a PIK3IP1 plasmid DNA and used these cells to conduct proliferation and migration studies in vitro. We found that there was a significant inhibition of PCa cell proliferation (P&lt;0.05) and migration (P&lt;0.007) in all cell lines tested. We validated these finding with DU145 stable clones established by lentiviral transduction with a PIK3IP1 vector. Stable clones overexpressing PIK3IP1 significantly suppressed proliferation and especially migration and invasion of DU145 cells. We next transiently transfected DU145, PC-3 and LNCaP cells with PIK3IP1 plasmid DNA and performed phospho-protein array experiments to identify signaling molecules that might be modulated by PIK3IP1 to mediate these activities. These data revealed altered levels of molecules involved in several pathways including MAPK. We are currently conducting further in vitro and in vivo studies to assess the potential effects of PIK3IP1 on the modulation of prostate cancer progression and metastasis. In summary, we have identified and validated the urinary detection of PIK3IP1 as a novel liquid biopsy biomarker for localized PCa and have demonstrated that it can modulate both the migration and proliferation of several PCa cells including DU145, PC-3 and LNCaP. (Supported by The Ellison Foundation and the Advanced Medical Research Foundation)
Note: This abstract was not presented at the meeting.
Citation Format: Andrej Jedinak, Katherine Kaplan, Kevin Loughlin, Marsha Moses. PIK3IP1 regulates prostate cancer cell migration and proliferation and is a noninvasive biomarker of the disease [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 4016.
Abstract 4017: Clinical-genomic models of node-positive breast cancer: training, testing, and validation
Authors: Huang Tzu-Ting , Lu Tzu-Pin , Lei Lei , Cheng Skye H. 
Published: August 2019

Abstract
Purpose: We developed and validated clinical-genomic models for stratifying node-positive breast cancer patients into low- and high-risk groups.
Experimental design: The four datasets were (1) training group (n = 112); (2) testing group (n = 46); (3) validation group (n = 388); and (4) external validation group (n = 655). Patients who had undergone mastectomy or breast-conserving surgery and mRNA microarray analysis of their primary tumor tissue with a pathological stage of N0-N2 were enrolled. The validation groups included node-positive patients. Using pre-set cutoffs obtained from the training group, the models were tested and validated in the three other independent groups.
Results: Two clinical-genomic models were developed to predict any recurrence (recurrence index [RI]-local recurrence [LR]) and distant recurrence (RI-DR). In the validation dataset, the RI-LR distinguished between low- and high-risk groups according to 10-year LR-free interval (LRFI; 100% vs. 93.3%, P = 0.014), relapse-free interval (RFI; 88.4% vs. 79.0%, P = 0.017), and relapse-free survival (RFS; 82.2% vs. 73.3%, P = 0.029). The RI-DR distinguished the low- from the high-risk group according to 10-year RFI (90.2% vs. 79.3%, P = 0.007) and RFS (81.0% vs. 74.2%, P = 0.031). RI-DR was associated with regional node irradiation in N1-N2 patients (hazard ratio: 3.7, 95% confidence interval 1.2-12.0) by multivariate analysis. The RI-DR- and RI-LR-gene panels performed similarly in the external validation dataset with hazard ratios of 1.27 (0.93-1.74, P= 0.127) and 1.54 (1.11-2.13, P= 0.0094), respectively, in high-risk patients.
Discussion: The RI-DR shows better performance in partitioning N1-N2 patients into low- and high-risk groups than the RI-LR for any recurrence, although the latter is superior for predicting LRR.
Citation Format: Tzu-Ting Huang, Tzu-Pin Lu, Lei Lei, Skye H. Cheng. Clinical-genomic models of node-positive breast cancer: training, testing, and validation [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 4017.
Abstract 4029: Analysis of DLL3 and ASCL1 in surgically resected small cell lung cancer (HOT1702)
Authors: Furuta Megumi , Sakakibara-Konishi Jun , Kikuchi Hajime , Yokouchi Hiroshi , Nishihara Hiroshi , Minemura Hiroyuki , Harada Masao , Yamazaki Shigeo , Akie Kenji , Fujita Yuka , Takamura Kei , Kojima Tetsuya , Harada Toshiyuki , Minami Yoshinori , Watanabe Naomi , Oizumi Satoshi , Suzuki Hiroyuki , Nishimura Masaharu , Dosaka-Akita Hirotoshi , Isobe Hiroshi 
Published: August 2019

Abstract
Background:Delta-like protein 3 (DLL3) is a Notch ligand that has an important role in the tumorigenesis of small cell lung cancer (SCLC). Recently, rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, has been developed for treating SCLC and has shown improved clinical response in patients with high DLL3 expression. DLL3 is a transcriptional target of the achaete-scute homolog-1(ASCL1) transcription factor, which is involved in pulmonary neuroendocrine cell development. However, the relationship between DLL3 and/or ASCL1 expression and the clinical features of SCLC remains unknown, especially for early-stage resected SCLC. This study aimed to investigate the expression of DLL3 and ASCL1 in resected SCLC samples using immunohistochemical analysis.
Materials and Methods:We collected 95 formalin-fixed and paraffin-embedded SCLC samples, which were surgically resected at 11 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Immunohistochemistrystaining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients.
Results:Seventy-seven (83%) of 93 immunohistochemically evaluable samples were positive for DLL3 (expression in ≥ 1% of tumor cells), and DLL3-high expression (≥ 75%) was observed in 44 samples (47%). Sixty-one (64%) of 95 samples were positive for ASCL1 (expression in ≥ 5% of tumor cells). A positive correlation was observed between DLL3 and ASCL1 expression. DLL3 and ASCL1 expression were not associated with survival in SCLC patients. DLL3 and ASCL1 were more prevalent in patients with advanced clinical disease and pure SCLC, respectively.
Conclusion:DLL3 and ASCL1 were highly expressed in surgically resected SCLC patients.
Citation Format: Megumi Furuta, Jun Sakakibara-Konishi, Hajime Kikuchi, Hiroshi Yokouchi, Hiroshi Nishihara, Hiroyuki Minemura, Masao Harada, Shigeo Yamazaki, Kenji Akie, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Toshiyuki Harada, Yoshinori Minami, Naomi Watanabe, Satoshi Oizumi, Hiroyuki Suzuki, Masaharu Nishimura, Hirotoshi Dosaka-Akita, Hiroshi Isobe. Analysis of DLL3 and ASCL1 in surgically resected small cell lung cancer (HOT1702) [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 4029.
Abstract 4039: Simultaneous quantification of activated immune cells and PD-L1 expressing circulating tumor cells (CTCs) in peripheral blood of cancer patients receiving checkpoint inhibitor therapy
Authors: Krupa Rachel , Richardson Robin , Ontiveros Priscilla , Schonhoft Joseph , Byun Jiyun , Lu David , Nisperos Sean , Wang Yipeng , Landers Mark , Dittamore Ryan 
Published: August 2019

Abstract
Purpose: Activated immune cell subpopulations and circulating tumor cells in patients receiving checkpoint inhibitor therapy were characterized with the aim of developing more sensitive diagnostic tools for prediction of immunotherapy response or resistance.
Methods: Blood samples from bladder, kidney, and prostate cancer patients undergoing checkpoint inhibitor therapy were collected at baseline and on-therapy at convenience and sent to Epic Sciences for processing. Red blood cells were lysed and nucleated cells were plated onto glass slides and stained with CTC (pan-CK, CD45, PD-L1 and DAPI) and immune panels (CD4, CD8, Ki-67, and DAPI). 2-3 million cells per patient were imaged using high throughput digital pathology pipelines and changes in immune cell sub-populations and changes in circulating tumor cell (CTC) burden with PD1/PD-L1 immunotherapy were assessed.
Results: A method to profile activated (CD8+Ki-67+ and CD4+Ki-67+) leukocyte subpopulations and PD-L1+ CTCs in a single blood sample was developed and feasibility was demonstrated in cell lines, healthy donor (HD), and patient blood. CTCs were detected in 73% (24/33) of patients tested. Of the 33 baseline samples tested, 12% (4/33) had PD-L1+ CTCs detected. No PD-L1+ CTCs were detected in on-therapy samples. Of 14 patients with matched samples, 57% (8/14) patients had an increase in activated CD4+ leukocytes and 36% (5/14) patients had an increase in activated CD8+ leukocytes in on-therapy samples compared to baseline. A decrease in activated CD4+ leukocytes was observed in 21% (3/14) patients and a decrease in activated CD8+ leukocytes was also observed in 7% (1/14) patients with therapy.
Conclusions: We developed a liquid biopsy-based platform that can simultaneously measure immune related biomarkers in CTCs and leukocytes at single cell resolution from ~1 mL of blood. The platform has extreme sensitivity over conventional methodologies and immune cell populations existing in less than 1% of the total are readily quantified. Efforts to identify morphological sub-populations within each canonical leukocyte category and comparison of leukocyte and CTC biomarker panels to patient outcomes are ongoing.
Citation Format: Rachel Krupa, Robin Richardson, Priscilla Ontiveros, Joseph Schonhoft, Jiyun Byun, David Lu, Sean Nisperos, Yipeng Wang, Mark Landers, Ryan Dittamore. Simultaneous quantification of activated immune cells and PD-L1 expressing circulating tumor cells (CTCs) in peripheral blood of cancer patients receiving checkpoint inhibitor 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 4039.
Abstract 4071: A novel combination therapy of high intensity focused ultrasound and PDL1 blockades against advanced breast cancer
Authors: Abe Shinya , Osada Takuya , Kaneko Kensuke , Zhong Pei , Lyerly Herbert K. 
Published: August 2019

Abstract
Background: Previous studies have reported that tumor debris and inflammation made by high-intensity focused ultrasound (HIFU) therapy induced the antitumor immune response, however, HIFU as a monotherapy is still not potent enough to eradicate tumors and treat distant metastasis. We have reported that mechanical HIFU (M-HIFU), that will mechanically destroy tumor cells/tissues through acoustic cavitation, induced stronger antitumor immune response compared to conventional thermal HIFU (T-HIFU) that will cause thermal ablation of tumors. In the present study, we established an immune based combination therapy of M-HIFU and immune checkpoint blockade to enhance systemic antitumor immune response and treated distant/metastatic tumors in murine breast cancer models.
Methods and Results: HER2 oncogene-dependent murine breast cancer cell line, MM3MG-HER2, was established in our lab. In mice with bilateral implantation of MM3MG-HER2 tumors, M-HIFU monotherapy induced stronger HER2-specific cellular response and inhibited the growth of HIFU-untreated distant tumors as well as HIFU treated-tumors, more potently than T-HIFU. Flow cytometry and immunohistochemical analysis of tumor microenvironment revealed significantly stronger accumulation of activated T cell and NK cells in M-HIFU-treated tumors. On the other hand, M-HIFU induced stronger expression of programmed death-ligand 1 (PD-L1) on various immune cells in both sides of tumors than T-HIFU therapy or no treatment control. Based on these findings, we investigated the combination therapy of M-HIFU and PD-1/PD-L1 axis blockades, and found significantly enhanced tumor-specific cellular immune response compared to each monotherapy, which resulted in improved therapeutic effect against distant tumors as well as HIFU treated-tumors. Furthermore, immune cell depletion studies demonstrated that both CD8+ T cells and NK cells played an essential role for the antitumor efficacy in this combinatory therapy against both HIFU-treated tumors and untreated distant tumors.
Conclusion: this study provides strong rational evidence that M-HIFU combined with PD-1/PD-L1 axis blockades could be a promising treatment strategy against advanced breast cancer with metastatic lesion.
Citation Format: Shinya Abe, Takuya Osada, Kensuke Kaneko, Pei Zhong, Herbert K. Lyerly. A novel combination therapy of high intensity focused ultrasound and PDL1 blockades against advanced 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 4071.
Abstract 4086: Preclinical evaluation of pharmacokinetics, pharmacodynamics and efficacy of the dual CD73-A2AR Inhibitors
Authors: Chikkanna Dinesh , Narayanan Kishore , Panigrahi Sunil , Priyadarshini Garima , Goyal Megha , Mani Jiju , Samiulla DS , dadhania Sagar , Aravind AB , Daginakatte Girish , Anthony Thomas , Nellore Kavitha , Samajdar Susanta , Ramachandra Murali 
Published: August 2019

Abstract
As a potent immunosuppressor adenosine is essential for maintaining tissue homeostasis and preventing an overzealous immune response during inflammation and infection. However, adenosine generated within the tumor microenvironment by the action of ecto-nucleotidases including CD73 hinders the immune reaction towards cancer cells by signaling through adenosine receptors such as high affinity A2AR expressed on immune cells. Inhibitions of either adenosine generation or signaling by inhibiting CD73 or A2AR have been shown to be effective therapeutic approaches. Interestingly, the co-blockade of CD73 and A2AR results in a more pronounced anti-tumor activity than blockade of either, likely due to increased CD73 expression upon A2AR inhibition and compensatory activity of other adenosine receptors such as A2BR. In view of this, we sought to discover and develop small molecule inhibitors that dually target CD73 and A2AR with oral bioavailability for ease of administration and use in combination with other anti-cancer therapies. Aurigene’s dual inhibitors exhibit potent inhibition of both A2AR and CD73 in respective biochemical and cellular assays. High potency translated into rescue of NECA or AMP induced repression of IFNΥ and IL2 in human PBMCs. Lead compounds exhibited desirable drug-like properties including solubility, permeability, lack of CYP inhibition, and pharmacokinetic exposure. In Syngeneic tumour model, treatment with lead compounds resulted in significant tumour growth inhibition while correlating well with tumour drug levels and modulation of pharmacodynamic markers. In summary, we have identified first-in-class dual inhibitors with good drug like properties, which showed significant antitumor efficacy. Evaluation of these lead compounds in additional tumour models and in vivo toxicity studies is currently under way.
Citation Format: Dinesh Chikkanna, Kishore Narayanan, Sunil Panigrahi, Garima Priyadarshini, Megha Goyal, Jiju Mani, DS Samiulla, Sagar dadhania, AB Aravind, Girish Daginakatte, Thomas Anthony, Kavitha Nellore, Susanta Samajdar, Murali Ramachandra. Preclinical evaluation of pharmacokinetics, pharmacodynamics and efficacy of the dual CD73-A2AR 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 4086.