bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2217: Serum metabolic profiling identified a distinct metabolic signature in bladder cancer smokers: A key metabolic enzymes associated with patient survival
Authors: Amara Chandra S. , Ambati Chandrashekar R. , Vantaku Venkatrao , Danthasinghe Piyarathna W b , Donepudi Sri Ramya , Ravi Shiva S. , Arnold James M. , Putluri Vasantha , Chatta Gurkamal , Guru Khurshid A. , Badr Hoda , Terris Martha K. , Bollag Roni , Sreekumar Arun , Apolo Andrea B. , Putluri Nagireddy 
Published: August 2019

Abstract
Urinary bladder cancer (BLCA) is the 9th most common malignant disease and the 13th most common cause of cancer death worldwide. Occupational exposure to carcinogens has been long associated with increased BLCA risk. Tobacco smoke contains more than 60 carcinogens causing at least 18 different types of cancer including BLCA. Reliable biomarkers for accurately predicting survival in Bladdder cancer (BLCA) smokers is lacking due to complex genomic and transcriptomic heterogeneities associated with the disease. We performed liquid chromatography-mass spectrometry (LC-MS) based targeted metabolomic analysis for &gt;300 metabolites in serum obtained from two independent cohorts of BLCA never smokers, smokers, healthy smokers, and healthy never smokers. 40 metabolites (FDR &lt;0.25) were identified to be differential between BLCA never smokers and smokers. Increased abundance of amino acids (tyrosine, phenylalanine, proline, serine, valine, isoleucine, glycine, asparagine) and taurine levels were observed in BLCA smokers. Integration of differential metabolomic gene signature and transcriptomics from TCGA cohort resulted in intersecting 17 gene signature that showed significant correlation with patient survival in BLCA smokers. Importantly Catechol-O-Methyltransferase (COMT), Iodotyrosine Deiodinase (IYD), and Tubulin Tyrosine Ligase (TTL) showed a significant association with patient survival in publicly available BLCA smokers datasets and did not have any clinical association in never smokers.
Note: This abstract was not presented at the meeting.
Citation Format: Chandra S. Amara, Chandrashekar R. Ambati, Venkatrao Vantaku, Piyarathna W b Danthasinghe, Sri Ramya Donepudi, Shiva S. Ravi, James M. Arnold, Vasantha Putluri, Gurkamal Chatta, Khurshid A. Guru, Hoda Badr, Martha K. Terris, Roni Bollag, Arun Sreekumar, Andrea B. Apolo, Nagireddy Putluri. Serum metabolic profiling identified a distinct metabolic signature in bladder cancer smokers: A key metabolic enzymes associated with patient survival [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 2217.
Abstract 2218: Exosomal PD-L1 and T lymphocyte status predict the effect of anti-PD-1 therapy
Authors: Qu Xiujuan , Zhang Chaoxu , Fan Yibo , Che Xiaofang , Liu Yunpeng 
Published: August 2019

Abstract
Background: Anti-PD-1 therapy is approved to be remarkable for cancer treatment. However, the response rate is dissatisfactory. PD-L1 expression in tumor tissue, which affected by chemotherapy, radiotherapy and activity of signal transduction pathways, is unreliable to predict treatment response. Recent studies suggest that exosomal PD-L1 not only exerts immunosuppressive effects besides tumors, but also plays a significant role in development of tumor microenvironment in the distance. A deeper research of exosomal PD-L1 assessment is needed to improve the predictive value and treatment efficacy.
Method: We enrolled 28 patients with advanced tumor, including 8 lung adenocarcinoma, 7 lung squamous carcinoma, 4 esophageal carcinoma, 2 colorectal carcinoma, 2 cholangiocarcinoma, 1 small cell lung cancer, 1 gastric carcinoma, 1 duodenal adenocarcinoma, 1 nasopharyngeal carcinoma and 1 tongue squamous cell carcinoma, who were treated by anti-PD-1 therapy followed the standard regimens. Exosomes were collected and purified from plasma with exosome isolation kit. Exsomal PD-L1 was detected by ELISA. Peripheral blood mononuclear cells (PBMCs) were isolated using Ficoll gradient. Exhausted T lymphocyte were stained for cytometry.
Result: Compared with responder, exosomal PD-L1 of non-responders is significantly higher than responder (P=0.036) before treatment. Moreover, the CD4+ and CD8+ T lymphocyte count is higher and the percentage of exhausted T lymphocyte rate is lower in responder than the non-responder cohort before treatment.
Although there is no statistical difference, the level of exosomal PD-L1 decreased in responder cohortat on 6 to 8 weeks after treatment, on the contrary, increased in non-responder cohort after anti-PD-1 therapy. Concurrently, exosomal PD-L1 and tumor burden were decreased when the therapy was effective.
Conclusion: Low levels of exosomal PD-L1 and exhausted T lymphocyte rate on baseline and decreasing expression of exosomal PD-L1 after treatment could screen out the potential benefit populations of anti-PD-1 therapy in a variety of solid tumors. These findings suggest that expression of exosomal PD-L1 and exhausted T lymphocyte cell rate could be attractive and predictive biomarkers for clinical responses to anti-PD-1 treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Xiujuan Qu, Chaoxu Zhang, Yibo Fan, Xiaofang Che, Yunpeng Liu. Exosomal PD-L1 and T lymphocyte status predict the effect of anti-PD-1 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 2218.
Abstract 2222: Progastrin a new biomarker for hepatocellular cancer patient follow-up
Authors: Prieur Alexandre , Dupuy Marie , Joubert Dominique , Assenat Eric 
Published: August 2019

Abstract
Background and aims: Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) patient follow-up, even though around 30% of HCC do not express AFP and its capacity to reliably monitor treatment efficacy is questioned. Interestingly, progastrin, a direct target of the oncogenic Wnt/beta-catenin pathway that is commonly activated in HCC, is secreted as such from tumor cells of various origin, from the very first steps of tumorigenesis. Here, we show the first study evaluating the potency of blood progastrin levels to monitor treatment efficacy and compared it with AFP.
Methods: Progastrin was quantified in the blood of 87 patients with HCC (focal (n=23), locally advanced (n=49) or metastatic (n=19). AFP was available in 79 patients. The cancerREAD technology (CE marked since 2017) specifically designed to detect progastrin with a high sensitivity and not any maturation products such as gastrin or gastrin glycine extended was used to assay progastrin in the blood. Patients received a systemic (nevaxar, tepotinib, regorafenib, nivolumab, anti FGR, or carbozantinib) and/or a local treatment. Variations in the levels of progastrin and AFP were analyzed in relationship with evolution of the disease: progression, decrease, stable, in remission, without taking into account the different treatment regimens.
Results: Progastrin was detected in 80% of the patients (cut-off value 1 pM, range 0 to 75.9 pM, mean value +/- SE 16.29 +/-1.97 pM). Patients in remission had a significantly lower blood progastrin compared to focal (p=0.019), locally advanced (p=0.0001) or metastatic HCC (p=0.015) (Focal 16.96 +/- 4.82 pM; locally advanced 18.57 +/- 2.75 pM; metastatic 17.81 +/- 4.9 pM; in remission 4.89 +/- 1.05 pM). AFP was above 10 ng/ml (a common threshold value) in 59.4% of the samples; levels of progastrin were not statistically correlated with those of AFP. Blood samples for follow-up of treatment were available for 48 patients. Compared to AFP, progastrin was a better biomarker of the evolution of the disease in 35.1% of the patients. Both biomarkers were equivalent in 32.4% and none were good in 10.8%. AFP was better than progastrin only in 21.6%.
Conclusion: Thus, and for the first time, we showed that not only progastrin is a better blood biomarker than AFP to detect HCC but also is better for the follow-up of HCC patients, whatever the treatment of the patient. This is the first study that shows the potential of progastrin (alone or in combination with AFP) as a tool for follow-up of cancer treatment efficacy.
Citation Format: Alexandre Prieur, Marie Dupuy, Dominique Joubert, Eric Assenat. Progastrin a new biomarker for hepatocellular cancer patient follow-up [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 2222.
Abstract 2225: Exosomes in plasma for protein based cancer biomarkers: A clinical research tool using UHPLC-MS
Authors: Sarracino David A. , Xie Xiaolei , Martel Courtney E. , Luan Shen , Rosenblatt Kevin 
Published: August 2019

Abstract
Introduction:
Exosomes have been used as a source of biomarkers in diagnostics for many diseases, including cancer, and are now being used as therapeutic delivery systems. To date, the most efficient method for isolating exosomes from serum or plasma samples has been to use a size exclusion, chromatography (SEC) based isolation. The conditions of the SEC separation can be modified to yield extracellular vesicles of different sizes and diagnostic value. Apoptotic bodies, 50-5000nm, microvesicles, 50-1000nm, and exosomes, 30-120nm, all have different diagnostic and targeted applications. Here, we show a routine and robust method for the isolation and monitoring of proteins in exosomes isolated from plasma samples. The methods and conditions used here are focused on rapidly providing a high yield of exosome vesicles in a monodisperse 40nm size range from a plasma sample.
Materials and methods:
K2EDTA plasma samples from donor disease and control groups were collected with IRB approval. All SEC columns and reagents for exosome isolation were obtained as a kit (NX Prenatal, Houston, TX). The 40nm exosome fraction from the column was lysed, the proteins reduced, alkylated and digested with trypsin; the subsequent peptides were analyzed by ultra-high performance liquid chromatography (Vanquish Horizon, ThermoFisher Scientific), tandem mass spectrometry (Q-Exactive, ThermoFisher Scientific), to quantify and identify greater than 500 proteins from exosomes, isolated from a single plasma sample, in a 1 hour method. Subsequent isolations of 40nm exosome fractions were labeled with a sulfo-NHS-biotin linker, followed by lysis and enrichment with streptavidin columns, and an identical LC-MS analysis to obtain quantitative analysis of the surface membrane protein contents on the exosomes.
Results:
Raw data was analyzed using the label-free quantitation module in Proteome Discoverer (Thermofisher Scientific). Peptide peak areas from three technical replicate runs were used to ascertain the reproducibility of the method across both normal and disease samples. Membrane protein extracts LC-MS data was further grouped by Protein Center (ThermoFisher Scientific) by cell type and tissue of origin.
Conclusions:
The methods shown here provide a robust and efficient platform for 40nm exosome isolation from human plasma samples, and quantitative analysis of the protein content thereof for the purposes of biomarker discovery, quantification and screening purposes.
Citation Format: David A. Sarracino, Xiaolei Xie, Courtney E. Martel, Shen Luan, Kevin Rosenblatt. Exosomes in plasma for protein based cancer biomarkers: A clinical research tool using UHPLC-MS [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 2225.
Abstract 223: Antibody intracellular activated drug conjugate (AiADC) as novel ADC technology
Authors: Suwa Atsushi , Komiya Kazuo , Kadotsuji Kenta , Ochiai Shoko , Takanashi Yosuke , Sugaru Eiji , Ban Hitoshi 
Published: August 2019

Abstract
Antibody drug conjugate (ADC) consisting of antibody and modifier (potent cytotoxic drug with chemical linker) is expected to selectively eliminate cancer cells expressing corresponding cell-surface antigen. More than 60 ADCs are in clinical trials and about 75 percent of its modifiers are based on three series (auristatin, maytansine, and pyrrolobenzodiazepine). Whereas some ADCs show promising clinical benefits, several ADCs may not have shown maximum value of ADC due to their narrow therapeutic windows. The function of modifiers impacts on total characteristics of ADC such as the efficacy, tolerability, and pharmacokinetics (PK). Therefore, further exploration of new types of modifier for ADC technology platform is needed. We designed hydrophilic modifiers which can be activated only inside of target cells. The ADC consisting of certain IgG1 monoclonal antibodies and this modifier (DSP-ADC) showed selective and potent cytotoxicity to target cells with IC50s at picomolar range. The DSP-ADC with the average drug-to-antibody ratio (DAR) of 7-8 was stable in blood circulation and showed favorable PK profiles in mice. Additionally, administration of the DSP-ADC led to dose-dependent suppression of cancer cell proliferation in mice xenograft models and achieved complete remissions at 3 mg/kg without body weight reduction. The toxicity studies of DSP-ADC in rats showed no effect on hematologic parameters up to 100 mg/kg. These modifiers are applicable to various monoclonal antibodies. Taken together, our modifiers can be fundamental component for ADC technology. We present here the novel ADC technology named as antibody intracellular activated drug conjugate (AiADC).
Citation Format: Atsushi Suwa, Kazuo Komiya, Kenta Kadotsuji, Shoko Ochiai, Yosuke Takanashi, Eiji Sugaru, Hitoshi Ban. Antibody intracellular activated drug conjugate (AiADC) as novel ADC technology [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 223.
Abstract 224: Antibody-drug conjugates (ADCs) of a new class of N-10 amino linked DNA alkylating indolino-benzodiazepines (IGNs)
Authors: Miller Michael L. , Reid Emily E. , Archer Katie E. , Harris Luke , Maloney Erin K. , Bartle Laura M. , Ab Olga , Wilhelm Alan J. , Ponte Jose F. , Singh Rajeeva , Keating Thomas A. , Chari Ravi V. 
Published: August 2019

Abstract
We have previously reported on our antibody-drug conjugates (ADCs) that incorporate a highly potent novel DNA alkylating indolino-benzodiazepine (termed IGN) dimer. ADCs of these DNA alkylating IGNs were found preclinically to demonstrate better tolerability and an improved overall therapeutic index (TI) compared with those of the corresponding DNA crosslinking IGNs (Miller, et al., Mol. Cancer Ther. 2016, 2018). IGN-containing ADCs that have reached the clinical stage bear DNA alkylating IGN compounds linked to the antibody via a cleavable linker, incorporated at the amino group of a centrally located anilino spacer moiety. In our ongoing effort to further explore the structure-activity relationship (SAR) of DNA alkylating effector molecules for ADCs, we disclose here a new class of IGNs possessing a self-immolative peptide linker attached at the N-10 amine of the imine-reduced IGN monomer subunit. We explored the impact of modifying the central spacer group connecting the IGN monomers, and site of linkage on in vitro potency and the interaction with DNA. A set of IGN molecules that met our potency criteria were identified and linkable forms of these compounds were prepared and conjugated to a folate receptor-α (FRα)-binding antibody. These ADCs displayed potent, antigen-specific in vitro activity across a panel of FRα-expressing cell lines. A lead ADC selected for in vivo studies demonstrated high stability in plasma and potent efficacy in various xenograft models, at doses well below the maximum tolerated dose. Thus, IGNs modified with an N-10 self-immolative peptide linker are promising DNA alkylating effector molecules for use in ADCs.
Citation Format: Michael L. Miller, Emily E. Reid, Katie E. Archer, Luke Harris, Erin K. Maloney, Laura M. Bartle, Olga Ab, Alan J. Wilhelm, Jose F. Ponte, Rajeeva Singh, Thomas A. Keating, Ravi V. Chari. Antibody-drug conjugates (ADCs) of a new class of N-10 amino linked DNA alkylating indolino-benzodiazepines (IGNs) [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 224.
Abstract 2249: Checkpoint inhibitor therapy after dendritic cell vaccination elicits tumor response in mesothelioma patients
Authors: Cornelissen Robin , Belderbos Robert , Aerts Joachim 
Published: August 2019

Abstract
In mesothelioma most patients do not have functional T cells present in the tumor. Therefore, PD-1/PD-L1 checkpoint inhibitor (CI) therapy is likely to induce an anti-tumor response in only a small portion of patients. Activated autologous dendritic cells (DCs) that have been directed against mesothelioma tumor cells have been shown to reinvigorate T cell responses. This T cell response that is induced is prone to be blocked by the tumor using the PD-1/PD-L1 mechanism.
Earlier, we published the results of three phase I/II trials in which patients were treated with DC immunotherapy as first line therapy of after completion of first line chemotherapy. 9 patients were subsequently treated with checkpoint inhibitor therapy in several trials and compassionate use programs. Six patients were treated with nivolumab, two with pembrolizumab and one patient was treated with combination treatment of nivolumab and ipilimumab. In all patients, the initial biopsy was stained for PD-L1 and TIM3, in five patients, repeat biopsy was done at time of progression. Radiological response was measured on CT scan using modified response evaluation criteria in solid tumors (RECIST). A radiological partial response was seen in three patients after PD-1 inhibition, stable disease was seen in five patients and one patients had progression of disease as best response on CI therapy, giving a disease control rate of 88%. No CTCAE grade 3-4 adverse events were seen. Updated adverse events, median PFS and OS will be presented at the meeting, as well as correlation of response with PD-L1 and TIM3 status.
We conclude that CI treatment after DC immunotherapy is safe and feasible. In addition, after induction of a T cell response, disease control could be achieved in all but one treated patient on subsequent CI therapy. This report is a proof of concept that the induced T cell response from DC immune therapy may be blocked by PD-L1 upregulation from the tumor which in turn can be targeted by CI.
Citation Format: Robin Cornelissen, Robert Belderbos, Joachim Aerts. Checkpoint inhibitor therapy after dendritic cell vaccination elicits tumor response in mesothelioma 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 2249.
Abstract 2260: Targeting PP2A with LB100 enhances efficacy of CAIX CAR-T cells against GBM
Authors: Cui Jing , Zhang Qi , Song Qi , Wang Herui , Dmitriev Pauline , Sun Mitchell , Rosenblum Jared S. , Yang Kaiyong , Kovach John , Gilbert Mark R. , Zhuang Zhengping 
Published: August 2019

Abstract
The need for novel therapies for glioblastoma multiforme (GBM) is well established. Chimeric antigen receptor (CAR)-engineered T cells represent a promising cancer treatment modality for treating GBM. However, CAR-T therapy has limitations, such as low penetration into solid tumors and short duration of CAR-T survival. Protein phosphatase 2A (PP2A) inhibition has been implicated in enhancing T cell anti-tumor activity. LB-100 is a novel, first-in-class, small molecule inhibitor of PP2A recently shown in a Phase I trial to be well-tolerated at doses resulting in stabilization of progressive solid tumors. We set out to overcome limitations of CAR-T therapy by activating the mTOR signaling pathway through inhibition of PP2A by LB-100. GBM highly expresses CAIX due to increased hypoxia signaling. Thus, antitumor CAIX-specific CAR T cells were developed and tested against GBM in vitro and in vivo. CAR-T cells displayed GBM cells cytotoxicity and increased IFN-γ, TNF-α, and IL-2 production. Intra-tumor injection of the CAR-T cells into an intracranial GBM xenograft mouse model efficiently suppressed the tumor growth. We found that PP2A inhibition by LB-100 further enhanced CAIX CAR-T activity and significantly prolonged mouse survival. Herein we demonstrate that CAIX represents a viable target for CAR-T cells and inhibition of PP2A enhances CAR-T efficacy against GBM. Targeting PP2A via inhibition with LB-100 may be a promising therapeutic strategy to improve CAR-T efficacy in other solid tumors.
Citation Format: Jing Cui, Qi Zhang, Qi Song, Herui Wang, Pauline Dmitriev, Mitchell Sun, Jared S. Rosenblum, Kaiyong Yang, John Kovach, Mark R. Gilbert, Zhengping Zhuang. Targeting PP2A with LB100 enhances efficacy of CAIX CAR-T cells against GBM [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 2260.