bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4244: Using lysosomal immunogenic cell death to target cancer via xanthine oxidase
Authors: Taritsa Iulianna , Fossel Eric , Neote Kuldeep 
Published: June 2022

Abstract
Lysosome-induced immunogenic cell death (LIICD) is a powerful mechanism of targeting cancer cells that kills circulating malignant cells and primes the host’s immune cells against future remission. Current immunotherapies for cancer are limited in preventing recurrence - a gap which can be bridged by training the immune system to recognize cancer neoantigens. Lysosomal leakage can be induced therapeutically to traffic antigens from dying cells to dendritic cells which can later present those tumorigenic antigens to T cells. We demonstrate that the oxidative agent native bovine xanthine oxidase can induce early markers of lysosome-induced immunogenic cell death in an in vitro human cancer cell line (CCL2). Specifically, we measured overall cell death, as well as surface-expressed calreticulin, extracellular ATP release, and HMGB1 production. These markers are consensus indicators of ICD. Flow cytometry, luminescence assays, and ELISA were used respectively to quantify biomarker levels between treated versus untreated cells. We also included a positive control group of cells dosed with doxorubicin (a known inducer of LIICD). We looked at each marker at various time points after cancer cells were treated with xanthine oxidase, doxorubicin, and an untreated group. Upregulated biomarkers after treatment with the protein indicate an immunogenic response. Further, we used confocal imaging to show lysosomal membrane permeabilization after treatment with Native Bovine Xanthine Oxidase using Lucifer Yellow staining. We thus show the potential for this protein to induce an anticancer effect paired with an adaptive immune response against tumor cells. Our research in human cell lines here provides evidence for the success of the same therapeutic method in patients and serve as the gateway to developing a new treatment approach against breast cancer.
Citation Format: Iulianna Taritsa, Eric Fossel, Kuldeep Neote. Using lysosomal immunogenic cell death to target cancer via xanthine oxidase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4244.
Abstract 4246: ABL103, A novel T-cell engaging bispecific antibody, exhibits potent in vitro and vivo antitumor activity and low toxicity via B7-H4 dependent 4-1BB activation in tumor microenvironment
Authors: Park Kyungjin , Lee Yangsoon , Lim Saeyi , Park Kyeongsu , Kim Eunjung , Lee Hanbyul , Yoo Jiseon , Pak Youngdon , Kim Yeunju , Ko Minji , Won Jonghwa 
Published: June 2022

Abstract
B7-H4 (B7x, VTCN1), a member of the B7-family, is overexpressed in majority of cancer patients with ovarian, endometrial and breast cancers. B7-H4 expression was also observed in tumor associated macrophages and implicated as an immune checkpoint regulating T cell responses. Although B7-H4 expression in normal tissues is quite limited, tumor-specific immune response by ABL103 would minimize potential adverse effects. ABL103, B7-H4 Grabody-T, is a First-in Class bispecific antibody targeting B7-H4 and 4-1BB and augments T cell function by a dual mechanism, i.e., 1) blocks the B7-H4 mediated T cell inhibition, and 2) elicits superior T cell activation through B7-H4-dependent 4-1BB clustering. Our data showed that simultaneous binding of B7-H4 and 4-1BB by ABL103 led to potent in vitro T cell activation only in the presence of B7-H4 expressing tumor cells. In the established tumor model, ABL103 potently inhibited tumor progression in a dose-dependent manner and showed higher rate of complete remission (CR) at 2 and 10 mg/kg dose groups. Moreover, mice were protected from the tumor re-challenge 3 months after cessation of ABL103 treatment, suggesting long-term memory has been established. In 4-week pilot tox study using cynomolgus monkeys, ABL103 was tolerable up to 100 mg/kg dosed weekly with no ABL103-related toxicity observations. To understand the relationship of target expression, expression of B7-H4, CD4, CD8, PD-L1, and 4-1BB was examined in 142 ovarian cancer patient biopsies. About 83% of ovarian cancer patient tissues showed B7-H4 positive staining and 62% of them showed strong positive. In addition, the staining of 4-1BB as well as CD4 and CD8 T cells were observed in both tumor nest and stroma, suggesting that cross-linking of B7-H4 and 4-1BB is feasible in tumor microenvironment. Overall, ABL103 has a strong in vitro and vivo anti-tumor activity and good safety profile via B7-H4-dependent 4-1BB activation. This strongly suggests ABL103 is a promising therapeutic agent potentially benefitting patients with B7-H4 overexpression.
Citation Format: Kyungjin Park, Yangsoon Lee, Saeyi Lim, Kyeongsu Park, Eunjung Kim, Hanbyul Lee, Jiseon Yoo, Youngdon Pak, Yeunju Kim, Minji Ko, Jonghwa Won. ABL103, A novel T-cell engaging bispecific antibody, exhibits potent in vitro and vivo antitumor activity and low toxicity via B7-H4 dependent 4-1BB activation in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4246.
Abstract 4249: Quantitative PBMC ADCC bioassay and ADCC reporter bioassays for immunotherapy and SARS-CoV-2 monoclonal antibody development
Authors: Stecha Pete , Wang Jun , Garvin Denise , Gilden Julia , Grailer Jamison , Hartnett Jim , Fan Frank , Cong Mei , Cheng Zhi-jie Jey 
Published: June 2022

Abstract
Fc effector function is one of the main mechanisms of action (MoA) for therapeutic monoclonal antibodies (mAbs). Quantitative measurement of antibody-dependent cellular cytotoxicity (ADCC) is critically required for understanding the Fc function in mAb drug development. Despite the increasing interest and clinical success of the mAb therapeutic, it has been highly challenging to measure their ADCC activity in a reproducible and quantitative manner due to the lack of consistency in current methods that are based on primary PBMCs or NK cells and use tedious assay procedures. To improve ADCC assay precision so they can be validated as potency assay in cGMP laboratories, we developed reporter based ADCC bioassays using engineered effector cell line stably expressing a luciferase reporter and FcγRIIIa (V or F variant) to replace primary PBMC to overcome the assay variation. The ADCC reporter bioassays have been validated according to ICH guidelines by many laboratories and are demonstrated to be suitable for product release and stability studies in a quality-controlled environment. For early research and antibody characterization, we developed an improved PBMC ADCC assay using ADCC-prequalified PBMCs and engineered HiBiT target cells so they can measure the target specific lysis in ADCC. The PBMCs used in the study are isolated from prescreened blood donors and QC tested in ADCC assay. When HiBiT target cells are incubated with an antibody and PBMCs, HiBiT are released to the culture medium where it binds to LgBiT in the detection reagent to form a functional NanoBiT luciferase to generate luminescence signal. This new PBMC ADCC bioassay is simple, homogenous, highly sensitive, and gives a robust assay window. We demonstrate that it can quantitatively measure the potency for mAb drugs in cancer immunotherapy (e.g., rituximab, trastuzumab), and for anti-SARS-CoV-2 spike antibodies in antiviral drug development. Additionally, it shows antibody potency comparable with the ADCC reporter bioassay. In summary, the new PBMC ADCC bioassay using HiBiT target cells can be a valuable tool for early antibody discovery and characterization and also for method bridging study with ADCC reporter bioassay.
Citation Format: Pete Stecha, Jun Wang, Denise Garvin, Julia Gilden, Jamison Grailer, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng. Quantitative PBMC ADCC bioassay and ADCC reporter bioassays for immunotherapy and SARS-CoV-2 monoclonal antibody development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4249.
Abstract 426: Development of oridonin-based proteolysis-targeting chimera (PROTAC) degraders as effective breast cancer therapeutics
Authors: Ma Ruixia , Wang Pingyuan , Xu Junhai , Xu Jimin , Fricke Doerte R. , Xue Yu , Kim Hyejin , Chen Haiying , Liu Xi , Zhou Jia , Shen Qiang 
Published: June 2022

Abstract
Natural products provide a wealth of resources as the molecular starting point for the development of therapeutic agents, including a plethora of anticancer drugs currently in clinical use. Oridonin is a natural diterpene compound enriched in the medicinal herb Rabdosia rubescens, and its anticancer property has been extensively studied. However, the potency of oridonin against triple-negative breast cancer (TNBC) limits its potential clinical translation. Previously, we developed a class of oridonin analogues including CYD0618 and others as effective anticancer agents to inhibit tumor growth of TNBC in vitro and in vivo. Intriguingly, CYD0618 has been shown to directly bind to and inhibit STAT3 transcription factor, which is constitutively activated in the majority of human cancers. Currently there are no FDA-approved direct STAT3 inhibitors in clinical use. Based on the proteolysis-targeting chimera (PROTAC) technology, our team designed novel oridonin- and CYD0618-based PROTACs in an attempt to achieve specific STAT3 binding and protein degradation. We determined anticancer effects of oridonin- and CYD0618-PROTACs on proliferation, colony formation, and apoptosis of the TNBC cell line MDA-MB-231. We found that oridonin- and CYD0618-based PROTACs inhibited the proliferation of MDA-MB-231 cells significantly, similarly effective as the lead compound CYD0618 and much more potent than oridonin. We then examined the expression of STAT3, pSTAT3 and protein biomarkers for tumor metastasis using Western blot. STAT3 and pSTAT3 protein levels were downregulated dose- and time-dependently in MDA-MB-231 cells treated with CYD0618 and CYD0618-PROTACs, respectively. Our results demonstrate impressive effects of CYD0618-based PROTACs against TNBC cells, primarily through direct targeting of STAT3. We are in the process of further characterizing the molecular profile of CYD0618-based PROTACs by studying its interaction with STAT3 and protein degradation as well as their efficacy against TNBC tumor xenografts in vivo.
Citation Format: Ruixia Ma, Pingyuan Wang, Junhai Xu, Jimin Xu, Doerte R. Fricke, Yu Xue, Hyejin Kim, Haiying Chen, Xi Liu, Jia Zhou, Qiang Shen. Development of oridonin-based proteolysis-targeting chimera (PROTAC) degraders as effective breast cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 426.
Abstract 483: Automated Ki67-LI assessment in prostate cancer using artificial intelligence in multiplex fluorescence immunohistochemistry
Authors: Blessin Niclas C. , Mandelkow Tim , Bady Elena , Simon Ronald , Hube-Magg Claudia , Lennartz Maximilian , Sauter Guido , Graefen Markus , Steurer Stefan 
Published: June 2022

Abstract
The Ki67 labeling index (Ki67-LI) is a strong prognostic marker in prostate cancer. Its analysis requires cumbersome manual quantification of Ki67 immunostaining in at least 200 tumor cells. To enable automated Ki67-LI assessment in routine clinical practice, we have developed and validated a framework for automated Ki67-LI quantification, which comprises three different artificial intelligence analysis steps and an algorithm for cell-distance analysis of multiplex fluorescence immunohistochemistry staining. The prognostic impact of the Ki67-LI was tested on a tissue microarray (TMA) containing one sample each of 12475 prostate cancers. A “heterogeneity TMA” containing 3 to 6 samples from different tumor areas was used to model Ki67 analysis of multiple different biopsies. The Ki67-LI provided strong and independent prognostic information in 11845 successfully analyzed prostate cancers (p&lt;0.001 each). The analysis of the heterogeneity TMA revealed that the Ki67-LI of the sample with the highest Gleason score (AUC:0.68) was similarly prognostic as the mean Ki67-LI of all six foci (AUC:0.71 [p=0.24]). The combined analysis of the Ki67-LI and Gleason grades obtained on identical tissue spots showed that the Ki67-LI added significant additional prognostic information in case of classical ISUP grades (AUC:0.82 [p=0.002]) and quantitative Gleason grades (AUC:0.83 [p=0.018]). The Ki67-LI is a powerful prognostic parameter in prostate cancer, which can be efficiently analyzed in multiplex fluorescence IHC. In case of multiple cancer positive biopsies, the sole analysis of the worst biopsy can be sufficient.
Citation Format: Niclas C. Blessin, Tim Mandelkow, Elena Bady, Ronald Simon, Claudia Hube-Magg, Maximilian Lennartz, Guido Sauter, Markus Graefen, Stefan Steurer. Automated Ki67-LI assessment in prostate cancer using artificial intelligence in multiplex fluorescence immunohistochemistry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 483.
Abstract 5006: Computational analysis of hypoxia-inducible factor 1-alpha and UBS109 in hepatocellular carcinoma
Authors: Merchant Neha Bahadur , Behera Santosh Kumar , Alam Afroz , Nagaraju Ganji Purnachandra , Basha Riyaz 
Published: June 2022

Abstract
Hypoxia-inducible factor 1-alpha (HIF-1α) is a heterodimeric transcription factor, which is elevated during hypoxic conditions in several malignancies. HIF-1α is known to stimulate hypoxia-responsive genes that are linked with malignant properties viz.: progression, metastasis, and resistance to therapy. The objective of the present study is to target HIF-1α by potential phytodrug, curcumin and its monocarbonyl analog UBS109 in hepatocellular carcinoma (HCC). Curcumin has been known to exhibit therapeutic properties for the management of HCC due to its powerful anti-inflammatory and antioxidant properties as well as its ability to regulate multiple signaling pathways. UBS109 possesses comparable antitumor and anti-inflammatory properties as curcumin without any of its limitations. To analyze the binding capacity and ligand efficacy of HIF-1α against curcumin and UBS109, computational approaches were applied including molecular docking and dynamics simulation that can provide detailed understanding of its implication in HCC treatment and a deeper analysis of the protein-drug interaction.
Citation Format: Neha Bahadur Merchant, Santosh Kumar Behera, Afroz Alam, Ganji Purnachandra Nagaraju, Riyaz Basha. Computational analysis of hypoxia-inducible factor 1-alpha and UBS109 in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5006.
Abstract 5010: Comprehensive characterization of 11 prognostic alternative splicing events in ovarian cancer interacted with the immune microenvironment
Authors: Zheng Guixi 
Published: June 2022

Abstract
Alternative splicing (AS) events play a crucial role in the tumorigenesis and progression of cancer. Transcriptome data and Percent Spliced In (PSI) values of ovarian cancer patients were downloaded from TCGA database and TCGA SpliceSeq. Totally we identified 1,472 AS events that were associated with survival of ovarian serous cystadenocarcinoma (OV) and exon skipping (ES) was the most important type. Univariate and multivariate Cox regression analysis were performed to identify survival-associated AS events and developed the prognostic model based on 11-AS events. The immune cells and different response to cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) blockers in low-risk and high-risk group of OV patients were analyzed. Ten kinds of immune cells were found up-regulated in low-risk group. Activated B cell, natural killer T cell, natural killer cell and regulatory T cell were associated with survival of OV. The patients in low-risk group had good response to CTLA-4 and PD-1 blockers treatment. Moreover, a regulatory network was established according to the correlation between AS events and splicing factors (SFs). The present study provided valuable insights into the underlying mechanisms of OV. AS events that were correlated with the immune system might be potential therapeutic targets.
Citation Format: Guixi Zheng. Comprehensive characterization of 11 prognostic alternative splicing events in ovarian cancer interacted with the immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5010.
Abstract 502: The association of metformin dose and cancer survival in older adults with advanced cancer: SEER-Medicare analysis
Authors: Scarton Lisa , Jo Ara , Xie Zhigang , O’Neal LaToya J. , Pena Juan M. , George Thomas J. , Bian Jiang 
Published: June 2022

Abstract
Cancer and type 2 diabetes (T2DM) are common diseases that have serious health consequences. T2DM is known to increase the risk for the development of many of the most common cancers. Metformin, one of the most commonly used drugs to treat T2DM, is increasingly being used for its anticancer effects; however, the literature is limited on the effect of metformin dose on OS in patients with advanced cancer. We examined the relationship between metformin dose and OS in persons with both T2DM and stage IV lung, breast, colorectal, prostate, or pancreas cancers.
Methods: We used a retrospective study design with cox proportional hazards regression analysis of the 2007-2016 of the Surveillance Epidemiology and End Results-Medicare dataset.
Results: A total of 7,725 patients with T2DM and a least one targeted cancer was included in the analysis. Of those patients, 38.5% had been prescribed metformin. Patients who used metformin had significantly better OS in both unadjusted (Unadjusted HR, 0.73; 95% CI, 0.69-0.76; p &lt; 0.001) and adjusted models (adjusted HR, 0.77; 95% CI, 0.73-0.81; p &lt; 0.001). The OS between patients who took metformin with average daily dose ≥ 1000mg or &lt; 1000mg were not statistically significant (aHR, 1.00; 95% CI, 0.93-1.08; p=0.90).
Conclusions: Metformin use, regardless of dose, increases OS in older adults with advanced cancer. Additionally, OS was not significantly different across race or ethnicity.
Citation Format: Lisa Scarton, Ara Jo, Zhigang Xie, LaToya J. O’Neal, Juan M. Pena, Thomas J. George, Jiang Bian. The association of metformin dose and cancer survival in older adults with advanced cancer: SEER-Medicare analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 502.
Abstract 5030: Intra-patient tumor evolution analysis in dogs with many mammary tumors identifies signatures of tumor aggression in early-stage breast cancers
Authors: Graim Kiley 
Published: June 2022

Abstract
Despite tremendous improvements in breast cancer detection, it remains unclear which early-stage tumors will later become aggressive. Dogs provide a unique opportunity to unravel early-stage tumor evolution, as dogs frequently develop multiple naturally occurring mammary tumors. To identify which early-stage human breast tumors will later become malignant, we analyzed mutational profiles of mammary tumors from two canine cohorts to identify patterns of tumor evolution. We compared our dog tumor signatures with human breast cancers. We found that dogs and humans share many known cancer driver mutations. Additionally, three of the five dogs with at least five mammary tumors had a single driver mutation present in most of their tumors. Despite sharing patient-level exposures and environment, passenger mutations significantly differ between these tumors, suggesting independent primaries initiated by a catalyzing factor causing the same driver mutation in each tumor. However, tumors from the same dog with the same driver gene mutations rarely exhibit the same expression-based breast cancer subtypes. Our analysis highlights the mutational similarities of dog and human breast cancers and provides insight into their development.
Citation Format: Kiley Graim. Intra-patient tumor evolution analysis in dogs with many mammary tumors identifies signatures of tumor aggression in early-stage breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5030.
Abstract 5076: Evaluation of the CNS penetration of a next generation PARP inhibitor, AZD9574, in cynomolgus monkey using positron emission tomography
Authors: Pike Andy , Balazs Amber , Cselényi Zsolt , Degorce Sébastien L. , Ghosh Avipsa , Hande Sudhir M. , Johannes Jeffrey , Johnström Peter , Packer Martin J. , Schou Magnus , Zheng XiaoLan 
Published: June 2022

Abstract
The current clinically approved PARP inhibitors have limited subtype selectivity and are to some degree restricted in their ability to penetrate the central nervous system (CNS) due to efflux transporters, potentially limiting their efficacy in treating metastatic disease or primary tumors in the brain. The current study evaluated the potential of AZD9574, a next generation, PARP1 selective inhibitor/trapper, to penetrate the CNS in cynomolgus monkey, and its occupancy of the PARP1 enzyme, using positron emission tomography (PET). In vitro bidirectional efflux assay data suggested AZD9574 showed minimal substrate potential compared to the clinically approved PARP inhibitors. This was reflected in an increased ratio of unbound brain to unbound plasma concentration (Kpuu) in the rat of ~0.31. Therefore AZD9574 was taken forward into cynomolgus monkey PET studies. Firstly, the Kpuu was determined following dosing of [11C]AZD9574, co-administered with unlabeled drug to minimize the impact of specific binding. The high specific signal observed lead to the development of [11C]AZ3391, a PARP1 selective, CNS penetrant PET tracer, which was subsequently used to directly assess the PARP1 target engagement of AZD9574 in the brain. AZD9574 was found to show a Kpuu in cynomolgus monkeys of 0.79, close to unity with unbound plasma concentrations suggesting minimal CNS restriction. Furthermore, an i.v. infusion dose response study with AZD9574, conducted to examine its ability to block target occupancy by the PET tracer [11C]AZ3391, demonstrated a reduction in [11C]AZ3391 accumulation in whole brain. The resulting calculated occupancy of AZD9574 ranged from 17% for the lowest dose (0.003 mg/kg) to 95% for the highest dose tested (0.05 mg/kg). Comparable reduction in occupancy was seen for peripheral tissue, such as bone marrow, supporting the conclusion that AZD9574 shows minimal CNS restriction. These data show that AZD9574 is the first PARP inhibitor to reach the clinic which combines PARP1 selectivity, trapping and high CNS penetration in a single molecule and supports its development as a potential therapy for the treatment of metastatic disease and primary brain tumors.
Citation Format: Andy Pike, Amber Balazs, Zsolt Cselényi, Sébastien L. Degorce, Avipsa Ghosh, Sudhir M. Hande, Jeffrey Johannes, Peter Johnström, Martin J. Packer, Magnus Schou, XiaoLan Zheng. Evaluation of the CNS penetration of a next generation PARP inhibitor, AZD9574, in cynomolgus monkey using positron emission tomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5076.