bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3096: A novel ZIP4-NOTCH3-HDAC4 axis in ovarian cancer stem cells
Authors: Xu Yan , Fan Qipeng , Emerson Robert 
Published: July 2021

Abstract
High grade serous ovarian cancer (HGSOC) is one of the most deadly and heterogenic cancers. We have recently shown that ZIP4 (gene name SLC39A4), a zinc transporter, is a novel cancer stem cell (CSC) marker in HGSOC. 100-200 ZIP4+, but not ZIP4-, cells from both PE04 and PEA2 cells formed larger tumors than those from 100-200 ALDH+ cells in mice. Mechanistically, we found that ZIP4 was an upstream regulator of another CSC-marker, NOTCH3, in HGSOC cells. NOTCH3 was functionally involved in spheroid formation in vitro and tumorigenesis in vivo in HGSOC. Drug-resistance is one of the main characteristics of CSCs, While ZIP4 converts drug-resistance to cisplatin (CDDP) and doxorubicin (DOX) as we reported previously, we unexpectedly found that ZIP4 induced a sensitization of HGSOC cells to histone deacetylase inhibitors (HDACis). In particular, only those HDACis against the Class IIa HDACs showed ZIP4-dependent sensitization. ZIP4 selectively up-regulated HDAC IIa HDACs, including HDAC4 and 5, with little or no effects to HDACs in other classes. ZIP4 knockout (KO) and HDAC4 knockdown (KD) increased cell resistance to LMK-235, a selective HDAC4/5 inhibitor. LMK-235 and HDAC4 knockdown (KD) inhibited spheroid formation in vitro and tumor development in vivo. Collectively, we revealed a novel ZIP4-NOTCH3-HDAC4 axis, which is functionally involved and important in CSC-related activities in vitro and tumorigenesis in vivo, and provide an innovative targeting strategy to CSC.
Citation Format: Yan Xu, Qipeng Fan, Robert Emerson. A novel ZIP4-NOTCH3-HDAC4 axis in ovarian cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3096.
Abstract 312: Targeted NanoSpheres (TNS)
Authors: Kang HyungGyoo , Nagy Jon , Upton Bryon , Upton Racheal , Triche Timothy , Triche Timothy 
Published: July 2021

Abstract
The tumor-targeted, nanoparticle delivery technology has shown the possibility of increasing the delivered dose of virtually any small therapeutics to tumor cells while limiting the drug uptake by normal tissues, thereby greatly increasing the effective MTD. By refining the early formulations and after extensive testing, we developed a novel targeted liposomal nanoparticle, Targeted NanoSpheres (TNS). We showed this novel nano-formulated platform can overcome many deficiencies of conventional nanoparticles and therefore has enhanced potential as an effective delivery vehicle for virtually any type of cancer for which a suitable tumor cell surface antigen is present. We have developedNV103, a first-in-class anti-CD99 TNS (CD99-TNS/Irinotecan), for the treatment of Ewing Sarcoma (EWS), a highly lethal pediatric and young adult bone and soft tissue tumor driven by a fusion protein, typically EWS/FLI1 in over 85% of cases. Cancer cells have the ability to develop resistance to the chemotherapy. Our present salvage/rescue study with NV103 showed that NV103 can overcome irinotecan resistance of Ewing tumor with simple change of dose schedule (dose intensification), not increasing the dose. The results from our salvage/rescue studies with NV103 suggested that successful dose intensification schedules with NV103 could be used to treat relapsed or resistant patients in future clinical trials. Furthermore, Targeted Nanosphere (TNS) can be used to overcome drug resistance of various cancers.This platform is also being investigated for other types of cancer that either express CD99, or other tumor antigens like GD2 and B7-H3.
Citation Format: HyungGyoo Kang, Jon Nagy, Bryon Upton, Racheal Upton, Timothy Triche, Timothy Triche. Targeted NanoSpheres (TNS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 312.
Abstract 3125: Analysis of intratumoral protein and gene expression heterogeneity in gastric cancer with a clustering analysis
Authors: Tsujio Gen , Yashiro Masakazu , Yamamoto Yurie , Sera Tomohiro , Sugimoto Atsushi , Kushiyama Shuhei , Nishimura Sadaaki , Yoshi Mami , Tamura Tasuro , Toyokawa Takahiro , Tanaka Hiroaki , Lee Shigeru , Muguruma Kazuya , Ohira Masaichi 
Published: July 2021

Abstract
Background/Aim: Intratumoral heterogeneity has been reported in various cancer types and may cause cancer metastasis and chemotherapy treatment resistance, including resistance to molecular targeted therapy. In gastric cancer, the intratumoral heterogeneity of cancer-associated molecules, such as HER2, has been reported and relates to the acquisition of chemotherapy resistance. To reveal whether intratumoral heterogeneity is related to cancer etiology, such as the mechanism of metastasis, and the development of new treatment strategies, such as combination therapy, we investigated intratumoral heterogeneity of gastric cancer with operative specimen and Cancer Genome Atlas (TGCA) data.
Methods: The study included 503 patients who underwent gastrectomy and immunohistochemical staining for gastric cancer between 2001 and 2006 and TGCA data. We conducted clustering analysis based on protein and gene expression data for FGFR2IIIb (FGFR2), HER2(ERBB2), CXCR2(CXCR2), CXCR4(CXCR4), cMet(MET), TGFβ1(TGFB1), IGF1R(IGF1R), and p-smad2(SMAD2), and we analyzed the relation of FGFR2IIIb (FGFR2) and HER2(ERBB2) expression with the expression of other proteins and genes. Additionally, we investigated clinicopathological feature correlations.
Result/Discussion: We divided gastric cancer specimens into nine clusters by immunohistochemical staining and 11 clusters using TCGA data. According to immunohistochemical staining, the high HER2 and FGFR2IIIb expression groups formed a cluster with high expression of various proteins. Analysis of stage 3-4 samples revealed more high protein expression clusters than the analysis of stage1-2, and this suggests that cancer acquires heterogeneity with cancer progression. In the TGCA data of stage 3-4, high FGFR2 and MET and high ERBB2 and SMAD2 or IGF1R expression formed clusters, which is consistent with the clustering analysis that was performed with immunohistochemical staining results.
Conclusion: Our findings suggest that the existence of a combination of intratumoral heterogeneity and clusters may change with cancer progression.
Citation Format: Gen Tsujio, Masakazu Yashiro, Yurie Yamamoto, Tomohiro Sera, Atsushi Sugimoto, Shuhei Kushiyama, Sadaaki Nishimura, Mami Yoshi, Tasuro Tamura, Takahiro Toyokawa, Hiroaki Tanaka, Shigeru Lee, Kazuya Muguruma, Masaichi Ohira. Analysis of intratumoral protein and gene expression heterogeneity in gastric cancer with a clustering analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3125.
Abstract 313: Synergistic interaction between gingerol, shogaol and paradol with platinum-based chemotherapeutic drugs against naïve and resistant breast cancer cells
Authors: Bawadood Aziza S. , Al-Abbasi Fahad A. , El-Halawany Ali M. , Al-Abd Ahmed M. 
Published: July 2021

Abstract
Breast cancer is one of the most common female cancers and contributes 25.4% of the total diagnosed malignancies in women in 2018. Shogaol, paradol, and gingerol are obtained from many plants belonging to the family Zingiberaceae such as dried ginger and grain of paradise and shows different pharmacological activities. The current study evaluated the anticancer potential of these compounds in combination with chemotherapeutic platinum drugs against breast cancer cells. Cytotoxicity assay, apoptosis assay, immunofluorescent staining cell surface marker analysis, and wound healing assay were used for evaluating the cytotoxic potential of these compounds alone and in combination with platinum chemotherapeutics agents against naïve and resistant breast cancer cell lines (MDA-MB-231 and MCF-7adr, respectively). Platinum drugs showed synergism in combination with shogaol and gingerol against the resistant breast cancer cells (MCF-7adr) with a Combination Index (CI) values of 0.39 and 0.54, respectively. A significant increase was observed in the percentages of early and late apoptotic cells for MDA-MB-231 cells treated with 6-shogaol for 24h. Significant decrease in CD44+/CD24- subpopulation was recorded in both cell lines using flowcytometric analysis. In the Wound healing assay, cells treated with the test compounds migrated significantly slower than control and needed a longer time to heal the scratch. In conclusion, gingerol, shogaol, and paradol compounds showed synergistic cytotoxicity with platinum-based drug and augmented their migration inhibitory activity, apoptotic effects, and tumor-associated stem cell suppressive the potential within naïve and resistant breast cancer cells.
Citation Format: Aziza S. Bawadood, Fahad A. Al-Abbasi, Ali M. El-Halawany, Ahmed M. Al-Abd. Synergistic interaction between gingerol, shogaol and paradol with platinum-based chemotherapeutic drugs against naïve and resistant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 313.
Abstract 3133: Clonal facilitation drives estrogen receptor positive (ER+) breast cancer growth and survival
Authors: Emond Rena , Grolmusz Vince K. , Griffiths Jason , Chen Jinfeng , Adler Frederick R. , Bild Andrea 
Published: July 2021

Abstract
Competition between different lineages of cells within a tumor has been included in thinking about cancer evolution and progression, but positive interactions like cooperation have received far less study. We have developed isogenic estrogen positive breast cancer cell lineages sensitive and resistant to CDK4/6 inhibition in order to investigate the mechanisms cell interactions under selective pressure. When these sensitive and resistant lineages are grown in co-culture under ribociclib treatment, sensitive survive and proliferate better than in mono-culture despite the effects of competition. Conditioned media taken from resistant cells grown in monoculture conditions reproduces this advantage, suggesting that secretion of some factor from resistant cells underlies the effect. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays were used to identify factors secreted by cell lineages. While the less active estrone metabolite was detected in all lineages, the highly active estradiol was only detectable in mono- or coculture with resistant cells. As sensitive cells are more dependent on estrogen signaling than resistant cells, they benefit more from the increase in local estradiol, leading to facilitative growth when cocultured. Cooperative signaling between isogenic cancer cells is enhanced through addition of estradiol and blocked by small molecule inhibitors targeting estrogen signaling pathways. We have developed mathematical models that quantify the strength of competition and facilitation between cell lines and evaluated the effects of treatments that modify these interactions. These analyses support the conclusion that these heterogeneous cell lineages cooperate to survive during therapy through the increased production and sharing of local estradiol. This multidisciplinary approach reveals interactions between ER+ cancer lineages during treatment and provides insight into cell cooperation and competition during treatment, and how these interactions promote cancer cell growth and survival during treatment.
Citation Format: Rena Emond, Vince K. Grolmusz, Jason Griffiths, Jinfeng Chen, Frederick R. Adler, Andrea Bild. Clonal facilitation drives estrogen receptor positive (ER+) breast cancer growth and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3133.
Abstract 3146: Heterogeneity of the antigen-expression pattern in primary and recurrent glioblastoma patients
Authors: Dufner Vera , Meyer-Hofmann Moritz , Feldheim Jonas , Maurus Katja , Monoranu Camelia , Nerreter Thomas , Hudecek Michael , Hagemann Carsten , Ernestus Ralf-Ingo , Löhr Mario 
Published: July 2021

Abstract
Introduction: Immunotherapy leads to promising results in the treatment of glioblastoma (GBM) patients. Recent clinical trials revealed a survival benefit of patients treated with monospecific CAR-T-cells. However, antigen escape mechanisms due to heterogeneous surface expression of target antigens still constitute a critical hurdle in the immunotherapeutic treatment of GBM and are a major reason for non-response or relapse. Therefore, we aim to characterize GBM's heterogeneity, the intratumoral distribution and changes of surface antigens in relapse.
Methods: We performed immunohistochemical staining of the ten in vitro and in vivo most targeted antigens in CAR-T cell therapy (HER2, EGFRvIII, CD70, B7H3, Il13Rα2, NY-ESO1, GD2, CD133, CSPG4 and EphA2). We analyzed 35 patients, who underwent surgery for primary (PT) as well as recurrent GBM (RL). To address intrapersonal heterogeneity, we examined five fields of view per slide. As controls, we stained cerebral, cerebellar and brain stem slides of three healthy specimens. We quantified the percentage of low, medium and high antigen expressing cells on each slide by applying a specialized macro in ImageJ. We further weighted this expression score by multiplication with 1 (low), 2 (medium) or 3 (high expression). Finally, we calculated the median expression values of all tumors combined for each antigen.
Summary: Median values of EGFRvIII (PT: 0.14; RL: 0.73), HER2 (PT: 0.67; RL: 4.00) and NY-ESO1 (PT: 0.00; RL: 0.16) expression were very low. Antigen expression of CSPG4 (PT: 4.67; RL: 2.78), Il13Rα2 (PT: 3.84; RL: 2.78), GD2 (PT: 7.50; RL: 27.03) and B7H3 (PT: 8.81; RL: 16.62) was mild. CD133 (PT: 52.16; RL: 56.13), CD70 (PT: 19.18; RL: 25.02) and EphA2 (PT: 60.65; RL: 55.46) showed moderate antigen expression. None of the evaluated antigens displayed high expression. Median values of HER2 (p=0.005, Cohen's r=0.48), EGFRvIII (p=0.042, Cohen's r=0.344), and GD2 (p=0.013, Cohen's r=0.42) were significantly increased in RL compared to PT. We found significant intrapersonal expression differences for each antigen. However, none of the healthy brain tissue specimens expressed any of the ten antigens.
Conclusions: Inter- and intrapersonal heterogeneity constitutes a major obstacle for the implementation of GBM immune therapies which avoid antigen escape mechanisms.
Citation Format: Vera Dufner, Moritz Meyer-Hofmann, Jonas Feldheim, Katja Maurus, Camelia Monoranu, Thomas Nerreter, Michael Hudecek, Carsten Hagemann, Ralf-Ingo Ernestus, Mario Löhr. Heterogeneity of the antigen-expression pattern in primary and recurrent glioblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3146.
Abstract 3177: Intrinsic and acquired resistance to RIG-I induced anti-tumor responses
Authors: Fraile-Bethencourt Eugenia , Khou Sokchea , Anand Sudarshan 
Published: July 2021

Abstract
The immune microenvironment plays a critical role in cancer orchestrating tumor progression and response to therapeutics. Strategies to manipulate the tumor immune microenvironment are invaluable to complement current standard of care treatments. Recently, approaches to target Pattern Recognition Receptors (PRRs) that recognize intracellular and extracellular pathogens have emerged as a promising strategy to enhance immune recognition of tumors. Among the PRRs, intracellular receptors that recognize DNA and RNA in the cells are unique in their ability to respond to both pathogenic and ‘self' nucleic acids that are generated as a result of aberrant cell division/transcription. We previously showed that targeting a cytosolic DNA sensor three prime exonuclease 1 (TREX1) enhanced immune responses in mouse tumor models including colorectal carcinomas (CRCs). Here we show that a cytosolic RNA sensing pathway, Retinoic acid Induced Gene 1 (RIG-I) acts as a robust immune activator across cancer types by enhancing the cellular and molecular correlates of anti-tumor immune responses. Using a stem loop hairpin RNA structure derived from a H1N1 sequence we elicited a potent RIG-1 response in CRC and breast cancers. Interestingly, activation of RIG also increased expression of TREX1 revealing potential cross-talk between the two pathways. We show that activation of tumor cell RIG-I alone is sufficient to decrease tumor burden with a concomitant broad cellular and molecular anti-tumor response. We observed a group of negative regulators of immune responses, including the NKG2a ligand - HLA-E, mono PARPs and the inhibitory checkpoint protein LAG3, are upregulated in RIG high tumors in cell culture, mouse and human tumors indicating how RIG-I high tumors may develop resistance to immune killing. Combination of RIG-I agonists synergized with inhibition of these resistance mechanisms in a tumor and context dependent manner. To understand intrinsic resistance to RIG signaling, we performed a focused RNAi screen and identified a few critical positive and negative modulators of RIG-I function in tumor cells. Taken together, our findings illustrate how tumor cell RIG-I is a potent inducer of cellular and molecular immune responses as well as highlight both intrinsic and acquired resistance to RIG-I induced anti-tumor responses.
Citation Format: Eugenia Fraile-Bethencourt, Sokchea Khou, Sudarshan Anand. Intrinsic and acquired resistance to RIG-I induced anti-tumor responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3177.
Abstract 3189: Integrated analysis for tumor-immune interaction and its application to ENKTCL immunotyping
Authors: Liu Yanbin , Gao Yan , Shao Yun , Meng Fang , Huang Huiqiang , Qin Frank Xiaofeng 
Published: July 2021

Abstract
Immunotherapy represents a major breakthrough for multiple cancer types, yet it remains necessary to expand disease indications and improve treatment efficiency based on better understanding of tumor-immune interaction. Three currently validated biomarkers (PD-L1, MSI/dMMR and TMB) are not sufficient to predict the efficacy and patient selection for immune checkpoint therapy. We hereby propose a comprehensive tumor-immune interaction typing strategy by integrating WES, RNA-seq and TCR-seq omic technologies for the detection of gene mutations, copy number variation, fusion genes, clone variation, HLA typing, tumor antigen prediction, tumor microenvironment immune repertoire analysis and tumor lymphocyte infiltration composition under the condition of one-time sampling. Thus enabling the systematic analysis of the tumor microenvironment characteristics. Applied to a cohort of ENKTCL patients, we studied the interactions between the tumor cells and the immune system tumor microenvironment. We discovered changes of tumor immunogenicity caused by DNA variation, e.g. abnormalities in immune regulatory region 6q21, DNA repair region, cases of fusion, CNV and LOH events. These mutational events summarizes the tumor intrinsic factors in NKTL. To study the TME and “extrinsic” factors, we investigated mRNA signature enrichment patterns in patient samples and found upregulation of various immune signatures such as macrophages, T helper cells in NKT tissue samples. As examples, CD274 and PDCD1 are significantly upregulated in NKTL tissue. We also found lower TCR diversity in NKTL patients. These discoveries suggest the association of tumor microenvironment with tumor intrinsic factors to elucidate the NKTL disease etiology. Taking together, our multi-omics datasets may also provide useful resources for further interrogating with treatment and clinical outcomes.
Citation Format: Yanbin Liu, Yan Gao, Yun Shao, Fang Meng, Huiqiang Huang, Frank Xiaofeng Qin. Integrated analysis for tumor-immune interaction and its application to ENKTCL immunotyping [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3189.
Abstract 341: Predicting clinical endocrine response in advanced breast cancers using a reproducible low-dimensional biomarker
Authors: Nath Aritro , Cohen Adam , Chang Jeffrey , Bild Andrea 
Published: July 2021

Abstract
In the absence of reliable and effective prognostic biomarkers, endocrine therapy remains the standard of care for all advanced and metastatic estrogen receptor-positive (ER+) breast cancers. Attempts to develop biomarkers using the baseline tumor transcriptome or genome of advanced ER+ breast cancers have so far been unsuccessful due to predictive models with poor reproducibility in independent studies. Here we present an approach to develop a low-dimensional biomarker that estimates the risk of adverse events on endocrine therapy using the baseline tumor transcriptome of patients. Using a framework for supervised dimensionality reduction of the gene expression feature space, we constructed an endocrine response signature (ENDORSE) modeled on the survival outcomes of ER+ breast cancers from METABRIC. ENDORSE outperformed transcriptome-wide and knowledge-based signature models while significantly improving upon routine histopathological and genomic classifiers in cross-validation analyses. The ENDORSE risk estimate accurately predicted the outcomes for endocrine therapy in three independent clinical trials for ER+ breast cancers. Further, analysis of the phenotypes enriched in high-risk categories show endocrine resistance was not associated with rates of proliferation, but instead with a potential loss of DNA damage repair and cell-matrix interaction pathways.
Citation Format: Aritro Nath, Adam Cohen, Jeffrey Chang, Andrea Bild. Predicting clinical endocrine response in advanced breast cancers using a reproducible low-dimensional biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 341.