bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimized Doxorubicin Chemotherapy for Diffuse Large B-cell Lymphoma Exploits Nanocarrier Delivery to Transferrin Receptors
Authors: Arumov Artavazd , Liyanage Piumi Y. , Trabolsi Asaad , Roberts Evan R. , Li Lingxiao , Ferreira Braulio C.L.B. , Gao Zhen , Ban Yuguang , Newsam Austin D. , Taggart Melissa W. , Vega Francisco , Bilbao Daniel , Leblanc Roger M. , Schatz Jonathan H. 
Published: February 2021

Abstract

New treatments are needed to address persistent unmet clinical needs for diffuse large B-cell lymphoma (DLBCL). Overexpression of transferrin receptor 1 (TFR1) is common across cancer and permits cell-surface targeting of specific therapies in preclinical and clinical studies of various solid tumors. Here, we developed novel nanocarrier delivery of chemotherapy via TFR1-mediated endocytosis, assessing this target for the first time in DLBCL. Analysis of published datasets showed novel association of increased TFR1 expression with high-risk DLBCL cases. Carbon–nitride dots (CND) are emerging nanoparticles with excellent in vivo stability and distribution and are adaptable to covalent conjugation with multiple substrates. In vitro, linking doxorubicin (Dox) and transferrin (TF) to CND (CND–Dox–TF, CDT) was 10–100 times more potent than Dox against DLBCL cell lines. Gain- and loss-of-function studies and fluorescent confocal microscopy confirmed dependence of these effects on TFR1-mediated endocytosis. In contrast with previous therapeutics directly linking Dox and TF, cytotoxicity of CDT resulted from nuclear entry by Dox, promoting double-stranded DNA breaks and apoptosis. CDT proved safe to administer in vivo, and when incorporated into standard frontline chemoimmunotherapy in place of Dox, it improved overall survival by controlling patient-derived xenograft tumors with greatly reduced host toxicities. Nanocarrier-mediated Dox delivery to cell-surface TFR1, therefore, warrants optimization as a potential new therapeutic option in DLBCL.

Significance:
Targeted nanoparticle delivery of doxorubicin chemotherapy via the TRF1 receptor presents a new opportunity against high-risk DLBCL tumors using potency and precision.
Induction of ADAM10 by Radiation Therapy Drives Fibrosis, Resistance, and Epithelial-to-Mesenchyal Transition in Pancreatic Cancer
Authors: Mueller Adam C. , Piper Miles , Goodspeed Andrew , Bhuvane Shiv , Williams Jason S. , Bhatia Shilpa , Phan Andy V. , Van Court Benjamin , Zolman Kathryn L. , Peña Brisa , Oweida Ayman J. , Zakem Sara , Meguid Cheryl , Knitz Michael W. , Darragh Laurel , Bickett Thomas E. , Gadwa Jacob , Mestroni Luisa , Taylor Matthew R.G. , Jordan Kimberly R. , Dempsey Peter , Lucia M. Scott , McCarter Martin D. , Chiaro Marco Del , Messersmith Wells A. , Schulick Richard D. , Goodman Karyn A. , Gough Michael J. , Greene Casey S. , Costello James C. , Neto Antonio Galveo , Lagares David , Hansen Kirk C. , Van Bokhoven Adrie , Karam Sana D. 
Published: February 2021

Abstract

Stromal fibrosis activates prosurvival and proepithelial-to-mesenchymal transition (EMT) pathways in pancreatic ductal adenocarcinoma (PDAC). In patient tumors treated with neoadjuvant stereotactic body radiation therapy (SBRT), we found upregulation of fibrosis, extracellular matrix (ECM), and EMT gene signatures, which can drive therapeutic resistance and tumor invasion. Molecular, functional, and translational analysis identified two cell-surface proteins, a disintegrin and metalloprotease 10 (ADAM10) and ephrinB2, as drivers of fibrosis and tumor progression after radiation therapy (RT). RT resulted in increased ADAM10 expression in tumor cells, leading to cleavage of ephrinB2, which was also detected in plasma. Pharmacologic or genetic targeting of ADAM10 decreased RT-induced fibrosis and tissue tension, tumor cell migration, and invasion, sensitizing orthotopic tumors to radiation killing and prolonging mouse survival. Inhibition of ADAM10 and genetic ablation of ephrinB2 in fibroblasts reduced the metastatic potential of tumor cells after RT. Stimulation of tumor cells with ephrinB2 FC protein reversed the reduction in tumor cell invasion with ADAM10 ablation. These findings represent a model of PDAC adaptation that explains resistance and metastasis after RT and identifies a targetable pathway to enhance RT efficacy.

Significance:
Targeting a previously unidentified adaptive resistance mechanism to radiation therapy in PDAC tumors in combination with radiation therapy could increase survival of the 40% of PDAC patients with locally advanced disease.
See related commentary by Garcia Garcia et al., p. 3158
Evolving Status of Clinical Immunotherapy with Oncolytic Adenovirus
Authors: Farrera-Sal Martí , Moya-Borrego Laura , Bazan-Peregrino Miriam , Alemany Ramon 
Published: February 2021

AbstractCancer immunotherapy targeting immune checkpoint inhibitors shows efficacy in several human cancers, but “cold tumors” that lack immune cells are typically unresponsive. Among the potential therapeutic approaches that could “heat” or promote lymphocyte infiltration of cold tumors, oncolytic viruses have attracted interest for their lytic and immunogenic mechanisms of action. In this article, we review the use of oncolytic adenoviruses in cancer immunotherapy, with a particular focus on preclinical and clinical data of oncolytic adenovirus-triggered immune responses against tumor antigens. We also discuss parameters to consider in clinical trial design and the combination of oncolytic adenoviruses with conventional treatments or other immunotherapies.
Abstract IA005: DNA damaging agents in endometrial cancer
Authors: Westin Shannon Neville 
Published: February 2021

Abstract
The time for “one size fits all” treatment is over in endometrial cancer. Endometrial cancer has a number of potential targetable molecular aberrations, including those that predict response to DNA damaging agents such as PARP inhibitors. This talk will explore the preclinical and clinical data to support DNA damaging agents, alone and in combination, in the treatment of endometrial cancer. Biomarkers for response will be critically reviewed.
Citation Format: Shannon Neville Westin. DNA damaging agents in endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA005.
Abstract IA006: Endocrine therapy and ER/PR combinations
Authors: MacKay Helen J. 
Published: February 2021

Abstract
Endocrine therapy is the “original” targeted therapy in endometrial cancer (EC). Despite over 60 years experience with this treatment modality we have yet to answer some key questions including which women derive benefit and how do we identify them? Despite a high proportion of ECs being ER and/or PR positive, endocrine therapy is only associated with modest benefit. Greater understanding of ER and PR biology may help identify patient populations who will derive benefit and assist in optimizing this approach. Favourable toxicity profiles and multiple pathway interactions suggest the potential for combining endocrine and other targeted agents. We discuss the preliminary data and hypothesize on potential strategies to accelerate the pace of development in this area.
Citation Format: Helen J. MacKay. Endocrine therapy and ER/PR combinations [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA006.
Abstract IA007: The mutational landscape of normal human endometrial epithelium
Authors: Moore Luiza 
Published: February 2021

Abstract
Human endometrium is a highly dynamic tissue that undergoes numerous cycles of breakdown, rapid repair and remodelling in response to the oscillating levels of oestrogen and progesterone. The marked regenerative capacity of the tissue’s epithelial compartment is maintained by the intra-glandular adult stem cells (ASCs) that are retained during menstruation. Although the endometrial epithelial ASCs were first described over a decade ago, they remain poorly characterised in comparison to their counterparts in other tissues, such as the small and arge intestine. In particular, the size of the stem cell pool within individual glands, clonal dynamics and genomic landscape are largely unknown. In this study, we laser-capture microdissected 257 morphologically normal endometrial glands from pre- and post-menopausal women (aged 19 to 81). In selected donors, we also obtained samples of normal endocervical and Fallopian tubular epithelium. Isolated cellular material was subjected to our modified library preparation protocol and subsequent whole genome sequencing (WGS). Analysis of the WGS data identified that the majority of the glands were clonal cell populations sharing a recent common ancestor. Somatic mutations accumulated at a rate of 29 substitutions per year. Total mutation burden in the normal endometrial epithelium is higher than in other normal cells and manyfold lower than in endometrial cancers. Overall, despite the heterogeneity in age, reproductive history and BMI, we found relatively homogenous mutational processes to be operative in this tissue with only occasional outliers. Remarkably, we not only identify recurrent acquisitions of certain cancer-associated mutations, particularly those that are advantageous to cell growth, proliferation and migration, but also show that such events occur early in life, potentially even before adolescence. Using a generalised linear mixed effect model, we found that age has a positive association with the accumulation of driver mutations, while parity has a negative association. Over time, the mutant ASCs serve as a reservoir for the acquisition of further driver mutations to the extent that in some cases, the entire sampled endometrium becomes ‘neoplastic’ on the genomic level while still retaining the apparently normal phenotype. Our data identify a distinct mutational landscape in normal endometrium that is in keeping with the presence of early positive selection in this highly regenerative tissue.
Citation Format: Luiza Moore. The mutational landscape of normal human endometrial epithelium [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA007.
Abstract IA008: Mismatch repair deficiency and survival in stage I endometrial cancer
Authors: Broaddus Russell R. 
Published: February 2021

Abstract
The importance of testing for DNA mismatch repair defects and high levels of tumor microsatellite instability (MSI) is established for screening colorectal and endometrial cancers for Lynch Syndrome and advanced solid tumor malignancies for treatment with checkpoint inhibitors. Therefore, accurate clinical assays are necessary to identify DNA mismatch repair defects and patients with cancers with high levels of MSI. While defects in DNA mismatch repair identified by immunohistochemistry may often overlap with tumor microsatellite instability as identified by PCR-based assays, the two molecular events are not synonymous and can be discordant in individual cancers. Cancers outside of the GI tract may have loss of DNA mismatch repair proteins but may have more subtle microsatellite instability or even be microsatellite stable. The College of American Pathologists has established an expert guideline committee to help navigate some of the clinical testing issues when trying to detect defects in DNA mismatch repair and MSI in cancers. In addition to these established clinical uses of DNA mismatch repair and MSI, their use as a prognostic biomarker for endometrial cancer is emerging. Data suggest that specific environmental factors may interact with DNA mismatch repair, causing a more variable phenotype in cancers with loss of DNA mismatch repair.
Citation Format: Russell R. Broaddus. Mismatch repair deficiency and survival in stage I endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA008.
Abstract IA012: Recent progress with PTEN
Authors: Parsons Ramon E. 
Published: February 2021

Abstract
PTEN is one of the most frequently mutated genes in cancer and is frequently mutated in endometrial carcinoma. Recent progress on PTEN will be presented from our laboratory regarding its role in metabolism, RNA polymerase II transcription, and its expression in tumors with p53 mutations. I) Loss of PTEN activates metabolism of glutamine to pyrimidine and inactivates the ATR DNA damage checkpoint elicited when pyrimidine synthesis is interrupted, which leads to DNA damage and cell death suggesting a metabolic strategy for cancer treatment. II) PTEN in the nucleus binds to RNA polymerase II as wells as CDK7 and CDK9 on chromatin at promoters and regulates RNA Pol II transcription of genes involved in cellular metabolism. Mutation of PTEN increases RNA poly II levels and phosphorylation and increases sensitivity to inhibition of CDK7 and CDK9. III) Mutation of p53 is associated with reduced expression of PTEN and other tumor suppressor genes in many forms of cancer. p53 was found to bind to a dozen tumor suppressor genes in its wild type state and activates their expression under basal low stress conditions when the level of p53 is at a low level. All of these tumor suppressor genes had p53 binding elements in their promoters and enhancers and deletion of the element in a PTEN enhancer lowered its expression. These findings suggest that p53 mediates tumor suppression by maintaining the expression of other tumor suppressor genes including PTEN.
Citation Format: Ramon E. Parsons. Recent progress with PTEN [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA012.
Abstract IA015: Molecular stratification: Beyond TCGA
Authors: Church David 
Published: February 2021

Abstract
The molecular endometrial cancer (EC) classification defined by TCGA has improved both understanding of disease biology and clinical risk stratification. In my talk, I will review data for other biomarkers with proven or potential utility to further refine risk stratification in EC. I will also present results of analysis of whole genome sequence data from the large cohort of ECs recruited to the Genomics England 100,000 Genomes Project, and highlight the promise of this initiative to define new tumour subsets and therapeutic targets.
Citation Format: David Church. Molecular stratification: Beyond TCGA [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA015.
Abstract IA020: Chromatin regulation of the endometrium: What are our models telling us?
Authors: Wilson Mike R. , Reske Jake J. , Chandler Ronald L. 
Published: February 2021

Abstract
ARID1A and PI3-Kinase (PI3K) pathway alterations are common in neoplasms originating from the uterine endometrium. ARID1A is a SWI/SNF chromatin-remodeling complex subunit. ARID1A loss in the mouse endometrial epithelium leads vaginal bleeding when combined with PI3K pathway activation. Sorted mutant endometrial epithelial cells display gene expression and promoter chromatin signatures associated with epithelial-to-mesenchymal transition (EMT), inflammation and estrogen signaling in vivo. ARID1A loss leads to the expression of EMT genes, suggesting ARID1A normally maintains endometrial epithelial cell identity by repressing mesenchymal cell fates. In contrast to its repressive roles, ARID1A is required for the activation estrogen responsive genes, including the progesterone receptor (PGR). Estrogen responsive genes are marked by bivalent chromatin domains containing both histone H3 lysine 4 trimethylation (H3K4me3) and lysine 27 trimethylation (H3K27me3). High H3K27me3 correlates with low PGR expression, suggesting Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 normally silences PGR. In support of this, pharmacological inhibition of PRC2 partially rescues PGR activation is estrogen treated, ARID1A-deficient cells. Given the known antagonistic relationship between SWI/SNF and PRC2 complexes, we propose that SWI/SNF normally opposes PRC2 mediated silencing of the PGR promoter in response to estrogen, leading to PGR expression. In the ARID1A mutant endometrium, PGR promoter silencing by PRC2 is maintained. In the absence of PGR, progesterone cannot oppose the actions estrogen in the endometrium, leading to unopposed estrogen signaling. Our data demonstrate ARID1A has both activating and repressive roles in the endometrium, and ARID1A loss contributes to multiple aspects of disease pathogenesis.
Citation Format: Mike R. Wilson, Jake J. Reske, Ronald L. Chandler. Chromatin regulation of the endometrium: What are our models telling us? [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA020.
Abstract PO002: Inducing homologous recombination deficiency in uterine serous cancer (USC) using AVB-500, a receptor tyrosine kinase AXL inhibitor
Authors: Toboni Michael D. , Blachut Barbara , Lomonosova Elena , Khabele Dineo , Kuroki Lindsay , Hagemann Andrea , McCourt Carolyn , Thaker Premal , Mutch David , Powell Matthew , Fuh Katherine 
Published: February 2021

Abstract
Background: Evidence suggests that inducing homologous recombination deficiency (HRD) can be a therapeutic target in endometrial cancer (EC). Given this, we determined whether AVB-500, an AXL inhibitor, could induce HRD measured by a reduction of RAD51 foci in response to DNA damage in a uterine serous cancer (USC). Methods: Baseline homologous recombination (HR) status was determined after inducing DNA damage by radiating USC cell lines (ARK1 and ARK4) with 10Gy radiation treatment (RT) and identifying RAD51 foci by immunofluorescence (IF). Both radiated and non-radiated cells were quantified in both cell lines. Cell lines were considered to be HR proficient if over 30% of the cells expressed RAD51 (&gt;5 foci per cell). AVB-500 (Aravive Biologics, Houston, TX) was given prior to radiation after baseline HR status was established. IF was conducted using a Leica confocal microscope and foci were quantified using FociCounter. Results: Both ARK1 and ARK4, showed HR proficiency at baseline. After radiation, there was an increase in gamma-H2Ax indicative of DNA damage and an appropriate increase in RAD51 foci in response. However, when cells were treated with AVB-500 prior to radiation, there was a decrease in RAD51 foci when compared to radiation alone in both ARK1 (2.7 foci for AVB + RT vs 7.3 foci for RT only, p=0.0003) and ARK4 (6.3 foci for AVB + RT vs 13.0 foci for RT only, p=0.0054). Furthermore, after treatment with AVB-500 followed by RT, the proportion of ARK1 cells expressing RAD51 decreased to 21%, indicating HR deficiency. Conclusions: ARK1 and ARK4 are HR proficient at baseline. Pretreatment with AVB500 followed by RT led to a decrease in RAD51 foci suggestive of inducing HRD. Additional therapeutic and mechanistic experiments are ongoing.
Citation Format: Michael D. Toboni, Barbara Blachut, Elena Lomonosova, Dineo Khabele, Lindsay Kuroki, Andrea Hagemann, Carolyn McCourt, Premal Thaker, David Mutch, Matthew Powell, Katherine Fuh. Inducing homologous recombination deficiency in uterine serous cancer (USC) using AVB-500, a receptor tyrosine kinase AXL inhibitor [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO002.
Abstract PO005: A comprehensive analysis of the transcriptional effects of progesterone receptor isoforms A and B identifies VEGF, PDGF and STAT3 as therapeutic targets
Authors: Leslie Kimberly K. , Leiva Stephanie M. , Dai Donghai , Zhang Yuping , Thiel Kristina W. 
Published: February 2021

Abstract
Progesterone prevents development of endometrial cancers through its receptors A (PRA) and B (PRB) although the molecular mechanisms have yet to be fully characterized. In this study, we performed a global analysis of gene regulation by progesterone using human endometrial cancer cells that express heterologous progesterone receptors. Functional replicate Affymetrix microarrays encompassing 54,000 transcripts were performed for two independent experiments. Data suggest that progesterone exerts the growth-limiting effects in endometrium via down-regulation of several growth factors important in angiogenesis and cell proliferation. In particular, progesterone down-regulates the vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), and signal transducer and activator of transcription 3 (STAT3) genes. Down-regulation of these pro-growth pathways required the co-expression of both PR isoforms A and B, whereas expression of either isoform alone resulted in unchanged or even elevated levels of PDGF and STAT3 transcripts. Our study identifies these pathways as central to the growth limiting effects of progesterone in endometrial cancer and suggests that these factors constitute important targets for future therapeutic interventions. We also provide a comprehensive catalogue of the transcriptional effects of PR isoforms in endometrial cancer for future reference.
Citation Format: Kimberly K. Leslie, Stephanie M. Leiva, Donghai Dai, Yuping Zhang, Kristina W. Thiel. A comprehensive analysis of the transcriptional effects of progesterone receptor isoforms A and B identifies VEGF, PDGF and STAT3 as therapeutic targets [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO005.