bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3607: RNA-binding proteins are essential for EGF-induced fibronectin expression and metastasis of head and neck squamous cell carcinoma
Authors: Chang Ting-Wei , Chang Wen-Chang , Chen Ben-Kuen 
Published: June 2023

Abstract
There is a higher expression level of epidermal growth factor receptor (EGFR) in up to 90% of advanced head and neck squamous cell carcinoma (HNSCC) tissue than in normal surrounding tissues. However, the precise mechanism involved in modulating EGF-associated metastasis in HNSCC remains unclear. In this study, we reveal that the concurrent expression of EGFR and fibronectin (FN1) was highly associated with the stages of HNSCC progression. EGF-induced fibronectin/integrin axis enhanced tumor-endothelial cell interaction and increased endothelial permeability, conferred HNSCC cell metastasis. Mechanistically, we found that ERK and NF-κB pathway activation was essential for EGF-induced fibronectin expression. In addition, EGF-enhanced mRNA stability of fibronectin occurred through the 5’ untranslated region (5’-UTR) of the gene and was mediated by nucleolin (NCL) and hnRNPA2/B1, which were also involved in the regulation of epithelial-mesenchymal transition gene expression. Intriguingly, the in vivo study showed that depletion of NCL, hnRNPA2/B1, and inhibition of the fibronectin/integrin axis significantly inhibited EGF-promoted HNSCC metastasis in the lung. Our data suggests that the nucleolin/hnRNPA2/B1-regulated fibronectin is essential for EGF-induced tumor-endothelial cell interactions to enhance HNSCC cell metastasis.
Citation Format: Ting-Wei Chang, Wen-Chang Chang, Ben-Kuen Chen. RNA-binding proteins are essential for EGF-induced fibronectin expression and metastasis of head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3607.
Abstract 3642: SPHK1 mediated regulation of antitumor immunity in ovarian cancer
Authors: Gupta Prachi , Kumar Sudhir , Kadamberi Ishaque Pulikkal , Mittal Sonam , George Jasmine , Geethadevi Anjali , Chaluvally-Raghavan Pradeep , Pradeep Sunila 
Published: June 2023

Abstract
Introduction: Sphingosine kinase 1 (SPHK1) is an enzyme that helps to synthesize biolipid sphingosine-1-phosphate (S1P). We showed extracellular vesicles facilitate an increased accumulation of S1P in the ovarian tumor microenvironment (TME). S1P enhances the exhaustion of CD8 T cells, thus downregulating anti-tumor immunity. Furthermore, we also found less ovarian tumor burden in SPHK1−/− mice compared to WT mice. Based on our preliminary data, we hypothesized that the SPHK1 depleted tumor microenvironment increases the infiltration of the immune cells and its activity downregulates the tumor progression.
Methods: SPHK1 global knockout mice and WT C57BL/6 mice were used in the study. Tumor cells (ID8 P53−/− BRCA−/−) were injected, and tumor progression was studied. Immunophenotyping was performed by flow cytometry on ascites and tumor samples. Activation of CD8 T cells, B cells, and dentritic cells were studied by flow cytometry. Bulk RNA sequencing was performed on SPHK1−/− and WT tumors.
Results: SPHK1−/− mice showed regression in tumor growth in multiple tumor models. Tumor tissues from SPHK1−/− mice enhanced infiltration of CD4 and CD8 T cells, B cells, and dentritic cells compared to WT mice. Furthermore, infiltrated immune cells were active in SPHK1−/− mice. Bulk RNA sequencing also showed enhanced immune response in SPHK1−/− tumors compared to WT tumors.
Conclusion: SPHK1−/- environment decreased the tumor growth by enhancing the infiltration and activation of immune cells. We are currently focusing on identifying the immune cells which are critical players in this process. We will further implement these findings in human immune cells for clinical benefits for ovarian cancer patients.
Citation Format: Prachi Gupta, Sudhir Kumar, Ishaque Pulikkal Kadamberi, Sonam Mittal, Jasmine George, Anjali Geethadevi, Pradeep Chaluvally-Raghavan, Sunila Pradeep. SPHK1 mediated regulation of antitumor immunity in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3642.
Abstract 3799: Regulation of p16-E2F1-CDK4/6 signaling by TRUC-16 ultraconserved long non-coding RNA
Authors: Fabris Linda , Knutsen Erik , Bertilaccio Maria Teresa S. , Calin Steliana , Bayraktar Recep , Eisenhoffer George T. , Girnita Leonard , Calin George A. 
Published: June 2023

Abstract
High phylogenetic conservation of genomic loci is a potential marker of essential biological functionality. Ultraconserved elements (UCEs) are DNA sequences entirely conserved through millions of years of evolution, but their functions are not well understood. Several long non-coding RNAs (lncRNAs) are transcribed from UCEs and play active roles in cancer development. Using a combination of in vitro and in vivo experiments with two animal models and 4 patient cohorts, we discovered several remarkable aspects of ultraconservation. Using a multi-step genetically defined carcinogenesis model, we identified one UCE, uc.206, and its associated overexpressed lncRNA TRUC-16 as a regulator of cell proliferation in chronic lymphocytic leukemia (CLL). High levels of TRUC-16 inhibit p16INK4A translation, causing increased proliferation through an E2F1-mediated mechanism in CLL patients, as well as in zebrafish and murine models. uc.206/TRUC-16 function is extremely conserved throughout evolution. We found cell cycle-related effects of TRUC-16 in both mice and zebrafish, in which we observed increased proliferation of blood cells after overexpression of the human TRUC-16. High levels of CDK4/6 consequent to TRUC-16 overexpression and p16 decrease can be specifically targeted in both CLL and Richter’s Transformation (RT), a rare but deadly consequence of CLL. Inhibition of CDK6 is a therapeutic option never tested in CLL, but in use for another type of B cell malignancy, such as the mantle cell lymphoma. Our results highlight the multifaceted contribution of a UCE to human tumorigenesis and open new possibilities for the use of long-noncoding RNAs in cancer therapies.
Citation Format: Linda Fabris, Erik Knutsen, Maria Teresa S. Bertilaccio, Steliana Calin, Recep Bayraktar, George T. Eisenhoffer, Leonard Girnita, George A. Calin. Regulation of p16-E2F1-CDK4/6 signaling by TRUC-16 ultraconserved long non-coding RNA. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3799.
Abstract 38: PBMC donor selection affects engraftment rates and onset of graft versus host disease in humanized NCG mice for use in cancer studies
Authors: Bronson Steven , Rowe Jenny , Eberle Christoph , Festin Stephen 
Published: June 2023

Abstract
Preclinical studies examining tumor biology and immunity are limited by differences between the mouse and human immune systems. Humanized mouse models offer a unique tool to assess the anti-tumor response by recapitulating aspects of human tumor biology. Humanized mice are created by injecting either human CD34+ hematopoietic stem cells or peripheral blood mononuclear cells (PBMCs) into an immunodeficient mouse strain. Here we utilized a PBMC humanized NCG mouse model to investigate human T-cell mediated anti-tumor response (&gt;95% CD3+ T-cells by day 21). The challenges encountered with this model include the onset of graft versus host disease (GvHD) and donor variability leading to donor specific engraftment rates. Consistency is required with humanized PBMC models to ensure their use as an appropriate research model. Therefore, we examined the relationship between donor selection and engraftment rates as well as the onset of GvHD. Inter-donor variability was assessed by collecting PBMCs from multiple healthy donors. Intra-donor consistency was assessed by collecting PBMCs from the same donors at subsequent collections and comparing to initial human immune cell profiling by flow cytometry. NCG mice were injected with 1 × 107 PBMCs from individual donors. Animals were weighed three times a week to monitor for changes in body weight and general health status. Peripheral blood was collected at day 9, 21 and 42 for flow cytometry screening of human immune cell engraftment (hCD45+, hCD3+, hCD4+ and hCD8+) at the initial collection. Human PBMCs isolated from additional collections from the same donors were also injected into NCG mice and flow cytometry was performed on the new cell lots at day 21. Donors were grouped into categories based on engraftment rates, which were donor dependent. Donor variability is an important aspect to consider when humanizing mice with human PBMCs. PBMC humanized models are important for the study of pre-clinical therapeutics, but donor engraftment rates must be considered when engrafting the mice to create a consistently humanized mouse.
Citation Format: Steven Bronson, Jenny Rowe, Christoph Eberle, Stephen Festin. PBMC donor selection affects engraftment rates and onset of graft versus host disease in humanized NCG mice for use in cancer studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 38.
Abstract 3809: Differential regulation of novel long non coding RNAs and their mechanism of action in p73 dependent manner
Authors: Bareja Chanchal , Uboveja Apoorva , Saluja Daman 
Published: June 2023

Abstract
The p53 tumor suppressor family is classically activated after DNA damage and plays a central role in cell fate decisions. Although, the p53 family activates many of the same genes in response to DNA damage, p73 plays distinct biological functions in development and metastasis. It is likely that p73 activates a unique transcriptional network which is critical for its anti-metastatic and anti-invasive action. Long non-coding RNAs (lncRNAs) are a class of mRNA- like transcripts longer than 200 nucleotides. They lack protein-coding ability and are believed to be involved in various kinds of biological processes. Increasing evidence suggests that lncRNA are frequently aberrantly expressed in cancers. Therefore, the roles of dysregulated functional lncRNA in human malignant tumors have attracted considerable scientific interest. The objective of our study is to find out novel long non-coding RNAs that can act as transcriptional targets of p73 and to delineate their role in p73-mediated anti-metastatic response. For this purpose, we performed transcriptome sequencing in HCT116p73wt and HCT116p73KD cells and screened the data for modulation of expression of lncRNAs in differential manner. Quantitative Real Time PCR was further carried out to validate the data obtained after screening RNA seq Data. Promoter analysis was carried out for the identification of p73 binding sites in the selected upregulated or downregulated lncRNAs which was further confirmed by Luciferase reporter, ChIP and site directed mutagenesis assays. About six lncRNAs were observed to be significantly upregulated while four were down-regulated upon knockdown of p73. The promoters of selected lncRNAs were analysed in silico using TF Bind and JASPAR software for p73 binding sites and luciferase reporter assays suggested regulation of lncRNAs by p73. Chromatin immunoprecipitation showed promoter enrichment of the selected lncRNAs. Together, our study provides insights into the differential regulation of long non- coding RNAs in p73 dependent manner which further will provide the mechanism of their action at the genome level.
Citation Format: Chanchal Bareja, Apoorva Uboveja, Daman Saluja. Differential regulation of novel long non coding RNAs and their mechanism of action in p73 dependent manner. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3809.
Abstract 381: Inhibition of CCR6-CCL20 axis enhances cytotoxic effect of chemotherapeutics in colon cancer
Authors: Mir Hina , Singh Shailesh 
Published: June 2023

Abstract
Response of chemotherapeutic offered to treat colon cancer are often short-lived due to chemoresistance and severe toxicity associated with the therapy. Hence, development of less toxic treatment options is imperative to improve efficacy and therapeutic outcome. We have shown that chemokine CCR6 and its natural ligand is expressed in colon cancer and correlates with advanced disease. Aim of this study was to establish the association of CCCR6/CCL26 signaling axis on development of chemoresistance and chemotherapeutic response. Our data shows higher expression of receptor, poor cytotoxic effect of 5-Fluorouracil (5-FU) when cells are treated with CCL20 while better response to 5-FU when CCR6 signaling is blocked using anti-CCR6 monoclonal antibody. The observed differences in the cytotoxic effects of 5-FU could be primarily due to CCR6-mediated alteration of cell cycle, activation of cell survival and anti-apoptotic signaling. Further investigations in a preclinical model will rationalize developing CCR6 directed therapies to improve response to conventional chemotherapeutics and offer less toxic treatment options to colon cancer patients.
Citation Format: Hina Mir, Shailesh Singh. Inhibition of CCR6-CCL20 axis enhances cytotoxic effect of chemotherapeutics in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 381.
Abstract 3857: Exploring mechanisms of resistance to elraglusib in pancreatic cancer PDX models
Authors: Weiskittel Taylor , Li Ding , Han Lingling , McDermott Joseph , Caneiro Benedito , Li Hu , Billadeau Daniel , Mazar Andrew 
Published: June 2023

Abstract
Metastatic pancreatic cancer patients who previously progressed on nab-paclitaxel/gemcitabine (average of 3 previous lines if treatment) were treated with elraglusib in combination with a rechallenge of this combination. The majority of patients demonstrated a prolonged progression free survival. While this early clinical evidence is highly encouraging, the biological determinants of elraglusib response are unknown. In vitro screens of elraglusib on pancreatic PDX cell lines showed that some tumor cells possess modest intrinsic resistance to elraglusib as measured by LD50 which ranged from 316.9 nM to 1080 nM in a screen of 10 cell lines. To explore this phenomena further, we induced resistance in three cell line models by growing cells in the presence of increasing concentrations of elraglusib. We then sequenced the transcriptome of the parental and resistant lines to identify potential mechanisms of elraglusib resistance. Comparison of RNA sequencing profiles identified upregulation of the Aldo-keto reductase (AKR) family of genes. This upregulation was confirmed by qRT-PCR and by immunoblot demonstrating that AKRs were upregulated at both the transcriptomic and protein level. We further quantified the AKR levels in the remainder of the 10 cell lines and found that many of the more resistant lines had high expression of AKR1C2. However, not all of the resistant lines had high expression which could be because they have a separate mechanism of resistance to elraglusib. A large body of literature has found that AKR genes provide resistance to many other small molecule inhibitors either by direct metabolism or by indirectly relieving oxidative stress. Given these results, we identify aldo-keto reductases as potentially associated with elraglusib resistance, but further investigation is warranted to establish a causal link between AKR and the resistant phenotype.
Citation Format: Taylor Weiskittel, Ding Li, Lingling Han, Joseph McDermott, Benedito Caneiro, Hu Li, Daniel Billadeau, Andrew Mazar. Exploring mechanisms of resistance to elraglusib in pancreatic cancer PDX models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3857.
Abstract 4129: Preclinical assessment of GlycoConnect™ ADCs with potency-modulated derivatives of PNU-159,682
Authors: van Delft Floris L. , van Geel Remon 
Published: June 2023

Abstract
PNU-159,682 is an oxidized secondary metabolite of nemorubicin (MMDX), and substantially more potent (2100-6400-fold) than the commonly used chemotherapeutic anthracycline doxorubicin/adriamycin, but without the dose-limiting cardiotoxicity. Based on these beneficial features, PNU-159,682 is currently being clinically evaluated (phase 1) for solid tumor indications as a payload in various antibody-drug conjugates (NBE-002, SO-N102). It must be noted, however, that the HNSTD of current PNU-based ADCs in non-human primates (~1 mg/kg) may end up in a clinical dose that is sub-optimal to achieve high tumor uptake, due to putative target-mediated drug disposition in healthy tissue.
We embarked on a program to develop a set of 2nd-generation PNU-159,682 analogues with attenuated potency, to enable the generation of ADCs with a potentially improved pharmacokinetic profile. Moreover, we reasoned that the adaptation of the new PNU analogues to our proprietary best-in-class ADC technology (GlycoConnect™)1, in combination with our polar spacer technology (HydraSpace™)2 might enable PNU-based ADCs with significantly expanded therapeutic index (TI).
We here exhibit the chemical synthesis of a panel of PNU-analogues with attenuated potency and enhanced tolerability, based on specific tailoring of the aminosugar morpholino group. Homogeneous and stable GlycoConnect™/HydraSpace™ ADCs were subsequently generated and evaluated in vitro and in vivo to assess efficacy and tolerability. These studies demonstrate the potential of attenuated PNU derivatives for application in stable and site-specific ADCs with anticipated higher clinic dose and potentially improved therapeutic index.
1 Wijdeven et al., Enzymatic glycan remodeling-metal free click (GlycoConnect™) provides homogenous antibody-drug conjugates with improved stability and therapeutic index without sequence engineering. mAbs 2022, 14.
2 Verkade et al. A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody-Drug Conjugates. Antibodies 2018, 7, 12, doi:10.3390/antib7010012.
Citation Format: Floris L. van Delft, Remon van Geel. Preclinical assessment of GlycoConnect™ ADCs with potency-modulated derivatives of PNU-159,682. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4129.
Abstract 416: Phosphorylation of CDK9 transduces ALK signaling to promote resistance to PARP inhibitors via RNA Pol II activated homologous recombination repair
Authors: Chu Yu-Yi , Gao Jianjun , Yu Dihua , Hung Mien-Chie 
Published: June 2023

Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are currently the most promising drugs to induce synthetic lethality in tumor with homologous recombination (HR) deficiency. However, development of resistance to PARPi is an almost universal occurrence in tumor despite initial sensitivity. Additionally, how to identify the right patients for PARPi monotherapy or in combination with other agents remains a substantial clinical challenge. Therefore, understanding the molecular underpinnings of PARPi resistance is critical to the development of rational combinatorial treatment strategies and identification of novel biomarkers which will in turn facilitate optimization of outcomes for patients receiving PARPi. By employing a screening procedure using phospho-RTK antibody array, our study identifies phosphorylated ALK (p-ALK) expression is higher in PARPi/platinum resistant cells relative to sensitive cells. We further demonstrate that p-ALK expression in human ovarian cancer tissue is associated with resistance to PARPi and platinum-based chemotherapy. Notably, FDA approved ALK inhibitors induce an HR-deficient phenotype and sensitize PARPi/platinum-resistant tumors to PARPi in vitro and in vivo. Mechanistically, ALK contributes to PARPi resistance by tyrosine phosphorylating CDK9 at Y19, thereby increasing the protein stability and kinase activity of CDK9 which in turn stabilizes positive transcriptional elongation factor b (P-TEFb) to activate RNA pol II and turn on HR repair genes transcription. Importantly, the phosphorylated counterparts of ALK/CDK9 complex (p-ALK/p-Y19 CDK9) can serve as a biomarker to identify patients with PARPi/platinum-resistant tumors which most likely to respond to dual PARP and ALK inhibition. Together, our findings identify p-ALK/p-Y19-CDK9 mediated stabilization of P-TEFb as a critical mechanism of PARPi resistance and supports a biomarker-guided therapeutic strategy combining ALKi and PARPi to induce synthetic lethality.
Citation Format: Yu-Yi Chu, Jianjun Gao, Dihua Yu, Mien-Chie Hung. Phosphorylation of CDK9 transduces ALK signaling to promote resistance to PARP inhibitors via RNA Pol II activated homologous recombination repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 416.
Abstract 4166: Effects of cyproheptadine in eliciting natural killer cell-mediated immune response in bladder cancer
Authors: Kumari Himani , Lin Guan-Ling , Yeh Chih-Chieh , Chen Ciao-Ni , Chuang Yu-Ming , Huang Wan-Hong , Huang Wen-Long , Lin Steven , Chan Michael W. 
Published: June 2023

Abstract
Bladder cancer is one of the most common occurring cancers in urothelial carcinoma. The previous study suggested that cancer cells undergo immunoevasion due to epigenetic silencing of NKG2DL, in which NKG2D-NKG2DL interaction induced natural killer (NK) cell-mediated cytotoxicity. We hypothesized that NK-mediated cytotoxicity can be reactivated by restoring the expression of NKG2DL on tumor cells. Our previous studies demonstrated that cyproheptadine (CPH) is a novel HDAC inhibitor exhibiting antitumor activity by cell cycle arrest and apoptosis. To understand the mechanism behind, RNA-seq showed an upregulation of ULBP2, a NKG2DL, in bladder cancer cells treated with CPH. Interestingly, upregulation of ULBP2, was accompanied with the enrichment of H3K27Ac and H3K4me3 at ULBP2 promoter, was observed in cells treated with CPH. Increased NK-specific lysis was observed in CPH-treated cells co-cultured with NK-92 cells. More importantly, treatment of CPH enhanced the efficacy of immune checkpoint inhibitor in a syngeneic mice bladder cancer model. In conclusion, our results suggested that CPH may be a novel HDAC inhibitor which may elicit immune response in NK-cell dependent manner.
Citation Format: Himani Kumari, Guan-Ling Lin, Chih-Chieh Yeh, Ciao-Ni Chen, Yu-Ming Chuang, Wan-Hong Huang, Wen-Long Huang, Steven Lin, Michael W. Chan. Effects of cyproheptadine in eliciting natural killer cell-mediated immune response in bladder cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4166.