bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB259: Distinct microRNA signature and suppression of ZFP36L1 define ASCL1-positive lung adenocarcinoma
Authors: Miyashita Naoya , Enokido Takayoshi , Horie Masafumi , Suzuki Hiroshi I. , Matsuki Rei , Brunnström Hans , Micke Patrick , Nagase Takahide , Saito Akira 
Published: April 2023

Abstract
Background: Achaete-scute family bHLH transcription factor 1 (ASCL1) is a master transcription factor involved in neuroendocrine differentiation. ASCL1 is expressed in approximately 10% of lung adenocarcinomas and exerts tumor-promoting effects. However, microRNA (miRNA) profiles regulated by ASCL1 in lung adenocarcinoma cells remain unexplored.
Method: We analyzed public database of gene expression profiling (RNA-sequencing and miRNA expression data). We also studied miRNA profiles in ASCL1-positive lung adenocarcinoma cells and identified a subset of miRNAs downregulated by ASCL1 knockdown. We examined functions of genes suppressed by miRNAs in ASCL1-positive lung adenocarcinoma cell line, VMRC-LCD.
Result: We identified miRNA profiles in ASCL1-positive lung adenocarcinomas and found several miRNAs closely associated with ASCL1 expression, including miR-375, miR-95-3p/miR-95-5p, miR-124-3p, and members of the miR-17~92 family. Similar to small cell lung cancer, Yes1 associated transcriptional regulator (YAP1), a representative miR-375 target gene, is suppressed in ASCL1-positive lung adenocarcinomas. ASCL1 knockdown followed by miRNA profiling in a cell culture model further revealed that ASCL1 positively regulates miR-124-3p and members of the miR-17~92 family. Integrative transcriptomic analyses identified the RNA-binding protein zinc finger protein 36 like 1 (ZFP36L1) as a target gene of miR-124-3p, and immunohistochemical studies have demonstrated that ASCL1-positive lung adenocarcinomas are associated with low ZFP36L1 protein levels. Cell culture studies have shown that ectopic ZFP36L1 expression inhibits cell proliferation, survival, and cell cycle progression. Mechanistically, ZFP36L1 negatively regulated tumorigenic genes, including E2F transcription factor 1 (E2F1) and snail family transcriptional repressor 1 (SNAI1), indicating a tumor-suppressing action.
Conclusion: Our study revealed that suppression of ZFP36L1 via ASCL1-regulated miR-124-3p could induce tumor-promoting effects, providing evidence that ASCL1-mediated regulation of miRNAs shapes malignant features of ASCL1-positive lung adenocarcinomas.
Citation Format: Naoya Miyashita, Takayoshi Enokido, Masafumi Horie, Hiroshi I. Suzuki, Rei Matsuki, Hans Brunnström, Patrick Micke, Takahide Nagase, Akira Saito. Distinct microRNA signature and suppression of ZFP36L1 define ASCL1-positive lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB259.
Abstract LB261: The Akt-IWS1 signaling axis regulates microRNA activity
Authors: Christodoulou Niki , Hatziapostolou Maria , Montiel-Duarte Cristina , Edwards Elisabetta Verderio , Tsichlis Philip N. , Polytarchou Christos 
Published: April 2023

Abstract
MicroRNAs are small single-stranded non-coding RNAs that regulate gene expression post-transcriptionally, by targeting the 3‘-untranslated region (3’-UTR) of mRNAs. The regulation of microRNAs at the transcriptional level is well-studied, however, how their activity is regulated remains largely elusive. The family of Akt serine/threonine protein kinases, comprised of Akt1, Akt2 and Akt3, regulates important cell functions including metabolism, survival, proliferation, and migration. We have previously shown that IWS1 (Interacts with Spt6), a factor involved in mRNA splicing and nuclear export, is phosphorylated specifically by Akt1 and Akt3 at Ser720/Thr721. Here, RNA extracts from NCI-H522 lung cancer cells, transduced with shIWS1 and reconstituted with wild type (Ser720/Thr721-IWS1) or phosphorylation-deficient IWS1 (Ala720/Ala721-IWS1) were subjected to RNA and microRNA sequencing. Bioinformatic analysis suggested that microRNAs expressed at similar levels in the two cell types have a different impact on their mRNA targets. microRNA activity reporter assays and western blot analysis for microRNA targets in these cells revealed increased microRNA activity in Ala720/Ala721-IWS1-expressing cells. Our findings were verified in a second cell line, the non-transformed immortalized colonic epithelial cells NCM460. microRNA activity reporter assays, western blot analyses and cell growth assays showed that microRNA effects are enhanced in cells expressing Ala720/Ala721-IWS1. Immunoprecipitation and proximity ligation assays showed that IWS1 interacts with proteins known to be associated with RISC, and this interaction is enhanced by Akt-mediated IWS1 phosphorylation. To evaluate the dependence of IWS1/RISC interaction on IWS1 phosphorylation, we employed Akt1− / −Akt2− / −Akt3− / − immortalized mouse lung fibroblasts, transduced with myc-Akt1 or myc-Akt2 or the empty retroviral vector. Immunoprecipitation experiments in these cells, before and after treatment with IGF1, revealed that IWS1 interacts with the RISC components specifically in Akt1-expressing cells upon Akt1 activation by IGF1. Overall, our data demonstrate that IWS1 interacts with RISC in a conserved Akt1-dependent manner and regulates the activity of microRNAs with significant effects on cellular properties.
Citation Format: Niki Christodoulou, Maria Hatziapostolou, Cristina Montiel-Duarte, Elisabetta Verderio Edwards, Philip N. Tsichlis, Christos Polytarchou. The Akt-IWS1 signaling axis regulates microRNA activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB261.
Abstract LB267: Nitric oxide suppression by secreted frizzled-related protein 2 drives retinoblastoma
Authors: Jayabal Panneerselvam , Ma Xiuye , Bondra Kathryn M. , Chen Yidong , Houghton Peter J. , Shiio Yuzuru 
Published: April 2023

Abstract
Retinoblastoma is a cancer of the infant retina primarily driven by the loss of the Rb tumor suppressor gene, which is undruggable. Here, we identified an autocrine signaling, mediated by secreted frizzled-related protein 2 (SFRP2), which suppresses nitric oxide and enables retinoblastoma growth. SFRP2 silencing resulted in rapid production of nitric oxide, leading to p53-dependent growth arrest of retinoblastoma cells. We show that coxsackievirus and adenovirus receptor (CXADR) is the cell surface receptor for SFRP2 in retinoblastoma cells, that CXADR functions as a "dependence receptor," transmitting a growth inhibitory signal in the absence of SFRP2, and that the balance between SFRP2 and CXADR determines nitric oxide production. Accordingly, high SFRP2 RNA expression correlates with high-risk histopathologic features in retinoblastoma. Targeting SFRP2 signaling by SFRP2-binding peptides or by a pharmacological inhibitor rapidly induced nitric oxide and profoundly inhibited retinoblastoma growth in orthotopic xenograft models. These results reveal a cytokine signaling pathway that regulates nitric oxide production and retinoblastoma cell proliferation, and is amenable to therapeutic intervention.
Citation Format: Panneerselvam Jayabal, Xiuye Ma, Kathryn M. Bondra, Yidong Chen, Peter J. Houghton, Yuzuru Shiio. Nitric oxide suppression by secreted frizzled-related protein 2 drives retinoblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB267.
Abstract LB290: Intracranial, intratumoral drug-releasing microdevices in patients with high grade gliomas may identify biomarkers of drug activity and predict tumor response to systemic chemotherapy
Authors: Jonas Oliver , Peruzzi Pier Paolo 
Published: April 2023

Abstract
The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle for the advancement of therapy for high grade gliomas (HGG), and particularly glioblastoma (GBM), one of the few cancers whose prognosis has not improved over the past several decades. With this pilot clinical trial we provide first in human evidence that drug-releasing intratumoral microdevices (IMD) can be safely and effectively used to obtain patient-specific, high throughput molecular and histopathological data to inform selection of drugs based on their observed antitumor effect in situ. The use of IMD is seamlessly integrated in standard surgical practice during tumor resection. None of the six enrolled patients experienced adverse events related to the IMD, and the retrieved tissue was usable for downstream analysis for 11 out of 12 retrieved specimens. Molecular analysis of the specimens provided, for the first time in humans, preliminary evidence of the robustness of the readout, with strong correlation between IMD analysis and clinic-radiological responses to temozolomide. We also identified novel transcriptomic and metabolomic biomarkers of response and resistance to a range of targeted and cytotoxic agents used on the IMD. From an investigational aspect, the amount of information obtained with IMD allows unprecedented characterization of tissue effects of any drugs of interest, within the physiological context of the intact tumor.
Citation Format: Oliver Jonas, Pier Paolo Peruzzi. Intracranial, intratumoral drug-releasing microdevices in patients with high grade gliomas may identify biomarkers of drug activity and predict tumor response to systemic chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB290.
Abstract LB314: Epigenetic regulator Menin-MLL1 maintains cancer stem cells and promotes neuroblastoma growth
Authors: Chilamakuri Rameswari , Agarwal Saurabh 
Published: April 2023

Abstract
Epigenetic regulators MLL1 and Menin plays important role in cancer progression, metastasis, and relapse. Apart from the oncogenic translocations in leukemias, MLL1 forms a COMPASS complex with Menin and other binding partners to act as an H3K4 methyltransferase. Inhibition of COMPASS complex by blocking the Menin-MLL1 interaction is reported to be effective in different cancers. In this study, we found that a specific Menin-MLL1 inhibitor, MI-503 inhibits neuroblastoma cancer stem cells (NB CSCs; CD114+ cells) to inhibit overall neuroblastoma (NB) growth in both in vitro and in vivo NB tumor models. NB is an extracranial solid pediatric cancer that accounts for about 15% of all pediatric cancer-related deaths, with the long-term survival of relapsed NB patients being less than 10%. We found that MI-503 significantly and in a dose-dependent manner inhibits cell proliferation in nine NB cell lines tested including MYCN amplified (NGP, LAN-5, IMR-32), MYCN non-amplified (SH-SY5Y, SK-N-AS, CHLA-255), and primary patient-derived NB cell lines (COG-N-415, COG-N-269, COG-N-357), in contrast to control fibroblasts. Additionally, MI-503 significantly inhibits NB 3D spheroidal tumor growth and live cell counts compared to control treatments. Further, flow cytometry analysis revealed that MI-503 specifically induces apoptosis and blocks cell cycle progression at the S phase in the NB CSCs (CD114+ cells) in comparison to non-CSCs (CD114- cells) that leads to significant inhibition of overall NB CSC levels in different NB cell lines. By inhibiting the COMPASS complex, MI-503 significantly inhibits H3K4me3 levels as determined by the histone immunoblot assays. This leads to the inhibition of multiple cancer stemness-related genes expression such as OCT4, Nanog, HOXA, AF9, and MEIS1. Further, we determined the efficacy of MI-503 in NB xenograft mouse models and found that MI-503 significantly inhibits overall NB tumor growth (12.3 fold; p&lt;0.001) and tumor burden (10.2 fold; p&lt;0.01) by directly inhibiting tumor NB CSCs (p&lt;0.01). We have not observed any drug-treatment-related toxicities or gender bias. Overall, our study highlights a novel epigenetic-based therapeutic approach for high-risk NB and underlines the role of epigenetic regulators in maintaining the NB CSCs and NB growth. In our future efforts, we will develop concomitant therapeutic approaches by combining MI-503 with current chemotherapies to target both NB CSCs and bulk tumor cells. This will lead to the development of effective, targeted, and clinically tractable therapies for NB patients.
Citation Format: Rameswari Chilamakuri, Saurabh Agarwal. Epigenetic regulator Menin-MLL1 maintains cancer stem cells and promotes neuroblastoma growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB314.
Abstract LB334: Assessment of the potential of graphene oxide as an antigen delivery platform for cancer immunotherapy
Authors: Chattrakarn Sorayut , Mallett Grace , Parker Helen , Lozano Neus , Kostarelos Kostas , MacDonald Andrew S. 
Published: April 2023

Abstract
Introduction: Novel cancer immunotherapies are urgently needed due to a lack of definitive treatments, as well as toxicity and cost of current therapies. 2-dimensional carbon graphene oxide (GO) nanomaterials provide a large surface area, high protein loading efficiency and good biocompatibility, as well as being inexpensive. Given these properties, we investigated whether and how GO could be an effective antigen delivery system for targeted cancer immunotherapies.
Methods: GO was non-covalently complexed with the model antigen ovalbumin peptide (OVA257-264) and the immunostimulant and toll-like receptor 3 agonist polyinosinic:polycytidylic acid (Poly (I:C)). We examined innate and adaptive immune responses after subcutaneous injection of GO complexes by histology and flow cytometry.
Results: We found that GO without Poly (I:C) had a very limited immunogenic potential. In contrast, GO complexed with Poly (I:C) significantly increased immune cell recruitment to the injection site, and enhanced activation and migration of dendritic cell subsets (cDC1s and cDC2s) in skin-draining lymph nodes 24 hours after injection. Additionally, we found that GO complexed with Poly (I:C) dramatically enhanced OVA-specific CD8+ T cell expansion and cytotoxic potential in both spleen and skin-draining lymph nodes 7 days after subcutaneous complex administration to mice which had previously been injected intravenously with traceable, OVA-specific (OT-I) CD8+ T cells.
Conclusion: Our results have revealed the immunomodulatory potential of GO when complexed with Poly (I:C) by attracting immune cells to the injection site and augmenting antigen-specific cytotoxic responses both locally and systemically. Ongoing work is determining the anti-tumor potential of this approach, and potential mechanisms by which GO complexes might limit tumor progression.
Citation Format: Sorayut Chattrakarn, Grace Mallett, Helen Parker, Neus Lozano, Kostas Kostarelos, Andrew S. MacDonald. Assessment of the potential of graphene oxide as an antigen delivery platform for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB334.
Abstract LB337: Inhibition of the E3 ligase CBL-B enhances the effector function and proliferation of natural killer cells
Authors: Qi Yilin , Kuai Jun , Bi Yingzhi , Greco David , Jaeger Samira , Carson Ken , Danaee Hadi , Reilly Timothy , Harriman Geraldine , Wang Fang 
Published: April 2023

Abstract
The E3 ubiquitin ligase CBL-B is a master regulator of effector T cells through its downstream regulation of T-cell receptor and co-stimulatory stimulation, but it has also been shown to play a negative feedback role in NK cells. CBL-B depletion enhances the production of IFNγ and the cytotoxicity of activated NK cells. Similar to the effect of depleting CD8 T cells in mice, depletion of NK cells abolishes the tumor growth delay observed in Cbl-b-/- mice. With emerging data supporting the potential role of exogenous NK cells in anti-tumor immunity, inhibition of CBL-B represents a promising approach to enhance both adaptive and innate immunity for cancer immunotherapy. Using one of our small molecules, allosteric CBL-B inhibitors, HOT-A, we demonstrated that CBL-B inhibition enhanced NK activation, IFNγ production and granzyme B secretion in response to the various stimulation conditions, including cytokines (such as IL-15 and IL12 + IL-18) and stimulatory receptors (such as NKp30 and NKG2D + CD244). NK cell proliferation was also enhanced in the presence of HOT-A. Single cell analysis further suggested that HOT-A increased NK polyfunctional cytokine expression during IL-12 + IL-18 activation. In a coculture system of NK cells and K562 target cells, HOT-A dose-dependently promoted primary human NK cell activation, cytokine production and cytotoxicity in the K562 cells. In the in vivo CT-26 tumor model, granzyme B+ NK cells in the TIL were significantly increased in the HOT-A treated tumor bearing mice and NK function gene signature was also increased by Nanostring analysis, suggesting an enhanced NK function in the tumor microenvironment. Taken together, the pre-clinical data presented here demonstrate that our CBL-B inhibitor enhances NK cell function in vitro and in vivo, suggesting that its enhancement of anti-tumor immunity may be driven through both effector T cell and NK cell-driven biology.
Citation Format: Yilin Qi, Jun Kuai, Yingzhi Bi, David Greco, Samira Jaeger, Ken Carson, Hadi Danaee, Timothy Reilly, Geraldine Harriman, Fang Wang. Inhibition of the E3 ligase CBL-B enhances the effector function and proliferation of natural killer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB337.
Abstract LB339: PARP inhibition reprograms CD8 T cells, enhancing their function and generation of prolonged memory, leading to greater anti-tumor immune response
Authors: Traboulsi Wael , Kundu Subhadip , Gaur Pankaj , Ramlaoui Zainab , Sarhan Dareen , Shobaki Nour , Lee Jacob , Jafarzadeh Nazli , Barry Simon T. , Valge-Archer Viia E. , Verma Vivek , Gupta Seema , Khleif Samir N. 
Published: April 2023

Abstract
Olaparib is the most widely studied third-generation PARP inhibitor (PARPi) in clinical practice with a significant clinical outcome in BRCA deficient tumors such as breast and ovarian cancers. However, innate and adaptive resistance in patients with DNA damage repair (DDR) gene mutations were reported after treatment with PARPi, highlighting the potential implication of other compartments such as the role of immune cells in the mechanism of resistance. Importantly, PARPi is shown to have an immune-modulatory capacity within the tumor microenvironment (TME) by activating the STING pathway and increasing interferon gamma (INF-gamma) and chemokine secretion and hence increasing the recruitment and function of CD8 T cells. In addition, PARPi is shown to affect other cells within the TME such as, macrophages, myeloid-derived suppressor cells (MDSCs) and cancer associated fibroblasts (CAFs), promoting either an immune enhancement or immune suppressor milieu that could indirectly affect CD8 T cell function. However, little is known about the direct effect of PARPi on CD8 T cells. In this study using two cold tumor models, we show that PARPi controls the tumor growth and increases survival in tumor-bearing mice. This effect is due to the enhancement of number and cytotoxicity of antigen-specific CD8 T cells and the maintenance of memory population within the TME. In vitro study shows that PARPi activates the SIRT-1/FOXO1 pathway, leading to the modification of gene expression related to memory and fatty acid oxidation (FAO) metabolism in CD8 T cells. As a result, a unique subpopulation of superior central memory cells with high recall responses and anti-tumor effects are generated after PARPi treatment. Interestingly this unique subpopulation was also generated after PARPi in human cells. Together, our findings highlight the direct effect of PARP inhibition on CD8 T cells and its ability to modulate and reprogram CD8 T cells within the TME, leading to a greater anti-tumor immune response.
Citation Format: Wael Traboulsi, Subhadip Kundu, Pankaj Gaur, Zainab Ramlaoui, Dareen Sarhan, Nour Shobaki, Jacob Lee, Nazli Jafarzadeh, Simon T. Barry, Viia E. Valge-Archer, Vivek Verma, Seema Gupta, Samir N. Khleif. PARP inhibition reprograms CD8 T cells, enhancing their function and generation of prolonged memory, leading to greater anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB339.