bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3798: lncRNA LIMp27 promotes p53-defective cancer pathogenesis
Authors: La Ting , Chen Song , Zhao Xiao Hong , Zhang Yuan Yuan , Feng Yu Chen , Zhang Xu Dong , Jin Lei 
Published: June 2023

Abstract
Inactivation of p53 occurs in approximately 50% of human cancers, where p53-mediated p21 activation is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, we show that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and promotes proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA, leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild-type and p53-mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53-mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53-mutant but not wild-type p53 COAD patients. These results uncover a lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers.
Citation Format: Ting La, Song Chen, Xiao Hong Zhao, Yuan Yuan Zhang, Yu Chen Feng, Xu Dong Zhang, Lei Jin. lncRNA LIMp27 promotes p53-defective cancer pathogenesis. [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 3798.
Abstract 3802: miR-199a and miR-199b stimulate the progression of diffuse gastric cancer through direct targeting of Frizzled-6
Authors: Park Jihye , Lee Sieun , Hong Soon Auck , Ko Yoon Ho , Ahn Young-Ho 
Published: June 2023

Abstract
There is no pathological difference between early and advanced diffuse gastric cancer (DGC), particularly in the gastric mucosa. In this study, we tried to identify microRNAs (miRNAs) as diagnostic biomarkers that can differentiate between early and advanced DGC. miRNA expression profiling was performed by NanoString nCounter method in human DGC tumors. miR-199a and miR-199b (miR-199a/b) were particularly up-regulated in advanced DGC compared with early DGC. Ectopic expression of miR-199a/b accelerated growth, viability, and motility of SNU601, human GC cells, and expedited tumor development in a mouse xenograft model. miR-199a/b also inhibited cell adhesion. Through 3’-UTR luciferase assay, Frizzled-6 (FZD6) was confirmed as a direct target of miR-199a/b. siRNA-mediated depletion of FZD6 increased cell growth and motility and addback of FZD6 restored cell growth, motility, and adhesion. To explore their clinicopathological roles in patients, miR-199a/b levels were measured by in situ hybridization in human DGC tumor sections. High miR-199a/b was correlated with advanced lymphovascular invasion, advanced T stages, and lymph node metastasis. Collectively, miR-199a/b promote the progression of DGC via targeting FZD6. These results imply that miR-199a/b can be used as diagnostic and prognostic biomarkers of DGC.
Citation Format: Jihye Park, Sieun Lee, Soon Auck Hong, Yoon Ho Ko, Young-Ho Ahn. miR-199a and miR-199b stimulate the progression of diffuse gastric cancer through direct targeting of Frizzled-6. [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 3802.
Abstract 3859: Alterations in hormone receptors regulome following response to kinase inhibitors in lethal prostate cancer
Authors: Adelaiye-Ogala Remi M. , Gulla Surendra , Bard Jonathan E. , VanderWeele David J. , Kelly Kathleen 
Published: June 2023

Abstract
The androgen receptor (AR) signaling axis is critical for prostate cancer (PCa) pathogenesis and all subsequent phases of disease progression. Although initial success with androgen deprivation therapy and AR-targeted agents such as enzalutamide or abiraterone, most patients inevitably relapse due to therapeutic resistance. Previous studies have shown that genomic AR is unchanged despite resistance to AR antagonists, and its gene expression is unaltered. Therapeutic resistance is broadly classified into two categories; restoration of AR activity and tumor progression despite AR blockade. Indeed, others have noted an extensive reprogramming of the AR cistrome in clinical and preclinical specimens, where a shift in canonical to non-canonical AR cistrome is associated with an increase in Gleason grade. In previous studies, we observed increases in known AR target genes following exposure to kinase inhibitors which was marked by a decrease in tumor growth. We hypothesized that restoration of canonical AR cistrome can be mediated through kinase inhibition and is associated with re-sensitization to AR-targeted therapy. In addition, we treated cell lines and patient-derived xenograft models of advanced prostate cancer with kinase signaling pathway inhibitors, AR signaling inhibitors, or a combination of both for 24 hours (in vitro) or five days (in vivo). In addition, samples were collected and processed for RNA-seq and ChIP-seq. Our transcriptomic analysis showed enrichment of previously published non-canonical AR target genes in cells resistant to AR-targeted agents. When resistant cells were exposed to kinase inhibitors, we observed an enrichment of canonical AR target genes. In addition, we identified unique AR-enriched peaks at active sites associated with resistance. Through GSEA of gene annotated peaks, we found unique regulatory transcription factor targets, some of which are associated with cell proliferation and differentiation and may play a functional role in AR cistrome adaptation to resistance and survival. Overall, our data suggest that AR transcription adapts to the therapeutic resistance of AR antagonists via the enrichment of non-canonical AR cistrome. Furthermore, restoration of canonical AR cistrome is achieved following kinase signaling pathway inhibition and is associated with re-sensitization to AR-targeted therapy.
Citation Format: Remi M. Adelaiye-Ogala, Surendra Gulla, Jonathan E. Bard, David J. VanderWeele, Kathleen Kelly. Alterations in hormone receptors regulome following response to kinase inhibitors in lethal prostate 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 3859.
Abstract 4128: AJ17 potentiates agonist CD40 antibody efficacy and attenuates agonist CD40 induced PD-L1 expression and associated toxicity in murine tumor models
Authors: Gaur Vidit , Barnwal Anjali , Ateeq Bushra , Bhattacharyya Jayanta 
Published: June 2023

Abstract
Agonist CD40 antibody (αCD40) has shown excellent anti-tumor efficacy in both pre and early clinical studies. However, in clinics, αCD40 has failed to prove its potential as αCD40 is associated with dose-limiting toxicity due to cytokine release syndrome (CRS), grade 3 to 4 hematological and liver toxicities. In addition, αCD40 induces immune checkpoint proteins (PD-L1, CTLA-4) which makes the tumor microenvironment (TME) immunosuppressive. In this context, this study investigates the therapeutic efficacy of a novel combination of αCD40 and AJ17, a small molecule inhibitor of receptor tyrosine kinase. Combination treatment showed a significant delay in the tumor growth and improved overall survival in mice bearing B16-F10 melanoma and 4T1 orthotopic tumor by increasing the population of CD8+ T cells and lowering the expression of PD-L1, Foxp3+, and arginase in both tumor and spleen. Most interestingly, AJ17 lowered the in vivo toxicity associated with αCD40 monotherapy by lowering the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and IL-6 in serum. In conclusion, this combination can be further explored in clinics to improve the in vivo anti-tumor efficacy of αCD40 while lowering the associated toxicity.
Citation Format: Vidit Gaur, Anjali Barnwal, Bushra Ateeq, Jayanta Bhattacharyya. AJ17 potentiates agonist CD40 antibody efficacy and attenuates agonist CD40 induced PD-L1 expression and associated toxicity in murine tumor 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 4128.
Abstract 4132: Effect of mechanical cues on T cell killing of cancer cells
Authors: Dada Hannah , Do Kun , Cartagena-Rivera Alexander , Altan-Bonnet Grégoire 
Published: June 2023

Abstract
Cancer immunotherapies have focused on strategies to strengthen immune cell activation and effector function. These treatment strategies enhance the effector function of immune cells, particularly cytotoxic T cells (CTL), driving tumor eradication. Methods to improve the killing mechanisms of CTLs are not well studied and largely focused on assessing/strengthening the antigenic responses of T cells. We hypothesize that the mechanical landscape of CTL-tumor interactions can also drastically impact CTL cytotoxicity. By altering the physical context for T cell recognition of tumors, we measured cytotoxicity changes and subsequently used these changes in killing capacities to train and generate a quantitative parametrization of T cell killing. CTLs utilize cytokine expression to kill and shape the inflammatory milieu. Taking advantage of a robotic platform that enables the automatic collection of cytokines, we assembled datasets of T cell attacks of tumor cells grown on substrates with varying stiffness levels. The stiffness levels were altered using polyacrylamide (PAA) gels and ranged from 0.2kPa to approximately 113 kPa. Preliminary results from two different models (i.e., mouse and human TCR-transgenic T cells) suggest that there exists an optimal stiffness value for maximal response by T cells. These results suggest that CTLs utilize biophysical cues in addition to molecular cues (antigen) to properly elicit an immune response—modeling and fine-tuning these mechanical cues can be a novel and effective approach to improving cancer immunotherapies.
Citation Format: Hannah Dada, Kun Do, Alexander Cartagena-Rivera, Grégoire Altan-Bonnet. Effect of mechanical cues on T cell killing of cancer cells. [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 4132.
Abstract 4167: Translational control of T cell exhaustion in melanoma, perspectives in therapeutics
Authors: Muhammadnejad Samad , Biswas Biswendu , Guemiri Ramdane , Benannoune Naima , Lavigne Jérémy , Quidville Virginie , Scoazec Jean-Yves , Vagner Stephan , Robert Caroline 
Published: June 2023

Abstract
Background: Eukaryotic initiation factor 4F (eIF4F) complex plays a pivotal role in the selective translational control of protein expression in cancer. We previously showed that the inhibition of eIF4F had both a direct antitumor effect that could overcome resistance to BRAF inhibition in BRAFV600 melanoma and an indirect immune-mediated antitumor effect via PD-L1 down regulation resulting from STAT1 decreased translation. We now explore further the translational control of immune checkpoints (ICs) on T cell and its link with lymphocyte exhaustion.
Methods: We performed polysome profiling (PP) on peripheral blood-derived activated and resting T lymphocytes as well as tumor-infiltrating lymphocytes (TILs) isolated from melanoma specimens in the presence or absence of silvestrol as an eIF4A (the helicase component of eIF4F) inhibitor. We studied the expression of ICs and exhaustion-associated transcription factors on lymphocytes at the various stages of exhaustion. The tumor cell lysing capacity of PBMC was evaluated with and without silvestrol. We also assessed the effect of silvestrol on tumor microenvironment in the BP syngeneic melanoma tumor model.
Results: Silvestrol decreased the translation of multiple ICs in activated CD4+ and CD8+ T cells, including TOX, NFAT1, NFAT2, LAG3, and TIM3 (the two latter being also transcriptionally regulated). FACS analysis confirmed the dose-dependent decrease of protein expression of exhaustion-associated transcription factors TOX, NFATc1, TCF1 and T-bet in activated lymphocytes. This effect was more prominent in more exhausted T cells. Silvestrol decreased T cell proliferation but, in co-culture experiments, it increased immune cell killing of melanoma cells by T-lymphocytes. In the BP murine model, the antitumor effect of silvestrol was associated with denser T cell infiltration and less exhausted TILs than control tumors.
Conclusion: Our findings demonstrate the role of eIF4F in the orchestrated regulation of functionally related proteins involved in T cell exhaustion. They highlight the drugability of eIF4A for the cancer treatment and suggest that eIF4A inhibitors could be useful with IC inhibitors in combination or sequentially.
Citation Format: Samad Muhammadnejad, Biswendu Biswas, Ramdane Guemiri, Naima Benannoune, Jérémy Lavigne, Virginie Quidville, Jean-Yves Scoazec, Stephan Vagner, Caroline Robert. Translational control of T cell exhaustion in melanoma, perspectives in therapeutics. [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 4167.
Abstract 4420: Carbohydrate-CD11b engagement enhances differentiation of tumor-associated myeloid cells in immunotherapy of solid cancers
Authors: Zhang Mei 
Published: June 2023

Abstract
Background: Methods to perturb tumor-associated myeloid cell function are being actively pursued to overcome these challenges in immunotherapy and search for a cure. CD11b is a potential therapeutic target to modulate suppressive myeloid derived cells and induce tumor-reactive T-cell responses. However, CD11b can bind to multiple carbohydrate ligands that trigger a variety of myeloid cell functions like adhesion, migration, and even phagocytosis and proliferation. This has created a major challenge to understand the molecular basis by which CD11b converts differences in receptor-ligand binding into subsequent immune signaling responses, and to use this knowledge for therapeutic development.
Methods: This study investigated a previously reported carbohydrate ligand, BG34-200, that showed anti-tumor effect through modulating CD11b+ cells. Applying modern approaches of peptide microarray, multi-parameter FACS analysis, cellular/molecular immunological technology, advanced microscopic imaging, and transgenic mouse models of solid cancers, we studied the BG34-200-CD11b carbohydrate-protein engagement and immunological changes it triggered in the context of solid cancers including osteosarcoma, melanoma and pancreatic cancer.
Results: Our results show that BG34-200 can mediate direct, specific, multi-site and multivalent binding to integrin CD11b to trigger cellular differentiation in a suppressive tumor-associated myeloid cell subset. In melanoma, osteosarcoma, and pancreatic cancer, we detected this rare myeloid cell subset in blood, which displayed an inflammatory monocyte phenotype and exhibited immunosuppressive behavior. BG34-200-CD11b engagement could induce differentiation of these tumor-associated inflammatory monocytes into dendritic cells by inducing phagocytosis that effectively trigger F-actin cytoskeletal rearrangement and intrinsic ICAM-1 clustering important for antigen presentation and effector T cell stimulation.
Conclusions: Our findings improve understanding of molecular basis by which CD11b converts difference in carbohydrate ligands into subsequent immune signaling responses, may lead to development of safe and novel therapies modulating myeloid derived cell function for immunotherapy of solid cancers.
Citation Format: Mei Zhang. Carbohydrate-CD11b engagement enhances differentiation of tumor-associated myeloid cells in immunotherapy of solid cancers. [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 4420.
Abstract 4425: GlycoConnect™ immune cell engagers (GC™-ICEs). A non-genetic approach to targeted IL-15 immunotherapy
Authors: van Geel Remon , van Delft Floris 
Published: June 2023

Abstract
Engagement of T cell or NK cells to harness a patient’s immune system is a promising approach in immuno-oncology. An immunocytokine, i.e. a tumor-targeting antibody (fragment) genetically fused to an immunostimulatory cytokine, is specifically designed for this purpose. Fusion antibody-IL-15 immunocytokines, based on a variety of molecular architectures, are currently finding their way to the clinic with promising results.
Here we demonstrate how GlycoConnect™, a site-specific conjugation technology anchoring on the native antibody glycan, can be applied for attachment of IL-15 without prior antibody engineering. Moreover, the immunostimulatory activity of these GlycoConnect™ immune cell engagers (GC™-ICEs) can be modulated by tailoring linker design and payload stoichiometry. In particular, we demonstrate how a protease-cleavable mAb-IL-15 conjugate can be used to prevent systemic activation of the immune system, leading to a significantly improved therapeutic index in rodent models. In vitro and in vivo studies will be presented to showcase the biological activity of these GC™-ICEs in comparison to conventional immunocytokines obtained via genetic engineering.
Citation Format: Remon van Geel, Floris van Delft. GlycoConnect™ immune cell engagers (GC™-ICEs). A non-genetic approach to targeted IL-15 immunotherapy. [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 4425.
Abstract 4432: A highly differentiated A2AR inhibitor for potential use in cancer therapy
Authors: Venkateshappa Chandregowda , Narayanan Kishore , Nair Rashmi , AB Aravind , Putta Ramakishore VP , Nagaraj Jwala , Goyal Megha , Ahuja Vijay Kamal , Dhudashiya Amith A , DS Samiulla , Daginakatte Girish , Antony Thomas , Nellore Kavitha , Samajdar Susanta , Ramachandra Murali 
Published: June 2023

Abstract
As a potent immunosuppressor adenosine is essential for maintaining tissue homeostasis and preventing an overzealous immune response during inflammation and infection. However, adenosine generated within the tumor microenvironment by the action of ectonucleotides hinders the immune reaction towards cancer cells by signaling through adenosine receptors such as high affinity A2AR expressed on immune cells. Tumors evade the immune response by usurping pathways that negatively regulate normal immune responses. Resistance to inhibition of immune checkpoint targets arises because of an upregulation in the expression of the CD39-CD73 axis and the resulting increase in production of adenosine in the tumor microenvironment. Inhibition of either adenosine generation or signaling by inhibition of A2AR along with other immune activation strategies have been shown to be effective therapeutic approaches.
In view of this, we sought to discover and develop novel small molecule inhibitors that dually target A2AR and an immuno-suppressive ligand expressed in the tumor microenvironment. Aurigene’s dual inhibitors exhibit potent inhibition of both A2AR and an immuno-suppressive target of relevance in respective biochemical assays. Potent biochemical activity translated into rescue of chemokines and IL-2 in human PBMCs. Lead compounds exhibited desirable drug-like properties and excellent pharmacokinetic exposure in rodents. In a syngeneic tumor model, lead compounds demonstrated significant tumor growth inhibition. Anti-tumor efficacy correlated well with tumor drug levels and modulation of pharmacodynamic markers. In summary, we have identified first-in-class dual inhibitors with good drug like properties, which showed significant antitumor efficacy. Evaluation of these lead compounds in additional tumor models and in vivo toxicity studies will be presented.
Citation Format: Chandregowda Venkateshappa, Kishore Narayanan, Rashmi Nair, Aravind AB, Ramakishore VP Putta, Jwala Nagaraj, Megha Goyal, Vijay Kamal Ahuja, Amith A Dhudashiya, Samiulla DS, Girish Daginakatte, Thomas Antony, Kavitha Nellore, Susanta Samajdar, Murali Ramachandra. A highly differentiated A2AR inhibitor for potential use in cancer therapy. [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 4432.
Abstract 4434: A PD-1-targeted, receptor-masked IL-2 immunocytokine with maintained potential to engage endogenous IL-2Ra drives selective stimulation of PD-1+ T cells and robust anti-tumor efficacy
Authors: Wu Jiaxi , Bloch Nicolin , Chang Aaron , Bhavsar Ramandeep , Patel Supriya , Wang Qingqing , Ahmed Hassan Shakil , Garg Vidur , Amatulli Michael , Yan Yuetian , Wang Shunhai , Dudgeon Drew , Ramos Willy , Krueger Pamela , Rafique Ashique , Huang Tammy , Ullman Erica , Hermann Aynur , Olson William , Lin John , Smith Eric , Zhang Tong 
Published: June 2023

Abstract
Interleukin-2 (IL-2) is a key cytokine for T cell proliferation, differentiation, and effector function. Recombinant IL-2 has been used for the treatment of metastatic melanoma and renal cell carcinoma, and induced complete, durable tumor regression in some patients. ​However, its broader use in cancer immunotherapy has been limited by severe toxicity. A new generation of IL-2 therapies with decreased binding to IL-2 receptor α-chain (IL-2Rα) is being developed to reduce toxicity and Tregs expansion yet with limited clinical success so far. Here, we show that the ability to engage IL-2Rα is critical for maximal anti-tumor activity of a systemic IL-2 therapy, and an alternative approach to circumvent systemic toxicity is to deliver IL-2 specifically to tumor-reactive T cells. We developed REGN10597, a PD-1-targeted, receptor-masked IL-2 immunocytokine with attenuated systemic IL-2 activity but maintained capacity to engage endogenous IL-2Rα on PD-1+ T cells. Compared to WT IL-2, receptor masked IL-2 shows improved PK and diminished systemic toxicity in mice. REGN10597 shows PD1-targeting-dependent IL-2 activity in vitro and drives selective expansion of tumor-infiltrating PD-1+ CD8 T cells with vigorous effector functions in vivo. In preclinical syngeneic tumor models in PD-1 humanized mice, REGN10597 demonstrates robust anti-tumor efficacy both as a single agent and in combination with PD-1 or PD-L1 blocking antibodies. These findings highlight the therapeutic potential of REGN10597 as a novel targeted and receptor masked WT IL-2 therapy, supporting its clinical development for the treatment of cancer.
Citation Format: Jiaxi Wu, Nicolin Bloch, Aaron Chang, Ramandeep Bhavsar, Supriya Patel, Qingqing Wang, Hassan Shakil Ahmed, Vidur Garg, Michael Amatulli, Yuetian Yan, Shunhai Wang, Drew Dudgeon, Willy Ramos, Pamela Krueger, Ashique Rafique, Tammy Huang, Erica Ullman, Aynur Hermann, William Olson, John Lin, Eric Smith, Tong Zhang. A PD-1-targeted, receptor-masked IL-2 immunocytokine with maintained potential to engage endogenous IL-2Ra drives selective stimulation of PD-1+ T cells and robust anti-tumor efficacy. [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 4434.