bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5606: GlycoConnect™ immune cell engagers (GC™-ICEs). A non-genetic approach to targeted IL-15 immunotherapy
Authors: van Geel Remon , van Delft Floris 
Published: June 2022

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. The molecular architecture of the resulting immune cell engagers (ICEs) can be readily tailored to 2:2 or 2:1 ratio (anti-TAA:IL-15) to mitigate cytokine release syndrome. Moreover, we show how immunostimulatory activity can be regulated via linker design, either by tailoring of IL-15-antibody spacing or by generation of a conditionally active IL-15 format. Structural and functional studies will be presented to corroborate the architecture of these GC™-ICEs and in vitro and in vivo activity in a syngeneic mouse model.
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 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5606.
Abstract 5615: YH008, a PD-1-CD40 bispecific antibody, inhibits tumor growth in vivo through PD-1-dependent activation of CD40 signaling
Authors: Liu Baihong , Yang Hao , Hui Li , Yang Benny 
Published: June 2022

Abstract
PD-1/PD-L1 inhibition immunotherapy is very popular in cancer treatment and has become one of the most pursued therapeutic strategies in the field. Combination treatment using anti-PD-1/PD-L1 agents with other immunomodulators brings additional benefits, such as preventing refractory effects towards PD-1/PD-L1 antibodies, and better inhibitory effects on tumor growth. Biocytogen developed YH008, a tetravalent anti PD-1/CD40 Fc-silenced IgG1 bispecific antibody (BsAb) that agonizes CD40 in a PD-1-dependent manner. Previously, YH008 demonstrated dose-dependent inhibitory efficacy against B16F10 engrafted tumors in PD-1/CD40 double humanized mice (established by Biocytogen: B-hPD1/CD40). Interestingly, in humanized CD40 mice that do not express human PD-1 expression, YH008 did not show tumor inhibition activity against the MC38 engrafted tumor. This observation indicates that YH008 activates the CD40 pathway in a PD-1 dependent manner. When compared with an anti-PD-L1/CD40 BsAb, YH008 showed superior tumor growth inhibition (TGI) against MC38 engrafted tumors in a triple humanized PD-1/PD-L1/CD40 mouse model (B-hPD-1/hPD-L1/hCD40). YH008 was observed to promote the proliferation and activation of dendritic cells, as well as increase CD8+/Treg ratio in B16F10 tumor-infiltrating lymphocytes (TILs). Furthermore, YH008 showed a superior liver toxicity profile compared to a selicrelumab analog. At a high dose of 100mg/kg, YH008 did not elevate liver enzymes in the blood of B-hPD1/hCD40 mice. Similarly, no significant adverse events were observed in a cynomolgus dose-escalation study. YH008 is currently in pre-clinical development with anticipated IND application in 2022.
Citation Format: Baihong Liu, Hao Yang, Li Hui, Benny Yang. YH008, a PD-1-CD40 bispecific antibody, inhibits tumor growth in vivo through PD-1-dependent activation of CD40 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5615.
Abstract 5617: A novel genetically modified oncolytic vaccinia virus selectively replicates in tumors to activate an inflammatory TME and induce tumor regression
Authors: Goenaga Anne-Laure , Wang I-Ming , Clay Bryan S. , Lang Susanne , Wang Annabel , Weady Peter , Pillai Smitha P.S. , Ram Sripad , Mitchell Leah , Eisenbraun Michael , Binder Joseph , Avidal Liliana Maruri , Kirn David , Hollingsworth Robert , Lees Clare 
Published: June 2022

Abstract
Oncolytic viruses (OVs) have been widely investigated as cancer immunotherapy platforms and are represented by a diverse group of DNA and RNA viruses. We are currently investigating a genetically modified oncolytic vaccinia virus as a best-in-class tumor-selective investigational product for the treatment of solid tumors. Specifically, the viral thymidine kinase (TK) has been deleted to enhance safety by greatly limiting replication in healthy tissues while taking advantage of relatively higher endogenous TK levels in tumors. In addition to tumor-selective replication, the oncolytic vaccinia virus encodes an IL-2 variant (IL-2v) protein, which diminishes preferential activation of immunosuppressive Treg cells while preserving activation of CD8+ and NK cells and avoiding toxicities associated with wild type IL-2. Using a murine surrogate of the oncolytic vaccinia virus, we assessed preclinical efficacy in multiple murine syngeneic tumor models demonstrating selective tumor localized replication resulting in tumor growth inhibition. Consistent with tumor selective virus replication, viral copy number and IL-2v transgene levels were increased and had prolonged expression in the tumors compared to the periphery. Intratumoral colocalization of the virus and IL-2v was confirmed by IHC and ISH, respectively. Tumor growth inhibition was associated with increases in tumor infiltrating CD8 and NK effector cells. Additionally, efficacy of the mouse surrogate virus was associated with systemic increases in circulating total CD8 and NK cells as well as pSTAT5+ CD8 and NK cells in the blood. In summary, we have demonstrated that arming a TK-deficient oncolytic vaccinia virus with an IL-2v transgene can effectively couple short-term destruction of tumor cells through oncolysis with the activation of anti-tumor immune response in the tumor microenvironment. These data support the study of this therapy in Phase 1 clinical trials.
Citation Format: Anne-Laure Goenaga, I-Ming Wang, Bryan S. Clay, Susanne Lang, Annabel Wang, Peter Weady, Smitha P.S. Pillai, Sripad Ram, Leah Mitchell, Michael Eisenbraun, Joseph Binder, Liliana Maruri Avidal, David Kirn, Robert Hollingsworth, Clare Lees. A novel genetically modified oncolytic vaccinia virus selectively replicates in tumors to activate an inflammatory TME and induce tumor regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5617.
Abstract 5642: Discovery of SCR-8079, a novel and selective CDK2/4/6 inhibitor overcomes the resistance to CDK4/6 inhibition and demonstrates broad anti-tumor activities in breast cancers
Authors: Zhou Feng , Yang Guimei , Tang Feng , Zhang Yan , Yang Wenqing , Xue Liting , Chen Ping , Tang Renhong 
Published: June 2022

Abstract
The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival and overall survival in HR positive and HER2-negative breast cancer in combination either with letrozole or fulvestrant. However, resistance to the CDK4/6 inhibition inevitably develops. Preclinical models and clinical transcriptome specimen analysis disclosed that abnormal activation of Cyclin E/CDK2 due to CCNE gene amplification was one of the major reasons to CDK4/6 inhibition resistance. And inhibition of CDK2 either by gene knockdown of CCNE or by pharmaceutic approach rescued the sensitivity of resistant tumor cells to CDK4/6 inhibition. To overcome the resistance, a novel and selective CDK2/4/6 inhibitor, SCR-8079 was developed. In biochemical assay, SCR-8079 was demonstrated high potency on inhibiting CDK2/4/6 with IC50 of 3 nM, 1 nM and 2 nM, respectively. And SCR-8079 showed good selectivity over CDK1/9 isoforms (&gt;60 selectivity folds). SCR-8079 demonstrated closed inhibitory activities both on CDK4/6 sensitive and resistant lines. In MCF-7, a breast cancer cell line sensitive to PAL, SCR-8079 potently inhibited Rb phosphorylation (IC50, 53 nM) and cell proliferation (IC50, 28 nM). Meanwhile, SCR-8079 showed high potency on inhibiting on the growth of OVCAR3, an ovarian cancer cell line with elevated CDK2 activation and resistance to PAL. SCR-8079 inhibited Rb phosphorylation (IC50, 41 nM) and cell proliferation (IC50, 21 nM). In order to further mimic CDK4/6 resistance, a PAL resistant line (MCF-7R) was generated via induction of MCF-7 by gradient increased PAL. SCR-8079 potently inhibited MCF-7R cells growth (IC50, 3 nM) but PAL didn’t (IC50 &gt;1 µM). Moreover, SCR-8079 showed high potency on growth inhibition in a broad of breast cancer cell lines, including HR-positive, Her2-positive and triple negative lines. SCR-8079 displayed good oral bioavailability in multiple pre-clinical species and robust anti-tumor activities both in OVCAR3 and MCF7 xenograft models. In summary, SCR-8079 is a selective CDK2/4/6 inhibitor, which overcomes the CCNE-mediated resistance to CDK4/6 inhibition. Broad anti-tumor activity suggests SCR-8079 central role in breast cancer treatment.
Citation Format: Feng Zhou, Guimei Yang, Feng Tang, Yan Zhang, Wenqing Yang, Liting Xue, Ping Chen, Renhong Tang. Discovery of SCR-8079, a novel and selective CDK2/4/6 inhibitor overcomes the resistance to CDK4/6 inhibition and demonstrates broad anti-tumor activities in breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5642.
Abstract 5644: Activation of p53 in prolonged prometaphase
Authors: Anderson Megan , Levesque Aime A. 
Published: June 2022

Abstract
The tumor suppressor p53 plays a critical role in protecting cells from aberrant divisions in the face of DNA damage, and while its role in DNA damage checkpoints have been extensively studied, its role in the mitotic checkpoint is less well characterized. The mitotic checkpoint prevents completion of mitosis until chromosomes have made bipolar kinetochore attachments to microtubules. Previous studies have shown that cells that experience a prolonged prometaphase(&gt;1.5 h) following treatment with microtubule destabilizing drugs will arrest in G1 following eventual exit from mitosis. Given its role in DNA damage checkpoints, p53 appears to be a likely candidate for involvement in this arrest. The goal of the current study is to investigate the role of p53 in this G1 arrest following prolonged prometaphase. Three cells lines were utilized:MCF10A, MCF10A/αp53 which overexpressed shRNA to p53, and MCF10A/OD which overexpresses the p53 oligomerization domain. Cells were treated with 9 μM RO-3306 for 18 h to synchronize cells at the G2/M transition. The RO-3306 was then removed and cells were treated with a microtubule destabilizing drug, nocodazole, at a concentration of 0.08 μM for 1.5 or 2.5 h to cause prometaphase arrest. The cells were then washed to remove nocodazole, and the cells were harvested at various time points and analyzed via flow cytometry and Western blot. Flow cytometry analysis in in all three cell lines showed an accumulation of cells in G1 at 12 hours in for both treatment times (1.5 and 2.5 h), with subsequent increases in sub-G1 populations by 24 hours. Western blot analysis revealed activation of p53 by phosphorylation of ser20 and activation of p21 in the MCF10A and MCF10A/OD, but not in the MCF10A/αp53 for both treatment times. Taken together, these results suggest that activation of p53 alone is not sufficient to elicit the G1 arrest, as the MCF10A/αp53 cells arrested in G1 despite the absence of p53 protein.
Citation Format: Megan Anderson, Aime A. Levesque. Activation of p53 in prolonged prometaphase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5644.
Abstract 5647: PTEN loss is associated with elevation of cell cycle signature in human glioblastoma transcriptome
Authors: Liu Tian , Or Penelope Mei-Yu , Wong Chi-Wai , Cheung Stanley Kwok-Kuen , Wang Yubing , Wang Yiwei , Ho Wayne Lut-Heng , Chan Andrew M. 
Published: June 2022

Abstract
Glioblastoma is the most lethal type of brain cancer with universally poor prognosis. Despite advanced treatment, the cancer recurs frequently. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene whose mutations have been found to be one of the most frequent events in GBM. PTEN acts as a negative regulator of the phosphoinositide 3-kinase (PI3K) pathway. GBM transcriptome data from The Cancer Genome Atlas (TCGA) revealed a positive enrichment of cell cycle and PI3K pathway. Moreover, weighted gene co-expression network analysis (WGCNA) on TCGA GBMLGG cohort revealed a cell cycle-related module (‘cell-cycle’ module), which was shown to be positively correlated with PTEN mutation status. This ‘cell-cycle’ module also showed a positive correlation with glioma aggressiveness.We then utilized a nestin-cre;Pten-fl/fl mouse model to investigate the consequences of PTEN loss that may be involved in GBM. Based on our preliminary data, transcriptomic profiling of primary astrocytes derived from Pten knockout mice revealed an overlapping enrichment of cell cycle related pathways with human GBM. Four cell cycle genes, RCC1, RCC2, NEK2, and CHK2, were validated to be significantly upregulated in Pten-null astrocytes by qRT-PCR. Regulator of chromatin condensation 1 (RCC1) and Regulator of chromatin condensation 2 (RCC2) both belong to the RCC1 family. Accumulating evidence demonstrated that both RCC1 and RCC2 are involved in tumorigenesis of multiple cancers and cell cycle progression. By siRNA inhibition, we demonstrated that silencing of either RCC1 or RCC2 in glioblastoma cell lines suppresses GBM cell growth. Moreover, we found that RCC2 is essential for both G1-S and G2-M transition. Additionally, RCC2 silencing and a PI3K inhibitor LY294002 inhibit glioblastoma cell viability in a synergistic manner. In summary, PTEN deficiency leads to the alteration of cell cycle progression, which may promote tumorigenesis of glioblastoma. RCC1 and RCC2 have been demonstrated to be potential targets regulated by PTEN and affects cell viability. RCC2 was shown to be a key regulator of cell cycle progression. To further explore the RCC1 and RCC2 roles, we will find the potential downstream target of RCC1 and RCC2 and its potential therapeutic effect in vivo. Funding: This work is supported by a General Research Fund grant (#14113519) from the University Grants Committee of Hong Kong.
Citation Format: Tian Liu, Penelope Mei-Yu Or, Chi-Wai Wong, Stanley Kwok-Kuen Cheung, Yubing Wang, Yiwei Wang, Wayne Lut-Heng Ho, Andrew M. Chan. PTEN loss is associated with elevation of cell cycle signature in human glioblastoma transcriptome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5647.
Abstract 5651: Characterization the mechanistic role of the proapoptotic receptor XEDAR and its therapeutic potential in TNBC
Authors: Lin Chih-Yi , Yu Chung-Jen , Wang Chih-Yang , Liu Kai-Jun , Lai Jiun-I 
Published: June 2022

Abstract
Breast cancer is one of the most common cancers and a leading cause of death in women worldwide. Among these subtypes, triple negative breast cancer (TNBC) has the worst prognosis, with a dismal outcome especially in metastatic disease. Metastatic TNBC treated with conventional chemotherapy has a median overall survival (OS) of ~ 18 months. The addition of checkpoint inhibitors extend the median OS to more than 2 years in PD-L1 positive patients, but ultimately most patients succumb to the disease. Currently TNBC still poses as a clinical unmet need, and further understanding of the cancer biology may shed light in improving therapeutics against this deadly disease. Apoptosis, or programmed cell death, is a crucial function for cell homeostasis. The ability to evade or circumvent apoptosis is an important hallmark of cancer cells. X-linked ectodermal dysplasia receptor (XEDAR), a cell membrane receptor that binds to the pro-apoptotic ligand EDA-A2, is a member of the TNF receptor family and has been reported to be downregulated in breast cancer cells. XEDAR has been shown to induce downstream apoptosis by binding to EDA-A2, by a mechanism similar to extrinsic apoptotic pathway. By interrogating clinical databases and cross comparison using TCGA, CCLE, and other breast cancer datasets, we discover XEDAR as substantially downregulated in TNBC. Transcription profile analysis between different XEDAR expressing profiles uncovered novel pathways that could be potentially targeted for TNBC treatment. RNA-seq profiling in XEDAR overexpressing TNBC cells were cross compared with aforementioned discovered pathways. Vulnerable pathways including angiogenesis were discovered as possible therapeutic targets. As a proof of concept, we combined angiogenesis inhibitors with EDA-A2 ligand treatment in XEDAR overexpression TNBC cells and observed synergistic effects for combination. Our study uncover XEDAR as a potential target for further treatment in TNBC, which remains to be further validated in preclinical and clinical studies.
Citation Format: Chih-Yi Lin, Chung-Jen Yu, Chih-Yang Wang, Kai-Jun Liu, Jiun-I Lai. Characterization the mechanistic role of the proapoptotic receptor XEDAR and its therapeutic potential in TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5651.
Abstract 5655: Brefeldin A mediates integrated stress response and in combination with Navitoclax induces apoptosis in prostate cancer cells
Authors: Ohtsu Akira , Arai Seiji , Sawada Tatsuhiro , Miyazawa Yoshiyuki , Sekine Yoshitaka , Suzuki Kazuhiro 
Published: June 2022

Abstract
Introduction and Objectives: Metastatic castration resistance prostate cancer is a lethal disease. New AR-axis-targeted agent are available, but they will eventually become ineffective. Brefeldin A, an endoplasmic reticulum (ER) protein transport inhibitor, has been shown to cause ER stress. Navitoclax is a BH3 mimetic drug that targets anti-apoptotic proteins (BCL2 and BCLXL) and induces apoptosis in some solid tumors. Here, we investigated the efficacy of Brefeldin A combined with navitoclax on prostate cancer cells.
Materials and Methods: We assessed the effect of combination therapy for prostate cancer cells using MTS assay, qRT-PCR, luciferase assay, and western blot.
Results: Combination therapy with Brefeldin A and navitoclax synergistically decreased cell viability in prostate cancer cells. Mechanistically, Brefeldin A induced MCL1 degradation and, combined with navitoclax, drove apoptosis. Further, integrated stress response was at least in part involved in Brefeldin A-induced MCL1 degradation.
Conclusions: Combination therapy with Brefeldin A and navitoclax shows synergistic anti-tumor effects in prostate cancer cells. These results suggest that Brefeldin A might still be effective in prostate cancer if used with navitoclax.
Citation Format: Akira Ohtsu, Seiji Arai, Tatsuhiro Sawada, Yoshiyuki Miyazawa, Yoshitaka Sekine, Kazuhiro Suzuki. Brefeldin A mediates integrated stress response and in combination with Navitoclax induces apoptosis in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5655.
Abstract 5670: TRPM8 ion channel role in prostate cancer: Actions as a rapid testosterone signaling receptor
Authors: Velpula Kiran , Shishido Katherine , Bayen Susovon , Asuthkar Swapna 
Published: June 2022

Abstract
The transient receptor potential melastatin 8 (TRPM8) is well-known for its role in cold sensation in somatosensory neurons. TRPM8 was first identified as a prostate epithelial cell-specific gene, however, its role was unclear due to the absence of its endogenous agonist. We are the first to discover the novel role of TRPM8 as a rapid testosterone receptor. The TRPM8 mRNA is highly expressed in prostate cancer (PC) and is lost during the transition to androgen-independent prostate cancer (AIPC). Although emerging studies have shed light regarding androgen regulation of TRPM8 mRNA expression, we found that the addition of androgen receptor (AR) on the lipid bilayers inhibited testosterone-TRPM8 induced Ca2+ uptake. Additionally, our IHC revealed increased internalization of the TRPM8 protein in high-grade PC and that TRPM8 protein was targeted for proteasomal degradation in PC. We observed that inhibition of AR and UBA1 promoted the stabilization of TRPM8 on the plasma membrane, triggering Ca2+-induced cytotoxicity and apoptosis in both androgen dependent and androgen independent PC cells. Furthermore, in line with previous studies, we showed that testosterone-induced TRPM8 activation on the planar lipid bilayers also required phosphatidylinositol 4,5-bisphosphate (PIP2). Loss of PTEN is associated with tumor recurrence and the transition to AIPC. Thus, PTEN loss mediated PIP2 deficiency may be an important mechanism of TRPM8 desensitization in PC. Therefore, we propose that the rescue of TRPM8 activity on the plasma membrane combined with AR targeting may be an effective therapy for PC.
Citation Format: Kiran Velpula, Katherine Shishido, Susovon Bayen, Swapna Asuthkar. TRPM8 ion channel role in prostate cancer: Actions as a rapid testosterone signaling receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5670.
Abstract 5677: βTrCP1 is a substrate of extracellular signal-regulated kinase 2
Authors: Lee Ga-Eun , Lee Cheol-Jung , An Hyun-Jung , Chen Weidong , Jeung Dohyun , Choi Youngwon , Cho Yong-Yeon 
Published: June 2022

Abstract
ERK1 and ERK2, downstream kinases of MEKs, transduce activation signals to a large number of cytosolic and nuclear substrates specifically involved in cellular signaling of transcription factors responsible for particular cellular processes. Thus, dysregulation of the cascade frequently leads to the development of diverse diseases, including &gt; 90% of all cancers. However, although signaling mechanisms of ERKs by phosphorylation have well-known, long-term protein amount regulation has not clearly elucidated. In this study, we proved that βTrCP1 is a novel binding protein of ERK2. The interaction between ERK2 and βTrCP1 was occurred via F-box and linker domains spanning aa 192-265. Amino acid alignment of βTrCP1 showed that there are two independent putative sites for ERK docking. The mutations of the putative docking sites from lysine to alanine abrogated the interaction between ERK2 and βTrCP1. Importantly, ERK activation induced by epidermal growth factor induces βTrCP1 phosphorylation, resulting in facilitation of βTrCP1 half-life. Although the phosphorylation sites of βTrCP1 by ERK2 has not been identified, βTrCP1 tumor suppressive activity may be regulated via ERK2 when the cells are stimulated by tumor promoters such as EGF.
Citation Format: Ga-Eun Lee, Cheol-Jung Lee, Hyun-Jung An, Weidong Chen, Dohyun Jeung, Youngwon Choi, Yong-Yeon Cho. βTrCP1 is a substrate of extracellular signal-regulated kinase 2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5677.