bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B173: The anti-tumor activity of CDK2 inhibition alone or in combination with other anti-cancer agents in human cancers
Authors: Chen Yaoyu , Chen Jinhong , Guo Yali , Pang Wei , Zhou Tingru , Liu Xipan , Schomer Nathan , Li Fang , Liang Jiaqi , Sheng Qing 
Published: December 2023

Abstract
Cyclin-dependent kinase 2 (CDK2) plays a crucial role in the regulation of the cell cycle and is involved in a variety of biological processes. It is responsible for phosphorylating proteins involved in G1 and S phase cell cycle progression, DNA damage response, intracellular transport, protein degradation, signal transduction, and DNA and RNA metabolism. CDK2 activity is particularly significant in cells exhibiting CCNE1 amplification or overexpression. Additionally, CDK2 activity has been linked to potential resistance against chemotherapy or targeted therapy. Several studies have indicated that abnormal activation of CDK2 may contribute to resistance against targeted therapies, such as CDK4/6 inhibitors and KRAS inhibitors. To investigate this hypothesis, we conducted experiments testing the combined effect of ARTS-021, a highly selective and potent CDK2 inhibitor, with Palbociclib, a CDK4/6 inhibitor, or AMG510, a KRAS-G12C inhibitor, in various xenograft tumor models. The combination of CDK2 inhibition with CDK4/6 inhibition demonstrated superior efficacy compared to either agent alone. This combination induced tumor regression in both Palbociclib-sensitive T47D parental cell line models and Palbociclib-resistant T47D cells overexpressing CCNE1. Similar benefits were also observed when CDK2 inhibition was combined with KRAS G12C inhibition in multiple KRAS-G12C lung cancer cell line xenografts. Importantly, these combination treatments were well tolerated. These findings suggest that CDK2 may play a crucial role in cancer cell resistance to chemotherapy or targeted therapy, and a CDK2 inhibitor may have broader applications beyond CCNE1-amplified cancers, as it can be combined with different treatment modalities.
Citation Format: Yaoyu Chen, Jinhong Chen, Yali Guo, Wei Pang, Tingru Zhou, Xipan Liu, Nathan Schomer, Fang Li, Jiaqi Liang, Qing Sheng. The anti-tumor activity of CDK2 inhibition alone or in combination with other anti-cancer agents in human cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B173.
Abstract C004: Liquid biopsy based on the lipid profiles in plasma-derived extracellular vesicles which can be utilized for breast cancer diagnosis
Authors: Kawashima Masahiro 
Published: December 2023

Abstract
Lipids are a major component of cells that can influence multiple cellular functions. Our group previously found that the breast cancer cells could dramatically change their lipid profile during their progression. Thus, we hypothesized that the lipid profile of extracellular vesicles (EVs) could be used as a biomarker for breast cancer (BC) since the lipid profiles of breast cancer cells can be reflected in that of EVs secreted from cancer cells. In the present study, we optimized a method to isolate EVs from human plasma samples that could be used for the comprehensive lipid analysis. We then explored specific lipid profiles in plasma-derived EVs that could discriminate BC and healthy individuals, tumor subtypes and stages. Plasma-derived EVs from breast cancer (n = 105), benign (n = 11), and healthy individuals (n = 43) were used for lipid analysis. The results showed that the change in proportion of the lipids in the EVs could well discriminate stages and subtypes of BC. The proportion of major phospholipids, phosphatidylethanolamines, phosphatidylserines, phosphatidylcholines (PCs) and phosphatidylinositols (PIs) showed different patterns at different stages. Importantly, PI (18:0/20:3), which we previously identified as a lipid biomarker of disease progression expressed in the primary breast cancer tissue, showed a similar trend in the plasma-derived EVs. This finding supports our initial hypothesis. Besides the phospholipids, sphingomyelins were found to be higher in stage IV. With regard to tumor subtypes, PCs and ceramides were enriched in HER2-positive subtype, while lysoPCs and polyunsaturated triglycerides were enriched in triple negative subtype. Furthermore, a BC diagnostic model consisting of three lipids was successfully established and the model showed good performance in discriminating between healthy individuals and BC in the two independent data sets (the area under the ROC curve was estimated around 0.759 to 0.804). In conclusion, profiling of lipids in plasma-derived EVs has the potential to be used as a liquid biopsy that can diagnose BC, and its stages and subtypes. Further validation and improvement in EV isolation technique would be needed to achieve sufficient performance sufficient for clinical application.
Citation Format: Masahiro Kawashima. Liquid biopsy based on the lipid profiles in plasma-derived extracellular vesicles which can be utilized for breast cancer diagnosis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C004.
Abstract C018: Prognostic worth of Nrf2/BACH1/HO-1 signals in the development of breast cancer
Authors: Barnes Precious , Saahene Roland Osei 
Published: December 2023

Abstract
Nrf2/BACH1/HO-1 signals have been implicated in the development and progression of tumors. However, there has been no comprehensive analysis of their expressions in breast cancer. This study evaluated Nrf2/BACH1/HO-1 signals expression and its clinical significance in breast cancer. 114 female breast cancer of different pathologic parameters and non-cancerous tissues were evaluated for Nrf2/BACH1/HO-1 signals expression using immunohistochemistry and western blot. The relationship connecting Nrf2/BACH1/HO-1 expression and clinicopathologic factors were assessed using the chi-square test. Nrf2 protein in cancerous tissues (74%) was significantly higher than in the non-cancerous tissues (43% p &lt; 0.002), BACH1 expression in cancerous tissues (61%) was significantly lower than that of non-cancerous tissues (20% p &lt; 0.031) and HO-1 protein expression in cancerous tissues (67%) was highly significant than in the non-cancerous tissues (17% p &lt; 0.001). The expressions of Nrf2 and HO-1 significantly correlated with tumor grade whilst BACH1 was significantly associated with tumor stage (p &lt; 0.05). Nrf2, BACH1 and HO-1 play key roles in the growth and development of breast cancer and can serve as probable biological markers for breast cancer diagnosis, prognosis as well as therapeutic targets.
Citation Format: Precious Barnes, Roland Osei Saahene. Prognostic worth of Nrf2/BACH1/HO-1 signals in the development of breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C018.
Abstract C040: Discovery and development of novel ATG13 degrading compounds that inhibit autophagy and treat Non-Small Cell Lung Cancer
Authors: Hagan Patrick M , Emami Atoosa , Austin Hilarie , Pass Ian , Limpert Allison , Sheffler Douglas , Cosford Nicholas 
Published: December 2023

Abstract
Autophagy is the process by which a cell maintains homeostasis by removing and recycling cytoplasmic debris. Autophagy provides lung cancer cells with essential nutrients for their increased proliferation and metabolism and aids in survival during anti-cancer treatments. CRISPR knockout or siRNA knockdown of the autophagy protein ATG13 inhibits autophagy and reduces viability of non-small cell lung cancer (NSCLC) cell lines. These data show that ATG13 is essential for autophagy and essential for lung cancer cell survival, making it a viable therapeutic target for cancer treatment. To identify compounds that degrade ATG13 and inhibit autophagy, we established a high-throughput screening (HTS) compatible Nano-Glo HiBiT assay where endogenous ATG13 was labeled on the C-terminus with HiBiT peptide via CRISPR. Optimization of this assay allowed for a signal to background Z’ factor of 0.71 and confirmed a positive control compound that induced up to 50% ATG13 degradation, thus indicating that this assay was suitable for compound screening. Currently, over 50,000 compounds from a variety of libraries have been screened in 1536-well format and 15 positive hits for ATG13 degradation have been identified. A series of counter-screens and secondary assays including In Cell Western Blot and Protein Thermal Shift assays will be used to confirm these hits. At the end of this testing funnel, we will have characterized novel compounds that degrade ATG13 and inhibit autophagy. These hits will provide a starting point for further chemical optimization to provide lead ATG13 degraders to evaluate in advanced preclinical proof-of concept studies of lung cancer.
Citation Format: Patrick M Hagan, Atoosa Emami, Hilarie Austin, Ian Pass, Allison Limpert, Douglas Sheffler, Nicholas Cosford. Discovery and development of novel ATG13 degrading compounds that inhibit autophagy and treat Non-Small Cell Lung Cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C040.
Abstract C043: Discovery of new drug combinations for metastatic colorectal cancer
Authors: In Eun-Jung , Tan Tao , Mouradov Dmitri , Sakthianandeswaren Anuratha , Au Amanda , Lowes Kym , Sieber Oliver 
Published: December 2023

Abstract
Colorectal cancer (CRC) is the second most common cause of cancer-related death worldwide. Despite a range of therapeutic options, drug resistance remains a significant challenge in CRC treatment. Drug combination therapy offers an opportunity to enhance therapeutic responses. There are several combination drug options that have been used for CRC patients such as FOLFOX (5-FU + Oxaliplatin) and FOLFIRI (5-FU + Irinotecan). This study aimed to discover novel drug combinations for CRC by conducting high-throughput screening of 800 pharmacologically active compounds in combination with the three main chemotherapy backbones used in CRC treatment: 5-FU, SN-38, and Oxaliplatin. Initially, we performed a primary drug screen using 11 human CRC cell lines, resulting in the identification of 72 candidate drug combinations (24 candidates x 3 backbones) exhibiting synergistic effects. Subsequently, we validated these candidates in a subset of 5 cell lines. Among them, 24 drug combinations (8 candidates x 3 backbones) were selected and further evaluated in an expanded panel of 44 CRC cell lines to determine the spectrum of drug responses and identify potential mutation, gene and protein expression biomarkers, that could predict the efficacy of the drug combinations. We investigated the molecular mechanisms underlying the synergistic effects of final 4 candidates combined with chemotherapeutic agents. Chk1 inhibitor MK-8776 showed significantly higher synergy scores in combination with SN-38 in TP53 mutated cell lines, which was further validated by in vitro apoptosis analysis and in vivo xenograft models using TP53 wildtype and knockout isogenic CRC cell lines. MK-8776 abrogated SN-38-mediated G2 cell cycle arrest, resulting in an increased cytotoxicity. These findings highlight the potential of the combination treatment involving SN-38 and MK-8776 as a promising strategy for CRC patients with TP53 mutations.
Citation Format: Eun-Jung In, Tao Tan, Dmitri Mouradov, Anuratha Sakthianandeswaren, Amanda Au, Kym Lowes, Oliver Sieber. Discovery of new drug combinations for metastatic colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C043.
Abstract C044: Discovery and characterization of novel fragment binders of the VHR phosphatase as a drug target for cervix cancer
Authors: WU Jiaqian , Baranowski Marek R , Cosford Nicholas D.P. , Tautz Lutz 
Published: December 2023

Abstract
The dual-specificity phosphatase 3 (DUSP3), also known as Vaccinia H1-related phosphatase (VHR) was reported to exhibit elevated protein level in cervix cancer cell lines compared to normal keratinocytes implicating VHR as a novel target for cervical cancer therapeutic. VHR belongs to the superfamily of protein tyrosine phosphatases (PTPs), a large class of human enzymes that is notoriously difficult to target with small molecules. Recent studies have demonstrated some PTP functions as oncogenes to promote tumor development including SHP2 (PTPN11), PTP1B (PTPN1), and VHR (DUSP3). Fragment-based drug discovery (FBDD) has merged as an effective strategy to provide potent ligands, particularly for challenging drug targets such as PTPs. In this study, we present an NMR-based discovery platform designed to discovery fragment hits that exhibit binding affinity to VHR. Our platform employed fluorine NMR, a robust ligand-observed NMR method, to screen fragment library. Subsequent validation of confirmed hits was accomplished through a series of biophysical and biochemical experiments. Structural study such as X-ray crystallography provide binding mode of action of potent molecules with the VHR protein. Using this platform, we have successfully identified several potent fragments that displayed relative selectivity for VHR. Furthermore, We discovered novel ligand binding sites distinguished from the active site. Initial structure-activity relationship (SAR) studies were also conducted, enabling us to explore a set of validated fragment hits that serve as starting point for medicinal chemistry optimization. Moreover, our fragment discovery platform is a promising strategy for discovering potent and selective fragments targeting other PTPs, thereby offering potential therapeutic options for a boarder spectrum of cancer types.
Citation Format: Jiaqian WU, Marek R Baranowski, Nicholas D.P. Cosford, Lutz Tautz. Discovery and characterization of novel fragment binders of the VHR phosphatase as a drug target for cervix cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C044.
Abstract C054: PARP16 modulates MYC expression and susceptibility of Ewing’s Sarcoma cells to PARP1 inhibition
Authors: Deng Ou , Li Xueli , Palve Vinayak C , Fang Bin , Reed Damon R , Rix Uwe 
Published: December 2023

Abstract
BACKGROUND: Ewing’s sarcoma (EWS) is a highly aggressive bone and soft tissue tumor with poor prognosis and an urgent need for novel therapies. We have identified that silencing of mono-ADP-ribosyltransferase PARP16 enhanced sensitivity of EWS cell lines to PARP1 inhibition. In this study, we explored the molecular mechanism of EWS vulnerability towards PARP16 targeting, alone and in conjunction with PARP1 inhibition, which may lead to development of PARP16-selective or dual targeting PARP1/16 inhibitors as new drugs for EWS.
METHODS: The effect of PARP16 on cell viability was analyzed using RNA interference with various siRNAs and doxycycline-inducible PARP16 shRNAs, as well as CRISPR/Cas9-mediated genomic deletion. The changes on total protein expression upon silencing of PARP16 with or without PARP1 inhibition was determined by mass spectrometry (MS). Protein interaction partners and downstream effectors of PARP16 were determined by Co-IP/MS and ADP-ribosylation proteomics, respectively.
RESULTS: Transient knockdown of PARP16 significantly reduced cell survival in EWS cell lines, particularly in combination with olaparib. Quantitative protein expression analysis by MS suggested doxycycline-induced shRNA-mediated PARP16 knockdown significantly reduced MYC protein expression in addition to PARP16 itself. Depletion of PARP16 in Cas9-expressing SK-N-MC EWS cells using different lentiviral sgRNAs further confirmed that targeting of PARP16 reduces cell survival and MYC expression, particularly in combination with PARP1 inhibition. Co-IP/MS using GFP-Trap agarose beads in mGFP/mGFP-PARP16 expressing cells suggested interaction of PARP16 with proteins that regulate post-translational modification of MYC in EWS cells. Further validation is ongoing.
CONCLUSION: Our data suggest that targeting PARP16 confers vulnerability to EWS cells either alone or in conjunction with PARP1 inhibition and that it is involved in regulation of MYC. Identification of novel PARP16 substrates and interaction partners is expected to produce molecular markers that enable the development of novel PARP16 inhibitors.
Citation Format: Ou Deng, Xueli Li, Vinayak C Palve, Bin Fang, Damon R Reed, Uwe Rix. PARP16 modulates MYC expression and susceptibility of Ewing’s Sarcoma cells to PARP1 inhibition [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C054.
Abstract C092: PRMT1 promotes pancreatic cancer development and resistance to chemotherapy
Authors: Ku Bomin , Eisenbarth David , Lim Dae-Sik 
Published: December 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer due to the lack of early diagnostic markers and effective therapeutic options. While epigenetic gene regulation is critically involved in the development of various types of cancer, its role in development of PDAC and the potential of therapeutically targeting epigenetic regulators remains underexplored. To identify a targetable epigenetic regulator, we utilized public datasets of pancreatic cancer and show that protein arginine methyl transferase 1 (PRMT1) is highly expressed in pancreatic cancer cells and that high expression of PRMT1 is a poor prognosis factor. Using loss of function studies in vitro and in vivo, we show that PRMT1 is essential for promoting cancer cell proliferation and tumorigenesis. We also demonstrate that the loss of PRMT1 relates to global changes in chromatin accessibility and gene expression pattern. Notably, we revealed that high PRMT1 negatively correlates with gemcitabine sensitivity and exhibit that pharmacological inhibition of PRMT1 in combination with gemcitabine had a greater anticancer effect on pancreatic cancer cells. Collectively, we suggest PRMT1 as a key factor of pancreatic cancer development and a potential candidate of chemotherapy.
Citation Format: Bomin Ku, David Eisenbarth, Dae-Sik Lim. PRMT1 promotes pancreatic cancer development and resistance to chemotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C092.
Abstract C093: Unlocking the potential of Metformin: Revealing its impact on colorectal cancer cells at a molecular level
Authors: Hijazi Jamila , Khoueiry Pierre , Eid Assaad , Darwiche Nadine , Nemer Georges 
Published: December 2023

Abstract
Metformin is a drug commonly used to treat type-2 diabetes, but recent studies suggest that it may also have anti-cancer effects by influencing cell cycle arrest and apoptosis. While previous studies have focused on metformin's effect on mTor, the downstream genetic pathways underlying its anti-proliferation mechanism remain unclear. Identifying these pathways may help predict patient response and allow for tailored treatment plans. This study aims to investigate the early genetic pathways involved in colon cancer using an in-vitro cell model and assess the impact of metformin on cell cycle and cancer proliferation in colon cancer cells, taking into account the p53/p21 status. Four different metformin concentrations were used on the HCT116 colon cancer cell line and its genetic modified forms. To determine cell viability and to measure cell cycle and apoptosis, MTT assay and flow cytometer were used. RNA-seq was performed on HCT116 after 24 hours of metformin treatment and pathway analysis was conducted using the Pathway Studio software. Results showed a significant decline in cell viability in response to metformin treatment, with an increase in the apoptosis phase. Transcriptomic analysis revealed that over 3,000 genes were significantly down-regulated, while 1,200 genes were up-regulated. Metformin promotes cell death and fragmentation at the SubG0 level, particularly in the case of p21 null, but p53 likely plays a primary role in driving apoptosis in colorectal cancer cells. In conclusion, metformin has potential in inhibiting proliferation and inducing apoptosis in colorectal cancer cells, affecting molecular pathways involved in the disease. However, further investigation through next-generation sequencing and molecular targeting is necessary to fully understand the disease at different levels.
Citation Format: Jamila Hijazi, Pierre Khoueiry, Assaad Eid, Nadine Darwiche, Georges Nemer. Unlocking the potential of Metformin: Revealing its impact on colorectal cancer cells at a molecular level [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C093.
Abstract C098: Targeting high-expression LGR5 by an R-spondin-based peptibody-drug conjugate is efficacious against neuroblastoma
Authors: Toh Yukimatsu 
Published: December 2023

Abstract
Neuroblastoma (NB) is a pediatric tumor that predominantly affects infants and young children, with high-risk (HR) disease being diagnosed in approximately 50% of patients at 18 months or older. LGR4-6 are membrane receptors that bind RSPO ligands, activating Wnt signaling. LGR5, specifically expressed in adult stem cells, is highly upregulated in gastrointestinal (GI) cancers. In NB, high LGR5 expression is associated with aggressive disease and poor outcomes. Knockdown of LGR5 reduces cell growth in LGR5-high NB cell lines. The R-spondin-LGR5 axis has emerged as a potential therapeutic target due to its involvement in stem cell proliferation and self-renewal, as well as its overexpression in certain cancers, including neuroblastoma. RSPO-based peptibody drug conjugate (PDC) is a promising approach to target LGR4/5 for HR-NB therapy. PDCs are designed to selectively deliver the potent Pyrrolobenzodiazepine (PBD) dimer SG3199 to LGR5 high-expressing neuroblastoma cells using a peptibody that mimics the R-spondin binding activity of LGR5 ligands. Our preclinical study showed the efficacy of DAR2 R-spondin-based PDCs, generated through microbial transglutaminase-mediated site-specific conjugation, inducing cell death both in vitro and in vivo. Furthermore, these PDCs demonstrate reduced tumor growth and improved survival in xenograft animal models of neuroblastoma derived from the SK-N-AS cell lines. Our findings suggest that targeting LGR5 with RSPO2-based PDCs may offer a promising potential for treating neuroblastoma.
Citation Format: Yukimatsu Toh. Targeting high-expression LGR5 by an R-spondin-based peptibody-drug conjugate is efficacious against neuroblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C098.