bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5643: YK-2168, a potent and selective small molecule CDK9 inhibitor
Authors: Ding Charles Z. , Liu Yingchun , Zhou Wang 
Published: June 2022

Abstract
Objective: Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. Specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Emerging evidence indicates that selective CDK9 inhibition may provide a therapeutic benefit against certain cancers. We disclose here for the first time a novel CDK9 inhibitor YK-2168 a clinical candidate and its preclinical results.
Method: The biochemical activities of YK-2168 for CDK9, CDK1 and CDK2 were measured by literature methods (Tinggui, 2014). The in vitro anti-proliferative activity was evaluated on selected leukemia cell line MV4-11, lymphoma cell line Karpas422 and gastric carcinoma cell line SNU16. The in vivo antitumor activity of YK-2168 was evaluated in cell-derived xenograft (CDX) models of Leukemia (MV4-11) and gastric carcinoma (SNU16), YK-2168 was administered by intravenous (IV) injection. PK/PD was assessed by western blot analysis of pS2-RNA Pol ll CTD expression and cleaved caspase 3 level in the treated tumor tissues.
Result: YK-2168 displayed potent selective inhibitory biochemical activity for CDK9 (IC50 : 7.5 nM), but that of CDK1 and CDK2 were modest (IC50 : 466.4 and 361.1 nM), indicative of good selectivity for CDK9. It also showed good anti-proliferative activities in tumor cell lines of different types, MV4-11 potency IC50 of 53.4 nM, Karpas422 potency IC50 of 91.1 nM, and SNU16 potency IC50 of 88.3 nM. YK-2168 showed in vivo antitumor activity in a MV4-11 CDX model with TGI =80 % @10 mpk QW (IV with 4 doses), compared with the same dose of BAY1251152 (TGI =65 % @10 mpk, QW). YK-2168 also showed good regressive antitumor activity in vivo in a SNU16 CDX model with TGI =115 % @10 mpk QW (while BAY1251152 totally inhibited growth with TGI =100%). Western blot analysis of the tumor samples showed that YK-2168 can also inhibit the expression of CDK9 downstream signal proteins and induced apoptosis in a dose-dependent manner.
Conclusion: We have discovered a potent and selective small molecule CDK9 inhibitor YK-2168, which showed potent CDK9 inhibition and strong antitumor activity in both in vitro and in vivo preclinical tumor models. These results together with GLP safety results are considered highly promising and warrant moving the compound forward to clinical investigation. In fact, YK-2168 was granted phase I clinical trials in both US and China.
Citation Format: Charles Z. Ding, Yingchun Liu, Wang Zhou. YK-2168, a potent and selective small molecule CDK9 inhibitor [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 5643.
Abstract 5665: LILRB2 mediates the immune escape of breast tumor cells by degrading HLA-A
Authors: Zhao Hui , jiang zhiyuan , wang zhiyu , chang yujie , ruan shunyi 
Published: June 2022

Abstract
Breast cancer has now risen to the number one cancer in the world, posing a great threat to human health. LILRB2 (leukocyte immunoglobulinlike receptor B2) is an important immunosuppressive receptor protein, which is mainly expressed in myeloid cells, such as macrophages and dendritic cells. At present, we have found clinically that patients with breast cancer bone and bone marrow metastasis have higher expression of LILRB2. In our research, we used Western blotting, real-time fluorescent quantitative Polymerase Chain Reaction (RT-PCR), flow cytometry, and other experimental methods to explore the expression and function of LILRB2 in breast cancer cells. In our research, we found that LILRB2does increase expression in breast cancer cells, therefore, we want to explore the role of LILRB2 in breast cancer cells. we find that LILRB2 will accelerate the proliferation of tumor cells and increase their migration ability. We tested the related signal pathways and found that LILRB2 can promote the enhancement of the NF-Kb signal pathway. Further, we have done related LILRB2 correlation analysis and found that LILRB2 can reduce human leukocyte antigen-A (HLA-A) Expression. Next, we tested the changes in the level of major histocompatibility complex (MHC-1) related mRNA and found that its mRNA expression increased, which was inconsistent with the decrease in its protein level we observed. Therefore, we used the proteasome inhibitor MG132 for treatment, and the results showed after adding MG132, the decrease in HLA-A expression caused by overexpression of LILRB2 was restored. Next, we knocked down the breast cancer cell line of membrane-associated ring finger (MARCH9). After we knocked down MARCH9, transfection of LILRB2 did not increase the ubiquitination of HLA-A. Therefore we show that LILRB2 can mediate the post-translational modification of HLA-A via MARCH9, which in turn mediates the degradation ofHLA-A. In conclusion, our research shows that LILRB2 maybe a candidate of clinical target for the treatment of breast cancer, preventing possible bone and bone marrow metastasis from breast cancer.
Citation Format: Hui Zhao, zhiyuan jiang, zhiyu wang, yujie chang, shunyi ruan. LILRB2 mediates the immune escape of breast tumor cells by degrading HLA-A [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 5665.
Abstract 5691: Preclinical evaluation of TFX05-01, a selective AKR1C3- targeted prodrug for solid tumor
Authors: Ding Charles Z , Cai Zhe , Sha Wei 
Published: June 2022

Abstract
Objective: Aldo-keto reductase 1C3 (AKR1C3), is a member of the aldo-keto reductase superfamily, catalyzing the NADP(H)-dependent stereospecific reduction of various aldehydes and ketones. AKR1C3 is overexpressed in a variety of cancer cells, including hepatocellular carcinoma (HCC), castration-resistant prostate cancer (CRPC), and leukemia cells. This study is to investigate the in vitro and in vivo antitumor activity of TFX05-01, a selective AKR1C3-activated anticancer prodrug, in preclinical models of AKR1C3 overexpressing cells. The studies provide solid foundation for nomination of TFX05-01 for clinical trials.
Method: Enzymatic activation of TFX05-01 was investigated in vitro using recombinant human AKR1C3. Cellular anti-proliferative activity was evaluated with a range of AKR1C3 overexpressed or low expressed cell lines. The in vivo antitumor activity was evaluated in various CDX mouse models with high expression of AKR1C3, including HepG2 and castration-resistant prostate VCaP, as well as PDX leukemia models
Result: TFX05-01 is a prodrug which selectively releases a DNA alkylating agent (TFX05-01A) upon exposure to AKR1C3. TFX05-01 inhibited cell proliferation in several AKR1C3 overexpressed HCC cell lines with an IC50 ≤ 100 nM. In contrast, TFX05-01 showed much lower anti-proliferative activity in low or no AKR1C3 expressed cells with an IC50 value greater than 1 μM. The cytotoxic potency of TFX05-01 in cancer cells correlates with the level of AKR1C3 expression, and the cytotoxic activity of TFX05-01 was inhibited when used in combination with a specific AKR1C3 inhibitor (IC50: 0.7 nM without inhibitor vs 188 nM with inhibitor in SNU-878 cells). TFX05-01 showed antitumor efficacy in AKR1C3 highly expressed HepG2 subcutaneously implanted xenograft model (TGI = 97% @2 mpk, QW, 3 doses IV). Concomitant PK studies showed that the concentration of active metabolites (TFX05-01A) in tumor was significantly higher (15~50 times) than that in plasma, which correlates with the selective release of the active DNA alkylating agent upon exposure to AKR1C3 in tumor tissues.
Conclusion: TFX05-01 is a novel selective AKR1C3-activated prodrug, which is different from traditional non-selective alkylating agents for cancer therapy. Preclinical studies have shown profound in vivo efficacy of TFX05-01 in AKR1C3 overexpressed mouse tumor xenograft models without marked toxicity. TFX05-01 represents a novel treatment option for AKR1C3 expressing solid cancers. Preclinical GLP safety evaluations were promising and TFX05-01 was nominated for clinical trials.
Citation Format: Charles Z Ding, Zhe Cai, Wei Sha. Preclinical evaluation of TFX05-01, a selective AKR1C3- targeted prodrug for solid tumor [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 5691.
Abstract 5701: HDAC inhibition decreases YAP1 expression but parodoxically activates TEAD transcription by the AP-1 pathway in breast cancer
Authors: Lin Ting-Yi , Tseng Yi-Ru , Wang Naikuan , Chao Ta-Chung , Liu Chun-Yu , Tseng Ling-Ming , Lai Jiun-I 
Published: June 2022

Abstract
The Hippo pathway is an evolutionally conserved pathway that is crucial in numerous aspects of cell biology, including contact inhibition, cell density, and others. Hippo pathway is well reported to be dysregulated in multiple cancer types and plays important oncogenic roles in human cancers. In mammalian cells, YAP is regulated by a phosphorylated cascade mediated by the kinases MST1/2 and LATS1/2, known as the canonical Hippo pathway. These upstream kinases phosphorylate YAP/TAZ and leads to its cytosolic degradation. Perturbation of the Hippo pathway leads to YAP intranuclear translocation and downstream activation of target genes, inducing proliferative signals and thus initiating oncogenesis. Novel mechanism linking the hippo pathway to various oncogenic mechanisms are rapidly discovered and reported, further establishing the significance of this pathway and its role in cancer biology. Breast cancer is the top leading cause of cancer in women and poses a significant morbidity and economic burden on society. Hormone positive (defined as positivity of the estrogen receptor ER and/or the progesterone receptor PR) breast cancer composes 70% of breast cancer. Endocrine therapy, chemotherapy, and more recently, CDK4/6 inhibitors and PI3K inhibitors are currently approved strategies towards breast cancer. Histone deacetylase (HDAC) inhibitors have been FDA approved for several hematological cancers, and recently have shown inconsistent results in clinical trials for breast cancer. In our study, we demonstrate and characterize a link between HDAC inhibition and the Hippo pathway. We discover that HDAC inhibitors suppress YAP expression both transcriptionally and translationally. Paradoxically, we demonstrate that although YAP is downregulated, TEAD mediated transcription of downstream Hippo targets is activated. Mechanistically, HDAC inhibition leads to upregulation of the AP-1 transcriptional machinery that cooperates with TEAD to facilitate transcription. By RNA-seq, chromatin studies and CRISPR knockout studies, we confirm that HDAC inhibition have the ability to activate downstream of Hippo pathway, suggesting a possible mechanism for breast cancer resistance towards HDAC inhibitor. Co-targeting HDAC inhibition and AP-1 results in enhanced efficacy of HDAC inhibitors and may be a promising approach for development towards breast cancer.
Citation Format: Ting-Yi Lin, Yi-Ru Tseng, Naikuan Wang, Ta-Chung Chao, Chun-Yu Liu, Ling-Ming Tseng, Jiun-I Lai. HDAC inhibition decreases YAP1 expression but parodoxically activates TEAD transcription by the AP-1 pathway in breast cancer [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 5701.
Abstract 5709: Transcriptional circuitry of NKX2-1 and SOX1 defines a previously unrecognized lineage subtype of small cell lung cancer
Authors: kong ranran , Patel Ayushi S. , Sato Takashi , Yoo Seungyeul , Sinha Abhilasha , Tian Yang , Jiang Feng , Powell Charles A. , Snyder Eric , Jiang Jiantao , Li Shaomin , Watanabe Hideo 
Published: June 2022

Abstract
Introduction: The current molecular classification of small cell lung cancer (SCLC) based on expression of four lineage transcription factors, SCLC-A (ASCL1), SCLC-N (NEUROD1), SCLC-P (POU2F3), and SCLC-Y (YAP1) still leaves its major subtype SCLC-A as a large heterogeneous group, necessitating more precise characterization of lineage subclasses.
Experimental procedure: To refine the current SCLC classification and to identify specific lineage features of the SCLC subtypes, we performed unsupervised hierarchical clustering of H3K27ac profiles on transcriptional regulators from 25 SCLC cell lines and determined the epigenomic features for each cluster. Functional significance of the transcriptional lineage regulators for the identified cluster was evaluated by cell growth, apoptosis and xenograft using CRISPR-Cas9-mediated deletion. The specific cistromic profiles by ChIP-seq and its functional transcriptional partners using co-immunoprecipitation followed by mass spectrometry were determined to reveal their functional output in the identified subtype. Rb1fl/flTrp53fl/fl and Rb1fl/flTrp53fl/flNkx2-1fl/fl genetic engineered mouse model were generated to explore the function of Nkx2-1 in tumor initiation and differentiation. H3K27ac profiles were further analyzed to reveal 6 human SCLC specimen and 20 mice tumors epigenomic landscapes.
Summary: We identified previously uncharacterized epigenomic sub-clusters of the major SCLC-A subtype, named SCLC-A1 and SCLC-A2. SCLC-A1 was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-A1, where it maintains neural lineage rather than pulmonary epithelial identity. We further found maintenance of this neural identity in SCLC-A1 is mediated by collaborative transcriptional activity with another neuronal transcriptional factor SOX1. ?
Conclusions: We comprehensively describe an additional epigenomic heterogeneity of the major SCLC-A subtype, and define SCLC-A1 subtype by the core regulatory circuitry representing NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain a neuronal linage state.
Citation Format: ranran kong, Ayushi S. Patel, Takashi Sato, Seungyeul Yoo, Abhilasha Sinha, Yang Tian, Feng Jiang, Charles A. Powell, Eric Snyder, Jiantao Jiang, Shaomin Li, Hideo Watanabe. Transcriptional circuitry of NKX2-1 and SOX1 defines a previously unrecognized lineage subtype of small cell lung cancer [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 5709.
Abstract 5712: Dietary polyphenols as BRD7 and 9 inhibitors for cancer interception
Authors: Kapoor Sabeeta , Dashwood Roderick H. 
Published: June 2022

Abstract
Introduction Epigenetic mechanisms play an important role in the initiation and advancement of colorectal cancer (CRC) and other malignancies due, in part, to deregulated bromodomain (BRD) functions1,2. We examined compounds from natural sources as BRD7/9 inhibitors, seeking lead candidates outside of the widely studied bromodomain and extraterminal (BET) family3.
Methods As reported4,5, docking in silico involved STRAP and AutoDock Vina, ligand-protein interactions employed PDBePISA and LPC/CSU, and BROMOscan®-Bromodomain arrays were used to screen for BRD7/9 interacting compounds. BRD7/9 inhibitors also were assessed by isothermal titration calorimetry (ITC) and by anticancer activities in human colon cancer cells.
Results Docking in silico identified several dietary polyphenols as potential BRD7/9 inhibitors, with binding energies ≤ -8.0 kcal/mol. BROMOscan® and ITC experiments prioritized aspalathin, orientin, epigallocatechin-3-gallate, quercetin and equol for further investigation. Treatment with selected polyphenols mimicked BRD7/9 siRNA-mediated knockdown in reducing colon cancer cell viability and inhibiting colony formation, leading to DNA damage and apoptosis induction. Normal colonic epithelial cells were unaffected by the treatments, signifying cancer-specific targeting. These findings suggest that dietary polyphenols can recognize and target BRD7/9 proteins for potential cancer interception.
Acknowledgements Research supported in part by NCI grant CA122959, the John S. Dunn Foundation, and a Chancellor's Research Initiative.1)Jung G et al., Nat Rev Gastroenterol Hepatol 2020;17:111-130. 2)Fujisawa T, Filippakopoulos P. Nat Rev Mol Cell Biol 2017;18:246-262.3)Damiani E et al., J Cancer Prev 2020;25:189-203. 4)Rajendran P et al., Cancer Res 2019;79:918-927. 5)Kapoor S et al., Cancers (Basel) 2021;13:1438.
Citation Format: Sabeeta Kapoor, Roderick H. Dashwood. Dietary polyphenols as BRD7 and 9 inhibitors for cancer interception [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 5712.
Abstract 5723: JDP2 interacts with p53 and enhances p53 transactivation and stability
Authors: Yang Wei-Hsiung , Price Kasey , Cardoso Leticia , Yang William , Wang Chiung-Min , Yang Richard 
Published: June 2022

Abstract
USAAP-1 protein mainly consists of proteins belonging to c-Jun, c-Fos, activating transcription factor (ATF), and Jun dimerization protein (JDP) family. In addition to AP-1 site, JDP2 also binds to cAMP responsive element (CRE) site in numerous cis-elements of the target genes. JDP2 has been shown to be involved in cancer development and cell-cycle regulation, suppression of adipocyte differentiation, and controlling bone homeostasis and antibacterial immunity. ATF3 and JDP2 share high similarity in C-terminal domains with identities of 65%. Previous studies have demonstrated that ATF3 can bind to p53 and regulate p53 transcriptional activity and stability. Though couple of studies have shown that JDP2 inhibits expression of p53 and p53 represses the transcriptional activity of JDP2 promoter; however, whether JDP2 directly interacts and regulates p53 transactivation remains largely unknown. Herein, we demonstrate for the first time that JDP2 can directly interact with p53. First, we found that both ATF3 and JDP2 can bind to p53 and the C-terminus of JDP2 is required for p53 binding. Secondly, in p53-null H1299 cells, JDP2 dose-dependently enhances p53 transactivation using p53RE-Luc (14X). Moreover, we demonstrated that JDP2 dose-dependently decreases p53 protein level in consistence with the previous reports. Finally, JDP2 increases p53 stability in CHX chase experiments. Taken together, our results demonstrate that JDP2 directly binds to p53 and enhances p53 transactivation and stability, suggesting that JDP2 is a novel regulator of p53.
Citation Format: Wei-Hsiung Yang, Kasey Price, Leticia Cardoso, William Yang, Chiung-Min Wang, Richard Yang. JDP2 interacts with p53 and enhances p53 transactivation and stability [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 5723.
Abstract 5796: Targeting poorly differentiated and anaplastic thyroid cancer microenvironment via TNF-α/TGF-β/LOX signaling to improve drug delivery and treatment efficacy
Authors: LAHA DIPRANJAN 
Published: June 2022

Abstract
A major limitation of current systemic solid cancer therapies is the failure to effectively deliver drugs to cancer cells. Solid tumors have high cell density and poor lymphatic drainage, leading to higher interstitial fluid pressure (IFP). We previously showed that the tumor microenvironment of poorly-differentiated (PDTC) and anaplastic thyroid cancer (ATC) can be selectively and effectively treated with nanomedicine carrying recombinant human Tumor Necrosis Factor α (TNFα)(CYT6091), resulting in vascular leakage, decreased IFP, and increased intratumoral concentration of paclitaxel in vivo. The purpose of this study is to investigate the mechanisms involved in a TNFα-induced reduction of IFP. We investigated the effects of TNF-α on cytokines and extracellular matrix (ECM) proteins in tumor microenvironment. Our data showed that TNFα treatment downregulated transforming growth factor-beta (TGF-β) and Lysyl oxidase (LOX) and upregulated several ECM proteins. However, we observed LOX upregulation when we treated thyroid cancer with siTNF-α-receptor 1 or 2 followed by TNF-α, suggesting the involvement of TNF-α-receptors in treatment resistance. In addition to the role of LOX in stiffening the ECM, causing a barrier to drug delivery, we showed overexpression of LOX in aggressive thyroid cancer. We observed increased vascular leakage in siLOX-treated thyroid cancer xenografts, mimicking the effect of CYT-6091. Furthermore, we confirmed that the LOX expression in thyroid cancer is positively associated with transforming growth factor receptor 1 (TGFBR1). In TCGA thyroid cancer database the mRNA expression of TGFBR1 was positively correlated with those of ECM regulatory genes (ITGB2, ITGA2 and COL1A1) which were downregulated with TNF-α treated thyroid cancer cells. To assess the role of TGF-β on vascular permeability, we found that the TGF-β inhibitor (SB-431542) induced in vitro vascular leakage, while the recombinant TGF-β reversed TNF-α-induced in vitro vascular leakage in HUVEC cells. SB-431542 and TGF-β neutralizing antibodies independently and markedly improved treatment efficacy of paclitaxel in in vitro thyroid cancer 3D tumor spheroids. Moreover, TGF-β1 inhibition downregulates the protein levels of Smad3 molecules in thyroid cancer cells. TCGA database studies of thyroid cancer patient samples showed that SMAD3 positively correlated with TGFBR1 and LOX, suggesting the involvement of SMAD3 in TGF-β/LOX signaling in the TME.
Citation Format: DIPRANJAN LAHA. Targeting poorly differentiated and anaplastic thyroid cancer microenvironment via TNF-α/TGF-β/LOX signaling to improve drug delivery and treatment efficacy [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 5796.