bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4481: Enhancing AOH1996 through structure activity relationship exploration for caPCNA inhibition
Authors: Haratipour Pouya , Zangi Maryam , Yaghoubi Mahshid , Gu Long , Jossart Jennifer , Perry John J. , Malkas Linda H. , Hickey Robert J. 
Published: March 2024

Abstract
Recently, we have developed AOH1996, a small molecule PCNA ligand currently in phase I clinical trial, designed to selectively inhibit the functions of cancer-associated PCNA (caPCNA). Seeking to enhance the potency and selectivity of AOH1996, we conducted an exhaustive Structure-Activity-Relationship (SAR) investigation. Over 100 analogues of AOH1996 were synthesized, systematically modifying its three main components: the naphthyl group, glycine linker, and diphenyl ether. The glycine linker underwent substitution with various natural and unnatural amino acids, while the 1-naphthyl group saw replacements with diverse monocyclic and bicyclic aromatic groups, including quinoline and isoquinoline derivatives. The diphenyl ether moiety was extensively explored by substituting the bridging oxygen with different functional groups (sulfonyl, imido, sulfur, amide), substituting both phenyl rings with various functional groups (fluorine, chlorine, hydroxy, methoxy, methyl, trifluoromethyl), and adopting a nitrogen-walk approach on the terminal phenyl ring to evaluate critical ligand/caPCNA-binding positions. This meticulous effort resulted in the identification of several analogues, such as AOH1160S (featuring a diphenyl thioether group), AOH1996S-4CH3 (with a methyl group at the para-position of the terminal thiophenyl ring), and AOH1996-3CH3 (incorporating an m-methoxy function in the terminal phenyl ring and bridging oxygen), exhibiting similar or superior potency compared to AOH1996. The target binding of these analogues was verified by capturing the binary complex of the more polar version of these analogues in the crystal structure. The synthesis, characterization, and detailed biological activities of these promising AOH analogues will be thoroughly described.
Citation Format: Pouya Haratipour, Maryam Zangi, Mahshid Yaghoubi, Long Gu, Jennifer Jossart, John J. Perry, Linda H. Malkas, Robert J. Hickey. Enhancing AOH1996 through structure activity relationship exploration for caPCNA inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4481.
Abstract 4486: Characterization of a novel mutant selective, EGFR sparing, ErbB2 inhibitor with activity across activating mutations in systemic and CNS tumors
Authors: Fulton Jennifer , Bettendorf Tanna , Blandon Abiezer , Bouhana Karyn , Brizendine Richard K. , Cable LouAnn , Chicarelli Mark J. , Crow Michelle , Fell Brad , Fischer John , Guarnieri Anna , Hillman Madison , Jalluri Ravi , Kumar Vijay , Malinky Cori A. , Rieger Rob , Robinson John , Stunkard Lee , Sullivan Francis , Trujillo John I. , Winski Shannon , Zhou Yeyun 
Published: March 2024

Abstract
Alterations in ErbB2, including amplification, overexpression, insertions, and point mutations, are established oncogenic drivers in many solid tumors. These mutations are found in approximately 3-4% of breast cancers and 3% of advanced lung cancers and have emerged as mechanisms of acquired resistance to targeted therapies. ErbB2 alterations are also found in metastatic breast and lung cancers that have advanced to the brain and remain a major clinical challenge with limited therapeutic options. Currently approved ErbB2 tyrosine kinase inhibitors have inferior potency against these mutations and lack sufficient brain penetration to be an impactful treatment option for patients. Herein, we describe advanced preclinical profiling of our candidate series of brain-penetrant EGFR-sparing ErbB2 inhibitors with activity against prevalent point mutations and exon 20 YVMA insertions.
Citation Format: Jennifer Fulton, Tanna Bettendorf, Abiezer Blandon, Karyn Bouhana, Richard K. Brizendine, LouAnn Cable, Mark J. Chicarelli, Michelle Crow, Brad Fell, John Fischer, Anna Guarnieri, Madison Hillman, Ravi Jalluri, Vijay Kumar, Cori A. Malinky, Rob Rieger, John Robinson, Lee Stunkard, Francis Sullivan, John I. Trujillo, Shannon Winski, Yeyun Zhou. Characterization of a novel mutant selective, EGFR sparing, ErbB2 inhibitor with activity across activating mutations in systemic and CNS tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4486.
Abstract 4521: Investigating bAP15, a new inhibitor of UCHL5/USP14 deubiquitinating enzymes, as a potential treatment for chondrosarcoma: A comprehensive in vivo and in vitro study
Authors: Kuo Kuan-Lin , Hsu Fu-Shun , Chang Shang-Jen , Liao Shih-Ming , Lin Wei-Chou , Ke Tzt-Yao , Liu Tzu-Ting , Huang Kuo-Yuan 
Published: March 2024

Abstract
Chondrosarcoma, a highly resilient cancer characterized by limited effective treatment options, represents a significant therapeutic challenge. bAP15, a novel inhibitor of deubiquitylating enzymes (DUBs), has emerged as a promising therapeutic agent, exhibiting anti-tumor activity in various cancer models. This study investigated the efficacy of bAP15 against chondrosarcoma in vitro and in vivo. To evaluate bAP15's effects on chondrosarcoma cells, the SW1353 and JJ012 cell lines were employed. Cell viability, apoptosis, and cell cycle progression were assessed using MTT assay and flow cytometry. Western blotting was utilized to analyze apoptosis, cell stress, and endoplasmic reticulum (ER) stress. Additionally, a xenograft mouse model was established to examine the in vivo anti-tumor potential of bAP15. Compared to normal cartilage tissue, chondrosarcoma cells exhibited significantly higher expression of the DUB UCHL5, suggesting its potential involvement in chondrosarcoma development. Treatment with bAP15 effectively induced apoptosis in chondrosarcoma cells by activating caspases and cleaving PARP. Furthermore, bAP15 enhanced ER stress by activating caspase-4 and CHOP. In the xenograft mouse model, bAP15 demonstrated remarkable anti-tumor efficacy with minimal toxicity. These findings highlight the potential of bAP15 as a therapeutic strategy for chondrosarcoma. Its ability to induce ER stress and cell cycle arrest, coupled with its in vivo anti-tumor activity, provides compelling evidence for its further development as a novel treatment option for this challenging cancer.
Citation Format: Kuan-Lin Kuo, Fu-Shun Hsu, Shang-Jen Chang, Shih-Ming Liao, Wei-Chou Lin, Tzt-Yao Ke, Tzu-Ting Liu, Kuo-Yuan Huang. Investigating bAP15, a new inhibitor of UCHL5/USP14 deubiquitinating enzymes, as a potential treatment for chondrosarcoma: A comprehensive in vivo and in vitro study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4521.
Abstract 4528: Improving carboplatin therapy: A novel albumin-targeted platinum(IV) prodrug with superior anticancer activity in vivo
Authors: Schueffl Hemma , Weinmuellner Regina , Sommerfeld Nadine , Keppler Bernhard K. , Berger Walter , Kowol Christian R. , Heffeter Petra 
Published: March 2024

Abstract
Platinum(II)-based chemotherapeutics are among the most commonly used anticancer drugs and are part of nearly every second treatment scheme. However, they lack in tumor specificity, causing severe sides effects, dose-dependent toxicity as well as drug resistance development. Due to their higher tolerability, platinum(IV) prodrugs are currently in the focus of interest. However, comparable to their platinum(II) counterparts, they show insufficient tumor accumulation and are frequently prematurely activated. A promising strategy to improve tumor targeting of anticancer drugs is to exploit the enhanced consumption and accumulation of albumin in the malignant tissue. Thus, we developed a new albumin-targeted maleimide-containing platinum(IV) prodrug, which releases carboplatin in a highly tumor-specific manner. The maleimide moieties enable the drug to selectively bind the endogenous albumin via its free thiol of cysteine 34. The aim of this study was to in-depth characterize the pharmacological behavior and anticancer activity in vivo of the new prodrug. To this end, several xenograft and allograft experiments were performed. To investigate tissue distribution and pharmacokinetics serum, urine, tumor and organ samples of mice were collected after drug treatment and were evaluated by (size-exclusion chromatography) inductively-coupled plasma mass spectrometry and immunohistochemistry (e.g cleaved caspase-3). These experiments revealed that the new prodrug fast and selectively binds to the serum albumin after intravenous injection, leading to an enhanced plasma half-life and an increased tumor accumulation in comparison to its corresponding platinum(II) drug carboplatin. Additionally, the new complex resulted in superior anticancer activity and prolonged overall survival based on the distinctly improved pharmacokinetic profile and enhanced apoptosis induction. In conclusion, these data support that albumin binding is a potent tool to increase the tumor specificity of platinum(IV) drugs and prevent their premature activation in other body compartments. Consequently, this very promising prodrug will be further developed towards clinical phase I testing.
Citation Format: Hemma Schueffl, Regina Weinmuellner, Nadine Sommerfeld, Bernhard K. Keppler, Walter Berger, Christian R. Kowol, Petra Heffeter. Improving carboplatin therapy: A novel albumin-targeted platinum(IV) prodrug with superior anticancer activity in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4528.
Abstract 4535: JAB-26766: A small-molecule, orally bioavailable PARP7 inhibitor with high potency and selectivity
Authors: Kang Di , Wang Yanping , Sun Xin , Yan Man , Li Haijun , Chen Mingming , Lin Yiwei , Long Wei 
Published: March 2024

Abstract
Background: PARP7 (also referred to as TIPARP or ARTD14) is a mono-ADP-ribosyl transferase that inhibits type I interferon (IFN) signaling. Targeting PARP7 to restore antitumor immunity represents a promising treatment strategy. We have developed JAB-26766, an orally bioavailable, highly potent, and selective PARP7 inhibitor.
Methods: A time-resolved fluorescence energy transfer (TR-FRET) assay was applied to determine the binding and inhibition of PARP7 by JAB-26766. IFN-β secretion assay, STAT1 phosphorylation assay, and ISG (interferon stimulated gene) mRNA assay were performed to evaluate the inhibitory activities of JAB-26766 on the downstream signaling of PARP7. CellTiter-Glo assay was performed to evaluate cell viability upon treatment of JAB-26766. In vivo PK-PD study was conducted to evaluate the relationship between JAB-26766 concentration and the level of tumor STAT1 phosphorylation. The antitumor activity of JAB-26766 either as a single agent or in different drug combinations was evaluated in multiple mouse models.
Results: High potency of JAB-26766 on PARP7 inhibition as well as &gt;1800-fold selectivity over PARP2 was observed through biochemical assays. At the cellular level, JAB-26766 induced IFN-β secretion, up-regulated ISG mRNA levels, increased phosphorylation of STAT1, and inhibited cell viability of multiple tumor cell lines (with most IC50 values below 50 nM). JAB-26766 combined with a STING agonist resulted in synergistic activation of STING pathway, as evidenced by increased CXCL10 secretion, and inhibited tumor cell proliferation. In vivo PK-PD study showed that JAB-26766 exposure in plasma and tumor has good correlation with induction of tumor STAT1 phosphorylation. Furthermore, JAB-26766 showed potent antitumor activity and good tolerability either as monotherapy or combined with STING agonist or anti-PD-1 antibody in mouse models of non-small cell lung cancer, breast cancer and colorectal cancer.
Conclusions: JAB-26766 is an orally bioavailable, highly potent, and selective PARP7 inhibitor that shows early promising anti-tumor activities.
Citation Format: Di Kang, Yanping Wang, Xin Sun, Man Yan, Haijun Li, Mingming Chen, Yiwei Lin, Wei Long. JAB-26766: A small-molecule, orally bioavailable PARP7 inhibitor with high potency and selectivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4535.
Abstract 454: microRNAs role in innate immunosenescence during anti-PD1 immunotherapy
Authors: Zhu Zhouting , Rana Tariq M. 
Published: March 2024

Abstract
Checkpoint inhibitors have achieved durable responses and long-lasting immunologic memory in cancer patients. However, the initial and acquired resistance remains an unsolved problem. It’s urgent to learn the molecular mechanisms causing resistance. microRNAs (miRNAs) are short transcripts that regulate many pathophysiological processes. Here, we investigated the miRNAs expression changes after GVAX combined with monoclonal PD-1 antibody treatment in the murine melanoma B16F10 tumors and identified microRNAs down-regulated in responsive tumors. Deletion of this family member in three different syngeneic mouse tumors did not affect their in vitro nor in vivo proliferation but sensitized anti-PD1 immunotherapy. The miRNA deletion with anti-PD1 therapy increased total CD45+ leukocyte infiltration with all types of hematopoietic cells except macrophages. Both tumor bulk RNA sequencing and single-cell RNA sequencing revealed activated innate sensing genes especially for pathogen recognition and phagosome formation. Importantly, we found specific miRNA-deletion effects rely on tumor resident macrophage, IFN-γ release in the tumor microenvironment (TME) and the miRNA regulating machinery protein Argonaut2 (Ago2). Notably, the miRNA expression status of melanoma patients correlates with the survival and innate immune sensing gene expression. Our results suggest that this family of miRNAs participate in initial resistance by escaping innate immunosurveillance. Deletion of the miRNA may turn immune “cold” tumors to “hot” tumors, providing potential therapeutic targets to overcome resistance in melanoma, colorectal, triple-negative breast cancer and possibly other cancers.
Citation Format: Zhouting Zhu, Tariq M. Rana. microRNAs role in innate immunosenescence during anti-PD1 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 454.
Abstract 4616: TBK1 and GSK3 mediated TRAF2 phosphorylation confers resistance to PI3K-AKT inhibition in breast cancer cells
Authors: Habelhah Hasem , Zhang Laiqun 
Published: March 2024

Abstract
Breast cancer (BC) is the most frequently diagnosed malignancy and the second leading cause of cancer mortality in Western women. As is the case for most other solid tumors, metastasis and drug resistance are the main causes of death. In ~80% of BC cases, the PI3K-AKT pathway is aberrantly activated, due to the alterations in genes encoding the pathway components, such as Ras, Her2, PTEN, PIK3C and AKT. Consequently, over 100 clinical trials are currently underway worldwide to evaluate the therapeutic efficacy of PI3K and AKT inhibitors in BC; however, initial data revealed that inhibition of this pathway is either not effective or often results in development of resistance and relapse of the disease. Thus, identification of additional targets and therapeutic combinations are urgently needed. We previously reported that TBK1-mediated TRAF2 Ser-11 phosphorylation enhances NF-κB activation to promote cancer cell survival under conditions of cellular stresses. Recently, we discovered that GSK3β directly phosphorylates TRAF2 at Thr-7 upon Ser-11 phosphorylation by TBK1, and that phosphorylation of both Thr-7 and Ser-11 is essential for sustained NF-κB activation and BC cell resistance to PI3K-AKT inhibition. TBK1 and its close homologue IKKε are overexpressed in ~70% of BC and play critical roles in BC cell survival. GSK3β is a constitutively active kinase activity in unstimulated normal cells, but its activity is suppressed in most cancer cell types by AKT-mediated phosphorylation. These published reports and our new findings suggest that inhibition of AKT in BC cells leads to increased phosphorylation of TRAF2 by TBK1 and GSK3β, which confers resistance to PI3K-ATK inhibition. Bioinformatic analyses revealed that TRAF2 and GSK3β are also overexpressed in invasive BC, and significantly correlate with poor prognosis. As expected, inhibition of both AKT and TBK1 or GSK3b synergistically induced apoptosis in BC cell lines in vitro and significantly suppressed xenograft BC tumor growth in vivo. Thus, our data suggest that further investigation of the efficacies of combined PI3K/AKT and TBK1/GSK3β inhibition in PDX models of BC has the potential to develop new strategies for BC treatment.
Citation Format: Hasem Habelhah, Laiqun Zhang. TBK1 and GSK3 mediated TRAF2 phosphorylation confers resistance to PI3K-AKT inhibition in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4616.
Abstract 465: Effect of Epstein-Barr virus lnc-BARTs on EBV genome maintenance in EBV-associated tumors
Authors: Liu Jiayan , Mok Bobo Wing-Yee , Chen Honglin 
Published: March 2024

Abstract
Most humans infected with Epstein-Barr virus (EBV) remain asymptomatic throughout the whole life. However, EBV is linked to several human cancers, including Burkitt's lymphoma, Hodgkin's disease, post-transplant lymphoproliferative disorder (PTLD), nasopharyngeal carcinoma (NPC), and gastric carcinoma. Among these EBV-associated tumors, EBV genome is present in 100% of NPC tumor cells. In NPC cells, EBV establishes a latent infection, expressing limited number of viral proteins but elevated levels of non-coding RNAs transcribed from the BamHI-A region of the EBV genome, also known as BamHI-A rightward transcripts (BARTs). The family of EBV BART RNAs includes BART-microRNAs (miRNAs) and long non-coding RNAs (lnc-BARTs). Although various functions of BART miRNAs have been identified, the role of EBV lnc-BARTs remains largely unknown. In this study, we provide evidence demonstrating that lnc-BARTs functions as a regulatory long non-coding RNA, referred to as lnc-BARTs. These lnc-BARTs play keys role in modulating the core networks that maintains EBV latency and promotes NPC oncogenesis through epigenetic mechanisms. Our study found that the apoptosis rate of NPC cells is significantly increased following the knockdown of EBV lnc-BARTs, indicating their anti-apoptotic role in EBV-associated tumors. Mass spectrometry analysis identified several host factors, including transcriptional regulators BRD4 and SC35’ interact with EBV lnc-BARTs in NPC cells. RNA-FISH assays showed lnc-BARTs co-localized with BRD4 and SC35 complexes in nuclear s peckles and such interaction were disrupted by JQ1, a BRD4 competitive inhibitor. Binding of lnc-BARTs to BRD4 RNA was confirmed using immunoprecipitation and pulldown assays. ATAC sequencing and transcriptome analyses showed that BART knockdown in EBV-harboring NPC cell line C666-1 led to reduced chromatin accessibility, downregulation of oncogenes, and decreased EBV episome replication and maintenance. Quantitative qPCR and DNA FISH analyses of cell samples treated with shRNA targeting lnc-BARTs or BRD4 reduced EBV copy numbers and EBNA1 RNA expression levels in EBV-infected NPC cells. Finally, ChIP sequencing analysis revealed that lnc-BARTs is critical for BRD4 binding to the oriP region of the EBV genome. These findings support a mechanism by which EBV lnc-BARTs epigenetically regulate host gene expression through functional interactions with elongation regulatory machinery and contribute to the maintenance of EBV latent genome by interaction with BRD4 complex.
Citation Format: Jiayan Liu, Bobo Wing-Yee Mok, Honglin Chen. Effect of Epstein-Barr virus lnc-BARTs on EBV genome maintenance in EBV-associated tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 465.
Abstract 4661: A dual degrader of HER2 and EGFR obliterates oncogenic signaling, overcomes therapy resistance, and inhibits metastatic lesions in HER2-positive breast cancer models
Authors: Yang Lu , Bhattacharya Arup , Peterson Darrell , Li Yun , Liu Xiaozhuo , Marangoni Elisabetta , Robila Valentina , Zhang Yuesheng 
Published: March 2024

Abstract
Background: HER2 is an oncogenic receptor tyrosine kinase (RTK) implicated in several types of human cancer. It is strongly expressed in about 20% of breast cancer (BC), known as HER2-positive BC (HER2+ BC), due to gene amplification. HER2 amplification or overexpression is a strong predictor of poor disease prognosis. HER2-targeted therapies are the linchpin of treating HER2+ BC. However, drug resistance is common. The main resistance mechanism is unknown. We exploited cell lines and mouse models (orthotopic patient-derived xenografts, and metastatic lesions in the brain and lung of therapy-resistant HER2+ BC) for experiments of genetic and pharmacologic depletion of HER2 and its family member EGFR, analysis of RTKs and no-RTKs, and evaluation of cell and tumor growth, to delineate the mechanism of HER2+ BC resistance to HER2 inhibitors and assess the therapeutic activity of PEPDG278D. PEPDG278D, a recombinant human protein, is the first-in-class dual degrader of HER2 and EGFR.
Results: Trastuzumab-resistant HER2+ BC cells and tumors are highly vulnerable to targeted degradation of HER2 and EGFR. Trastuzumab is the most commonly used HER2 inhibitor in the clinic. Targeted degradation of HER2 and EGFR by PEPDG278D, which binds to their extracellular domains, causes extensive inhibition of oncogenic signaling proteins in HER2+ BC cells resistant to trastuzumab. This is accompanied by strong growth inhibition of cultured cells, orthotopic patient-derived xenografts, and metastatic lesions in the brain and lung of trastuzumab-resistant HER2+ BC. siRNA knockdown shows that eliminating both HER2 and EGFR is important to maximize therapeutic outcome. Collectively, our results reveal the key vulnerability of trastuzumab-resistant HER2+ BC and shows a promising strategy that overcomes trastuzumab resistance by targeting this vulnerability.
Conclusions & Therapeutic Relevance: This study identifies a key therapeutic vulnerability of drug-resistant HER2+ BC and shows that an agent that targets this vulnerability is highly effective in overcoming drug resistance in this disease. The findings provide new insights and innovations to advance treatment of drug-resistant HER2+ BC that remains an unmet problem.
Citation Format: Lu Yang, Arup Bhattacharya, Darrell Peterson, Yun Li, Xiaozhuo Liu, Elisabetta Marangoni, Valentina Robila, Yuesheng Zhang. A dual degrader of HER2 and EGFR obliterates oncogenic signaling, overcomes therapy resistance, and inhibits metastatic lesions in HER2-positive breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4661.