bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5694: Elucidating areca nut-induced miRNA-mRNA regulatory networks in head and neck cancer pathogenesis
Authors: Huang Hung-Han , You Guo-Rung , Lin Kai-Hsin , Chen Yin-Ju , Cheng Ann-Joy 
Published: March 2024

Abstract
Areca nut has been considered a high-risk carcinogen for head and neck cancer (HNC) in Southeast Asia, while its molecular effects, especially on the miRNA regulatory roles, remain elusive. This study characterized miRNA-mRNA networks associated with areca nut-related HNC. We integratively analyzed the areca nut-induced mRNA profile and TCGA-HNSC gene set. A total of 2575 genes were identified, with 1971 upregulated and 604 downregulated in cancers. The KEGG pathway analysis revealed that these genes were enriched in the cellular functions related to motility and stress response. Experimental studies confirmed that arecoline promoted cell migration, invasion, and chemo-radioresistance. We further cross-analyzed the miRNAs induced by areca nut and dysregulated in TCGA-HNSC data and defined 71 molecules affected, with 35 upregulation and 36 downregulation. Using the multimiR tool to map potential mRNA-miRNA interactions, we uncovered that these miRNAs were connected to 2173 genes. These molecules participated in several oncogenic mechanisms, such as ErbB and PI3K-Akt signaling, cell adhesion, and DNA damage response. We endeavored to establish miRNA-mRNA interaction networks with the functions of cellular motility and stress response via the Cytoscape analytical method. Our data revealed nexus comprising 41 miRNAs with 83 mRNAs, and 38 miRNAs with 66 mRNAs, respectively, co-regulate these two malignant functions. A key miRNA, miR-410-3p, downregulated in HNC and decreased following areca nut treatment, was studied. Ectopic expression of miR-410-3p attenuated areca nut-induced cell invasion and exerted modulatory effects on its target oncogenes, CRK. Thus, our study delineates a comprehensive view of the miRNA-mRNA interplay altered by areca nut, illustrating a sophisticated mechanism of carcinogenesis and suggesting new avenues for diagnostic and therapeutic strategies in HNC.
Citation Format: Hung-Han Huang, Guo-Rung You, Kai-Hsin Lin, Yin-Ju Chen, Ann-Joy Cheng. Elucidating areca nut-induced miRNA-mRNA regulatory networks in head and neck cancer pathogenesis [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 5694.
Abstract 5733: Development of a topoisomerase 1 inhibitor platform technology for efficacious and well tolerated ADCs
Authors: Lyski Ryan , Bou Lauren , Sigurjonsson Johann , Meyer David , Neace Calvin , Ortiz David , Snead Katie , Smith Kaleb , Jin Steven , Stevens Nicole , Cochran Julia , Alizadeh Kaveh , Yeddula Narayana , McKinney Erica , Peterson Adam , Dotloe Lindsay , Simmons Jessica , Carosino Christopher , Emmerton Kim , Everds Nancy , Jeffrey Scott , Senter Peter 
Published: March 2024

Abstract
Topoisomerase 1 (TOP1) inhibitors are a class of cytotoxic small molecules that have demonstrated effectiveness as therapeutic agents in cancer. However, the broad clinical application has been hindered by poor pharmacokinetic profiles and off-target toxicities. Antibody-drug conjugates (ADCs) enable the targeted delivery of cytotoxic payloads by specifically targeting cell-surface antigens expressed on cancers reducing systemic exposure and toxicity. TOP1-ADCs have received FDA approval for HER2- (trastuzumab-deruxtecan) and Trop2- (sacituzumab-govitecan) expressing solid tumors, demonstrating the promise for this drug class to improve the lives of patients. We have developed a novel drug-linker using a potent TOP1 inhibitor with desirable ADME properties, and a hydrophilic glycoside linker as a platform technology enabling ADCs with favorable physicochemical and biological properties. The TOP1 inhibitor payload was optimized for potency, with reduced P-glycoprotein efflux and enhanced permeability. The hydrophilicity of the linker facilitates the development of highly loaded ADCs (8 drugs/mAb) with high plasma stability, low aggregation, and pharmacokinetics similar to parental antibody. The resultant ADCs are potent and immunologically specific with activity in multidrug-resistant tumor models and bystander activity in heterogenous antigen models. Human cancer cell derived xenograft models demonstrated potent and specific ADC anti-tumor activity with several targets and indications. Improved activity was observed compared to corresponding govitecan- and deruxtecan-based ADCs. ADCs prepared from this drug-linker technology were well tolerated in rats after repeat administration of 60 mg/kg every 4 days for 4 doses. The excellent anti-tumor activity in several models and favorable safety profile demonstrates this platform TOP1 drug-linker technology has the potential for development as ADCs against many cancer targets.
Citation Format: Ryan Lyski, Lauren Bou, Johann Sigurjonsson, David Meyer, Calvin Neace, David Ortiz, Katie Snead, Kaleb Smith, Steven Jin, Nicole Stevens, Julia Cochran, Kaveh Alizadeh, Narayana Yeddula, Erica McKinney, Adam Peterson, Lindsay Dotloe, Jessica Simmons, Christopher Carosino, Kim Emmerton, Nancy Everds, Scott Jeffrey, Peter Senter. Development of a topoisomerase 1 inhibitor platform technology for efficacious and well tolerated ADCs [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 5733.
Abstract 5741: siteDAR, complete antibody drug conjugate, ADC characterization
Authors: Martin Warham L. , Senseney Michael , Kusuma Bhaskar , Dugal-Tessier Julien , Jain Nareshkumar 
Published: March 2024

Abstract
Antibody drug conjugate characterization currently extends to the global determination of the drug -to- antibody ratio (DAR). However, there can be confounding batch variability in pharmacological outcome from ADCs of the same drug, antibody, and DAR. Previously, DAR was obtained by quantifying the extent of modification of the intact antibody or its protein subunits. The coupling chemistry is used to infer which type of amino acids were modified but generally no specific sites of modification are identified and if identification is obtained, it is not quantitative. Borrowing the rigorously reproducible proteolytic digestion methods from multi-atribute mapping (MAM) used in monoclonal antibody manufacture, and compiling a comprehensive quantitative assignment of every abundant peptide in the ADC digest we can both calculate a DAR from the ion volume ratios and a quantitative map of the specific modified sites. This method, termed “siteDAR”, is applied here to both commercial Kadcyla® (ado-trastuzumab emtansine) and in-house preparations of ado-trastuzumab emtansine. We show that preparations of Kadcyla® with the same DAR can have significantly different quantitative maps of modification sites. We use siteDAR analysis in our ADC design cycle to characterize an ADC, and have developed an ADC synthesis method that was quantitatively verified, and had increased biosimilarity with commercially available Kadcyla®. siteDAR for commercial Kadcyla siteDAR for initial in-house Kadcyla Initial biosimilarity
Citation Format: Warham L. Martin, Michael Senseney, Bhaskar Kusuma, Julien Dugal-Tessier, Nareshkumar Jain. siteDAR, complete antibody drug conjugate, ADC characterization [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 5741.
Abstract 5743: Liposome platform enables X-ray induced photodynamic therapy treatment against human triple negative breast cancer cells
Authors: Yang Biyao , Sang Rui , Li Yi , Goldys Ewa , Deng Wei 
Published: March 2024

Abstract
In this study, we employed X-ray induced photodynamic therapy (X-PDT) for the treatment on triple negative breast cancer (TNBC) cells. To do this, we rationally developed a liposome delivery system co-loaded with protoporphyrin IX (PPIX) and perfluorooctyl bromide (PFOB). Low-dose X-ray at 2Gy was employed to activate PPIX for reactive oxygen species (ROS) generation, and the co-loading of PFOB provided additional oxygen to augment ROS production. The highly toxic ROS triggered TNBC cell death. In vitro X-PDT effects including intracellular ROS generation, cytotoxicity, cell viability and apoptosis/necrosis assay in TNBC cells were studied. Our results indicate that the nanocarriers effectively induced X-PDT effect with very low dose radiation, which makes it possible to damage cancer cells. Our strategy may offer a paradigm-shifting treatment alternative for TNBC patients who need neoadjuvant radiotherapy but wish to avoid long term detrimental effect on functional outcome by undergoing X-PDT using only a fraction of the conventional radiotherapy.
Citation Format: Biyao Yang, Rui Sang, Yi Li, Ewa Goldys, Wei Deng. Liposome platform enables X-ray induced photodynamic therapy treatment against human triple negative 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 5743.
Abstract 5748: Inhibition of tumor growth using exosomes loaded with KRAS siRNA and surface-modified with tumor-targeted proapoptotic peptide
Authors: Kang Li , Jeon Soyeon , Vadevoo Sri Murugan , Kim Sang-Hyun , Lee Byungheon 
Published: March 2024

Abstract
Exosomes are extracellular vesicles naturally secreted by cells and serve as carriers of RNAs and proteins for cell-to-cell communications. KRAS is frequently mutated and plays a vital role in many tumors. Receptor expressed in lymphoid tissue (RELT), also known as tumor necrosis factor receptor superfamily 19-like, is upregulated in certain tumors such as lung and pancreatic tumors and is a potential tumor target. To selectively deliver cytotoxic agents to tumor, we loaded mesenchymal stem cell (MSC)-derived exosomes with a siRNA against KRAS and surface-modified them with the RELTpep-KLA peptide comprising a RELT-binding peptide (CRQTKN, named RELTpep) and proapoptotic peptide (KLAKLAKKLAKLAK, named KLA). Exosomes were isolated from cell culture medium using ultracentrifugation and transfected with the KRAS siRNA using a lipid-based reagent and then surfaced-modified with the RELTpep-KLA using a phospholipid-based membrane anchor. Compared with control peptide-KLA, RELTpep-KLA-targeted MSC-exosomes were more efficiently internalized into A549 lung tumor and Panc-1 pancreatic tumor cells expressing RELT on their surface and exhibited cytotoxicity to these tumor cells. RELTpep-KLA-targeted and KRAS siRNA-loaded MSC-exosomes reduced the phosphorylation of Erk and exhibited an enhanced cytotoxicity in A549 and Panc-1 tumor cells. Moreover, when intravenously injected, they inhibited tumor growth in Balb/c nude mice bearing subcutaneous Panc-1 human tumor xenografts more efficiently than those loaded with control siRNA or modified with control peptide-KLA. These results demonstrate that RELTpep-KLA-targeted MSC-exosomes carrying KRAS siRNA hold a potential for exosome-based targeted therapy against cancer.
Citation Format: Li Kang, Soyeon Jeon, Sri Murugan Vadevoo, Sang-Hyun Kim, Byungheon Lee. Inhibition of tumor growth using exosomes loaded with KRAS siRNA and surface-modified with tumor-targeted proapoptotic peptide [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 5748.
Abstract 5797: Next generation antibody drug conjugates: Multi-payload conjugates targeting multiple mechanisms of cell killing
Authors: Kendall Richard L. , Lobba Marco , Johri Saurabh , Symister Chanez , Trinter Devin , Nguyen Maxwell , Gutierrez Daniel , Brady Samantha , Lau Andrew , Francis Matthew B. 
Published: March 2024

Abstract
Introduction: ADCs have had tremendous impact on patient outcomes in breast cancer and are now second line therapy for stage IV HER2 positive metastatic breast cancer. However, many patients fail to respond or relapse after treatment with ADC therapies due to tumor heterogeneity and resistance to ADC payloads. We are developing next generation ADCs that deliver targeted combination chemotherapies with a single molecule.
Method: CatenaBio has developed a novel system capable of attaching distinct payloads at different sites to the same antibody, enabling the production of highly stable single-molecule targeted combination therapies, Multi-Payload-Conjugates (MPCs), with a well-defined drug-antibody ratio (DAR).
Results: We screened combinations of different payloads targeting several different mechanisms of cell division attached to trastuzumab at different DARs to optimize tumor cell killing. These targeted combination ADCs demonstrated robust killing in both HER2 high and low tumor cell lines. Additionally, these novel MPCs show potent inhibition of tumor growth in a HER2+ xenograft model of cancer.
Conclusion: Antibody Drug Conjugates have revolutionized the treatment of high HER2 positive breast cancer. More recently advances have been made in the design of ADCs to expand indications to include HER2 low as well as HER2 negative patients. Multi-payload Conjugates® offer the next step in ADC design and allow for the combination of multiple mechanisms of action in a single MPC that are highly effective across multiple breast cancer cell lines and HER2 expression levels. These molecules offer the potential to circumvent tumor resistance pathways and deliver deeper and more durable responses.
Citation Format: Richard L. Kendall, Marco Lobba, Saurabh Johri, Chanez Symister, Devin Trinter, Maxwell Nguyen, Daniel Gutierrez, Samantha Brady, Andrew Lau, Matthew B. Francis. Next generation antibody drug conjugates: Multi-payload conjugates targeting multiple mechanisms of cell killing [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 5797.
Abstract 5810: The impact of scaffold, linker, homogeneity and payload selection on the efficacy and tolerability of anti-tubulin ADCs
Authors: Collins Scott D. , Keirstead Natalie , Damelin Marc , Toader Dorin , Ishida Katsu , Kumar Niyanta N. , Lancaster Kelly L. , Catcott Kalli C. , Yau Annika , Bala Mohan , Lowinger Timothy B. 
Published: March 2024

Abstract
Antibody-drug conjugates (ADCs) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The properties of an ADC, including its activity and safety profile, can be highly influenced by its characteristics and individual components, commonly viewed as the antibody, payload, linker, and drug-to-antibody ratio (DAR). However, multiple other characteristics can also significantly influence an ADC’s overall drug-like properties, including DAR homogeneity, method of bioconjugation, hydrophilicity, and charge balance. Due to the multiparametric nature of ADC platform optimization, there are few examples in preclinical research, and even fewer in the clinical realm, where comparisons across platforms have been investigated for the same target, both preclinically and clinically, to elucidate how deliberate modifications in molecular design can improve drug-like properties and clinical outcomes. To that end, here we describe the improvements observed in preclinical characteristics, as well as their translational relevance to corresponding clinical characteristics. Two anti-NaPi2b ADCs were produced using two different platforms, XMT-1536 (Dolaflexin platform) and XMT-1592 (Dolasynthen platform), conjugated to the same antibody and employing the same payload. The Dolasynthen platform was deliberately designed, taking into account preclinical and clinical learnings from earlier ADC platforms, to improve both safety and efficacy. In addition, comparisons to clinically approved anti-tubulin ADC platforms are made to provide further context.
Citation Format: Scott D. Collins, Natalie Keirstead, Marc Damelin, Dorin Toader, Katsu Ishida, Niyanta N. Kumar, Kelly L. Lancaster, Kalli C. Catcott, Annika Yau, Mohan Bala, Timothy B. Lowinger. The impact of scaffold, linker, homogeneity and payload selection on the efficacy and tolerability of anti-tubulin ADCs [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 5810.
Abstract 5821: DXC008, a novel STEAP1 antibody-tubulysin analog conjugate with a function linker, demonstrates a potential to broaden therapeutic opportunities for prostate tumors
Authors: Yang Qingliang , Huang Yuanyuan , Jia Junxiang , Guo Huihui , Zhang Lingli , Zhou You , Ye Zhicang , Ye Hangbo , Xu Yifang , Li WenJun , Zhao Zhiyu , Zhao Lingyao , Bai Lu , Zheng Jun , Zhao Robert Y. 
Published: March 2024

Abstract
Six-transmembrane epithelial antigen of the prostate 1 (STEAP1), is a cell surface protein frequently expressed in prostate cancer, with limited expression in non-prostate tissues. A Steap1 antibody called Vandortuzumab conjugated with MMAE (DSTP3086S) was in the clinical phase I trial for treating STEAP1-expressing metastatic castration-resistant prostate cancer and showed acceptable safety at 2.4 mg/kg once every 3 weeks. However, many patients are nonresponsive to DSTP3086S due to low target expression levels and common treatment-related AEs which were caused by MMAE payloads. DXC008 was generated through screening the therapeutical index in vitro of conjugates of an anti-Steap1 antibody with varieties of payloads of tubulysin B analogs through function peptide spacer linkers. The generated DXC008 exhibited not only good affinity for Steap1 but also moderate affinity for Prostate-specific membrane antigen (PSMA) which is as well specifically overexpressed in most prostate cancer with limited expression in normal tissue. DXC008 demonstrated couple tens to a hundred of picomolar concentration (pM) of potency against several prostate tumor cells and over 60% internalization rate within 90 min in vitro. And in vivo it showed very good durable antitumor response as low dose as 1 mg/kg one injection in both high and moderate of both Steap1 and PSMA expression xenograft models. Pharmacokinetic profiles of DXC008 were favorable and the safety of Maximal Tolerable Dose (MTD) was over 120 mg/kg in single injection in mice. DXC008 has been forward to NHP toxicity study and it has potential to be a good STEAP1/PSMA-targeting ADC with a wide therapeutic window for prostate cancers.
Citation Format: Qingliang Yang, Yuanyuan Huang, Junxiang Jia, Huihui Guo, Lingli Zhang, You Zhou, Zhicang Ye, Hangbo Ye, Yifang Xu, WenJun Li, Zhiyu Zhao, Lingyao Zhao, Lu Bai, Jun Zheng, Robert Y. Zhao. DXC008, a novel STEAP1 antibody-tubulysin analog conjugate with a function linker, demonstrates a potential to broaden therapeutic opportunities for prostate 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 5821.
Abstract 5862: Retrotransposable elements mediate the drug-tolerant persistence in claudin-low breast cancer chemo-treatment
Authors: Zhang Zijian , Wang Yiyang , Luo Xinlong , Zhan Xiaomei , Ding Jun , Wu Tao P. 
Published: March 2024

Abstract
The emergence of acquired drug resistance through treatment remains a critical threat to efficient cancer therapies, which most often lead to relapse and metastasis. The development of resistance is an evolutionary adaptation process that heavily depends on tumor heterogeneity (underpinned by cellular plasticity). Therefore, a longitudinal deconvolution of treatment adaptation is critical to uncover the driving-force mechanisms underpinning resistance adaptation. In the clinic, chemotherapy remains the mainstream treatment for TNBC, and one of the primary chemo-agents is doxorubicin. Although the initial responsive rate of doxorubicin-based chemotherapies is up to 70%, it is well recognized that TNBC cells usually generate an adaptive response and result in acquired drug-resistance and multi-drug resistant phenotypes. Although numerous mechanisms of chemo-resistance evolution have been proposed, most of these studies focused on the initial and terminal states, from which we could not deconvolute the adaptation routes and might miss the transient fate-switching events. We hypothesize that the claudin-low TNBC chemo-resistant cells may derive from the early-stage reversible chemo-tolerant persistent state, and early-stage state-switching mediated by epigenetic landscape reprogramming might determine the adaptation through treatment. We developed an in vitro “pulsing-treatment” model to test the hypothesis, which could mimic the clinical treatment and provide therapeutically relevant insights into the acute drug-induced stress response and regrowth. Unexpectedly, we found that the human endogenous retrovirus-like elements (HERVs) show an aberrant bursting in the adaptation. To further interrogate the adaptation, we did the longitudinal single-cell multi-omics sequencing. With a novel bioinformatic workflow, we integrated the HERV’s expression information with protein-coding genes profiling and chromatin accessibility. The preliminary result indicated that a subpopulation of HERV-high cells might transiently mediate the persistence of cancer cells at the early stage of the treatment, which coupled with whole transcriptomic and chromatin landscape reprogramming, and molecular subtype switching. In this study, we employed a new strategy to investigate the longitudinal adaptation route through treatment and uncover a non-canonical element, which shed new light on drug resistance research and novel target screening.
Citation Format: Zijian Zhang, Yiyang Wang, Xinlong Luo, Xiaomei Zhan, Jun Ding, Tao P. Wu. Retrotransposable elements mediate the drug-tolerant persistence in claudin-low breast cancer chemo-treatment [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 5862.