bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5752: Enhanced cancer therapy strategies utilizing gelatin-lipidoid hybrid nanoparticles for RNA delivery
Authors: Gangula Abilash , Suresh Dhananjay , Babu Agasthya Suresh , Li Zhaohui , Upendran Anandhi , Kannan Raghuraman 
Published: March 2024

Abstract
Nanoparticle delivery platforms have provided impetus for the emergence of novel RNA-based cancer therapeutics due to their ability to circumvent the physiological and cellular barriers in the delivery. The clinical success of these strategies hinges primarily on the safety and efficacy of the delivery vehicle. Here, we have developed a gelatin-lipidoid hybrid nanoparticle (GLNP) that utilizes gelatin's biocompatibility, biodegradability, and lipidoids' high transfection efficiency. With GLNP, we have demonstrated the efficacy of delivering siRNA and silencing AXL, a receptor tyrosine kinase commonly associated with cancer progression, metastasis, and drug resistance. siRNA is attached to the surface of GLNP through covalent conjugation with gelatin, while the lipidoid on the system's interior electrostatically complexes with the siRNA. siRNAs are well protected by the GLNP when exposed to serum for at least 48 hours. The GLNP's bivalency significantly enhanced the downregulation of target genes in vitro and in vivo. Furthermore, the bivalent GLNP can simultaneously target and downregulate two oncogenes. Apart from siRNA, GLNP was also able to encapsulate and deliver mRNA, thereby suggesting the potential to simultaneously deliver RNA therapeutics to effect knockdown and expression of target proteins and maximize therapeutic effect. The length of the carbon chain of the lipidoid can be manipulated to influence the physico-chemical properties of the GLNP and its efficiency in encapsulating and delivering RNA drugs. Importantly, gelatin was found to effectively shield the cationic lipidoid and negate its toxicity. Toxicity studies indicate that high doses of GLNPs (up to 48 mg/kg BW) are well-tolerated with no significant changes in body weight, hematology, or serum chemistry. The co-administration of GLNP-siAXL and TKI in PDX models has shown notable control of tumor growth. It is important to note that immune checkpoint blockade (ICB) therapy has shown significant survival benefits in NSCLC patients. However, the therapeutic effect is limited to only 20% of patients due to several resistance mechanisms, such as increased expression of oncogenic proteins. Therefore, our future study will explore GLNP's ability to sensitize NSCLC tumors to immune therapy.
Citation Format: Abilash Gangula, Dhananjay Suresh, Agasthya Suresh Babu, Zhaohui Li, Anandhi Upendran, Raghuraman Kannan. Enhanced cancer therapy strategies utilizing gelatin-lipidoid hybrid nanoparticles for RNA delivery [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 5752.
Abstract 5759: Design of Au-graphene quantum dot nanocomposite as a potential drug delivery system to solubilize Tetrandrine
Authors: Salvá MiaSara Perez , Medina-Berrios Nataniel , Weiner Brad , Marrero Gerardo Morell 
Published: March 2024

Abstract
Prostate cancer, along with various other types of cancer, has been a prominent focus in medical and clinical discussions for many years due to its high fatality rates and significant health risks. To enhance oncological healthcare, various methods and technologies, such as drug delivery systems (DDS), have been extensively studied. Developing an effective DDS offers distinct advantages compared to other approaches to anticancer drug treatment. Some anticancer drug molecules possess unfavorable properties that directly impact metabolism and solubility, issues that DDS aims to address. Recent progress in nanomaterial synthesis has introduced innovative and efficient drug systems, providing a new perspective on cancer treatments. Gold nanoparticles, particularly in conjunction with semiconductor graphene quantum dots (GQDs), play a role in creating a unified carrier system applicable to multiple therapeutic methods. The choice of graphene quantum dots is based on their widespread applications and diverse benefits, ranging from compatible size and core-shell chemistry richness to substantial progress in achieving signal homogeneity by reducing the distance between molecules and substrate. The selected model for the DDS is the hydrophobic alkaloid Tetrandrine. Despite its use in treating conditions such as hypertension, and arthritis, and exhibiting anti-cancer activities, Tetrandrine is highly insoluble as an anti-cancer drug, with a solubility of 24.1 μmol/L [15 μg/mL] in water and only 5mM in ethanol and DMSO. This research aims to enhance the solubility of hydrophobic Tetrandrine by incorporating it into gold graphene quantum dot nanocomposites, serving as a potential drug delivery system for combating prostate cancer. The synthesis of nanocomposites (Au-GQD, Au-NGQD, Au-SGQD) and Tetrandrine-loaded products (AuGQD-T, AuNGQD-T, AuSGQD-T) will be examined. Additionally, the properties of Tetrandrine loaded onto the nanoparticles will be scrutinized and characterized using NMR spectroscopy, UV-Vis, and fluorescence spectrum analyses.
Citation Format: MiaSara Perez Salvá, Nataniel Medina-Berrios, Brad Weiner, Gerardo Morell Marrero. Design of Au-graphene quantum dot nanocomposite as a potential drug delivery system to solubilize Tetrandrine [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 5759.
Abstract 5761: A nanoplatform based on an in situ tumor vaccine and activation of STING and TLR7/8 pathways for enhanced NSCLC immunotherapy
Authors: Zhou Haiyu , Hou Hengliang , Xu Bin , Huang Yucheng , Qiu Hongrui 
Published: March 2024

Abstract
Background: Immunotherapy has emerged as a promising treatment for tumors following surgical, radiotherapy, and chemotherapy interventions. Therapeutic tumor vaccines are considered highly effective in eliminating tumors and preventing their recurrence and metastasis due to their ability to induce or enhance T cell-mediated immune responses. However, the therapeutic efficacy of these vaccines is impeded by the heterogeneity present both between and within tumors. In contrast, in situ tumor vaccines, prepared from autologous antigens in tumor patients, present another promising strategy for generating comprehensive immune responses.
Methods: In this study, we designed a multifunctional nanopolymer, the transformable nanoassembly PEG-Ce6@PAEMA/R848. This assembly includes the photosensitizer polyethylene glycol-chlorin-e6 (PEG-Ce6), the tumor pH-sensitive polymer poly(2-azepane ethyl methacrylate) (PAEMA), and the immune adjuvant Resiquimod (R-848). The objective is to confirm the activation of bone marrow-derived dendritic cells (DCs) at the cellular level. Subsequently, we investigated the maturation of DCs in lymph nodes and tumor sites in vivo.
Results: In the particle characterization process, successful synthesis of nanoparticles was achieved, along with the verification of their acid-responsive function and toxic effects. Furthermore, in vitro experiments demonstrated the activation of bone marrow-derived dendritic cells (DCs) (Figure 1).To further investigate the in vivo vaccine effects, C57BL/6 mice were euthanized, and lymph nodes were extracted to examine the accumulation of FITC-PAEMA. It can be observed that, due to the reduction in size of the particles in the tumor acidic environment, the immune adjuvant can easily enter the lymph nodes. Activation of the STING pathway in dendritic cells within the lymph nodes was detected through qPCR. The maturation of dendritic cells (DCs) in the lymph nodes was determined using flow cytometry (Figure 2).
Conclusions: In this study, we developed a straightforward yet potent strategy focused on in situ tumor targeting. This approach effectively inhibits tumor growth while inducing immunogenic cell death and eliciting a systemic anti-tumor immune response against cancer cells. Additionally, we intend to validate the therapeutic efficacy of this strategy on metastatic and distal tumors in subsequent investigations.
Citation Format: Haiyu Zhou, Hengliang Hou, Bin Xu, Yucheng Huang, Hongrui Qiu. A nanoplatform based on an in situ tumor vaccine and activation of STING and TLR7/8 pathways for enhanced NSCLC 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 5761.
Abstract 5769: Target identification of T-cell activating immunomodulatory tetrahydrothiazepines: DGKα and DGKζ inhibitors
Authors: Luebbers Thomas , Britschgi Adrian , Costa Veronica , Friess Thomas , Hau Jean-Christophe , Heidkamp Gordon , Kuehne Holger , Martin Laetitia J. , Roudnicky Filip , Tzouros Manuel , Vandemeulebroucke An 
Published: March 2024

Abstract
We became interested in bicyclic tetrahydrothiazepine derivatives described in a Patent (WO 2016/139181) having immunomodulatory activities on CD3-activated T cells (CD4+ & CD8+) and NK cell increasing the secretion of several cytokines such as, e.g., IL-2, IFN-γ and/or TNF-α whereas corresponding unstimulated immune cells do not respond. Surprisingly - in contrast to what has been described in the patent - the N-H of the Amides 1 and 2 described in the patent was not required for potency and the oxadiazoles 1 and 2 were significantly more potent in T-cell proliferation and IL-2 release. Compound 1 was in vivo active in a single dose PD study in mice after CD3 activation and in a MC38 xenograft mice model showing single agent activity. Amide 1 and Amide 2 were identified in a phenotypic screen and the mode of action was unknown. Because of the promising pharmacological profile and in vivo activity, we were interested in the target. Here we describe how we identified the potential targets DGKα and DGKζ.
Citation Format: Thomas Luebbers, Adrian Britschgi, Veronica Costa, Thomas Friess, Jean-Christophe Hau, Gordon Heidkamp, Holger Kuehne, Laetitia J. Martin, Filip Roudnicky, Manuel Tzouros, An Vandemeulebroucke. Target identification of T-cell activating immunomodulatory tetrahydrothiazepines: DGKα and DGKζ inhibitors [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 5769.
Abstract 578: Prediction of PD-1 treatment outcome in mismatch repair deficient metastatic colorectal cancer using a multi-omic approach
Authors: Saberzadeh-Ardestani Bahar , Emiloju Oluwadunni E. , Graham Rondell P. , Lewis Jason T. , Abbott Charles W. , Boyle Sean M. , Sinicrope Frank A. 
Published: March 2024

Abstract
Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with deficient DNA mismatch repair (d-MMR) cancers, yet less than half of patients with metastatic colorectal cancer (mCRC) receive clinical benefit. We analyzed heterogeneity within d-MMR tumors using a multi-omics approach inclusive of percent unstable microsatellite loci (MS).
Methods: We studied consecutive patients with d-MMR mCRC with available primary tumors (N=32) that were treated with an anti-PD-1 antibody at Mayo Clinic (2015-2022). Tumors were profiled using a whole exome and transcriptome platform (ImmunoID NeXT®). MSIsensor was used to calculate percent unstable microsatellite loci from whole exome sequencing data. CIBERSORT and ssGSEA were used to analyze immune gene expression in relationship to percent unstable microsatellite loci. An immune checkpoint gene expression signature was calculated as the mean expression of CD274, CTLA-4, HAVCR2, LAG-3, PDCD1, PDCD1LG2, TIGIT. Aforementioned variables were analyzed in relationship to objective tumor response (RECIST version 1.1). A Cox proportional hazards model was fit to predict progression-free survival (PFS).
Results: Among 32 patients with d-MMR mCRC treated with PD-1 blockade, 16 (50%) received first-line anti-PD-1 therapy; others had &gt; 1 prior chemotherapy regimen. Eighteen (56.3%) tumors harbored BRAFV600E, 4 (12.5%) had mutant KRAS, and median PFS was 24.6 months (95% CI: 8.4, NR) with 18 events. Neither tumor mutation burden (TMB) nor PD-L1 mRNA expression predicted PFS. Median percent unstable MS loci was 14.38 (IQR: 2.6-23.2). Patients whose tumors had higher percent unstable MS loci had significantly better PFS (Q2-4 vs Q1; HR: 0.22, 95%CI: 0.06, 0.62; P=0.003), and were associated with increased objective response (P=0.049). Tumors with higher unstable loci also had higher neoantigen clonality (R= 0.64; P= 0.0003) and increased M0 (resting) macrophages (P=0.02). Nonresponders (vs responders) to PD-1 blockade had an increased immune checkpoint expression signature (P= 0.005).
Conclusion: A higher percentage of unstable microsatellite loci, associated with higher neoantigen clonality and resting macrophages, was predictive of anti-PD-1 efficacy. Furthermore, an immune checkpoint gene expression signature was associated with objective response.
Citation Format: Bahar Saberzadeh-Ardestani, Oluwadunni E. Emiloju, Rondell P. Graham, Jason T. Lewis, Charles W. Abbott, Sean M. Boyle, Frank A. Sinicrope. Prediction of PD-1 treatment outcome in mismatch repair deficient metastatic colorectal cancer using a multi-omic approach [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 578.
Abstract 5785: Shedding light on PARP1-E2F1 interaction by Cryo-EM
Authors: Iglesias Pablo , Casajus-Pelegay Ester , Moreno-Morcillo Maria , González-Rendo Lara , Porres-Ventin Laura , Arce Victor M. , Fernandez-Leiro Rafael , Costoya Jose A. 
Published: March 2024

Abstract
Cell division is orchestrated by a complex network of interactions between proteins involved in numerous signaling pathways that control cell proliferation. One of these main players is the E2F family of transcription factors. The role of these key players is to regulate the expression of several genes important in cell proliferation, particularly those involved in progression through G1 and into the S-phase of the cell cycle. In fact, cell cycle deregulation is a hallmark of cancer, and multiple studies have highlighted the critical role of E2F hyperactivation in tumor progression, angiogenesis, and metastasis. However, targeting a master regulator of cell growth will also have a pernicious effect on non-cancerous cells, thus limiting its applications. In order to overwhelm these restrictions, we propose a therapeutic approach in which E2F transcriptional activity is specifically reduced in cells with hyperactivation of the pathway, such as cancer cells.We and others have shown that poly (ADP-ribose) polymerase 1 (PARP1) is a transcriptional co-activator of E2F1 and, owing to this, loss of PARP results in cell cycle re-regulation and reduction of tumor growth. Interestingly, this effect of PARP1 does not depend on its enzymatic activity, thus opening a completely new strategic approach. Furthermore, considering that most oncogenic processes are associated with cell cycle deregulation, disruption of PARP1-E2F1 interaction could provide a new therapeutic target with a wide spectrum of indications in cancer. Currently, we lack comprehensive structural details regarding the PARP-1/E2F1 protein-protein interaction. To address this, we used cryo-EM to investigate both the standalone structure of PARP1 (full length) and its interaction with E2F1. This approach yielded high-resolution structural insights into the PARP1-E2F1 complex, enabling precise identification of the protein-protein interaction interface (PPI). Through this exploration of structural and molecular determinants governing this interaction, we aim to develop innovative strategies for designing drugs targeted at disrupting this complex. This work was supported by Agencia Estatal de Investigación (AEl/10.13039/501100011033), Xunta de Galicia (GPC GI-1862, ED431B 2020/26; ED431G 2019/02) and European Regional Development Fund-ERDF.
Citation Format: Pablo Iglesias, Ester Casajus-Pelegay, Maria Moreno-Morcillo, Lara González-Rendo, Laura Porres-Ventin, Victor M. Arce, Rafael Fernandez-Leiro, Jose A. Costoya. Shedding light on PARP1-E2F1 interaction by Cryo-EM [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 5785.
Abstract 5788: Targeting p97-NPL4 pathway by copper chelators
Authors: Mistrik Martin , Skrott Zdenek , Loffelmann Martin 
Published: March 2024

Abstract
Copper chelators forming stable complexes, such as the bis(diethyldithiocarbamate)-copper complex (CuET), derived from Antabuse (disulfiram, DSF), have shown pronounced anticancer activity. CuET induces aggregation of NPL4, a crucial cofactor of the p97 segregase in the ubiquitin-proteasome system, leading to proteotoxic stress and subsequent cancer cell death. Our study investigates whether NPL4 inhibition is unique to CuET or extends to other dithiocarbamate-copper complexes and distinct copper chelators. Utilizing a cellular NPL4 aggregation screening assay, we examined various chelators for their ability to induce NPL4 aggregation. Our findings reveal that this capacity is relatively common among structurally diverse DTCs-copper complexes and other unrelated copper chelators. Compounds that caused NPL4 aggregation also triggered NPL4-p97 complex immobilization, polyubiquitinated protein accumulation, and unfolded protein and heat shock responses. These responses correlated strongly with cancer cell cytotoxicity, particularly potent at nanomolar concentrations, underscoring NPL4 as a critical target. Our results demonstrate the broad potential of copper chelators in targeting NPL4, inducing lethal proteotoxic stress in cancer cells, and offering significant implications for drug development.
Citation Format: Martin Mistrik, Zdenek Skrott, Martin Loffelmann. Targeting p97-NPL4 pathway by copper chelators [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 5788.
Abstract 5794: DX2206, a humanized monoclonal antibody that targets IL1RAP, exhibits potent inhibition of IL-1 pathways and activities against tumors in vitro and in vivo
Authors: Liu Qinghao , Ru Yaqi , Jiang Yan , Li Huimin , Li Wenbo , Yang Lan , Shi Qian 
Published: March 2024

Abstract
Background: The Interleukin-1 Receptor Accessory Protein (IL1RAP) is found on cancer cells, stromal cells, and infiltrating immune cells within the tumor microenvironment (TME) of various cancers. It plays an important role in tumor development at various stages by activating IL-1 superfamily pathway, thus become an interesting target in cancer treatment.
Methods: We investigated the correlation between IL1RAP and tumor prognosis through the analysis of the public dataset. An antibody discovery campaign was performed and DX2206 was identified as the top clone against IL1RAP. Epitope of DX2206 was determined by examining the binding of DX2206 with different IL1RAP structural domains and in silico analysis. The activities of DX2206 against IL-1, IL-33, and IL-36 were examined using multiple assays with HEK293-Luc reporter cells, primary HUVEC cells, and A431 human skin squamous carcinoma cells. In vivo efficacy was evaluated in a CDX model.
Results: Based on public data, IL1RAP is overexpressed in various types of cancer patients compared to healthy individuals, and high expression of IL1RAP is associated with poor prognosis in multiple cancer types. Furthermore, high expression of the members of the IL-1 superfamily, such as IL1RAP, IL-1, and IL-36, are negatively correlated with pan-Cancer OS. Our epitope analysis indicated that DX2206 binds to a unique epitope within IL1RAP domain 2. In vitro assays demonstrated that DX2206 inhibited the activities of all three pathways, IL-1, IL-33, and IL-36, with sub-nanomolar IC50s. Simultaneously, it induced a potent ADCC effect in the tumor killing assay. Finally, in a CDX model, DX2206 significantly inhibited tumor growth in vivo.
Conclusions: We discovered a potent antagonist antibody, DX2206, that binds to a unique epitope of IL1RAP, inhibits all three pathways of signaling, and demonstrates in vitro and in vivo activities against tumors. Considering these characteristics, DX2206 emerges as an outstanding preclinical candidate for cancer therapy. IND enabling study was ongoing to expedite the candidate into clinic.
Citation Format: Qinghao Liu, Yaqi Ru, Yan Jiang, Huimin Li, Wenbo Li, Lan Yang, Qian Shi. DX2206, a humanized monoclonal antibody that targets IL1RAP, exhibits potent inhibition of IL-1 pathways and activities against tumors in vitro and 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 5794.