bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 574: Adipocyte-derived FABP4 promotes non-alcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma by driving ITGB1-mediated β-catenin activation
Authors: Leung Carmen Oi Ning , Gurung Shilpa , Chung Katherine Po Sin , Chan Sze Man , Lee Terence Kin Wah 
Published: March 2024

Abstract
Nonalcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma (HCC) is an emerging malignancy in the developed countries. However, the mechanisms contributing to its formation remain largely unknown. Given the role of cancer stem cells (CSCs) in tumor initiation and therapeutic resistance, we hypothesize that adipocytes, one of the key cellular factors within the tumor microenvironment of NAFLD-induced HCC, may play a critical role in HCC development and drug resistance by regulating liver CSCs. Using a co-culture system in which differentiated adipocytes were grown with HCC cells, we found that adipocytes enhanced the self-renewal ability of HCC cells through indirect paracrine secretion. HCC cells pre-incubated with conditioned medium from adipocytes showed enhanced liver CSC properties including self-renewal, tumorgenicity, invasiveness and chemo-resistance to doxorubicin and sorafenib. Secretome profiles showed that FABP4 was preferentially secreted by adipocytes and its level was further augmented when co-cultured with HCC cells. Concurrently, recombinant FABP4 enhanced CSC properties of HCC cells. Drastic delay in the onset of tumor development in FABP4−/- mice upon DEN-injected and high fat diet-induced mouse models of NAFLD-HCC. Mass spectrometry analysis revealed ITGB1 as a direct binding partner of FABP4 for the first time. This data, together with the observation of significant downregulation of the Wnt/β-catenin pathway in tumors of FABP4−/− mice, revealed the role of adipocyte-derived FABP4 promotes liver CSC function by activating the PI3K/Akt/β-catenin signaling pathway via ITGB1. Overexpression of ITGB1 led to poorer survival of HCC patients with NAFLD as a risk factor. The development of a monoclonal neutralizing antibody against FABP4 successfully blocked FABP4-driven CSC functions, implicating the targetability of FABP4 for the treatment of NAFLD-induced HCC.
Citation Format: Carmen Oi Ning Leung, Shilpa Gurung, Katherine Po Sin Chung, Sze Man Chan, Terence Kin Wah Lee. Adipocyte-derived FABP4 promotes non-alcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma by driving ITGB1-mediated β-catenin activation [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 574.
Abstract 5747: Microwave responsive thermosensitive lipid nanoparticles for spatiotemporal delivery of chemotherapeutics
Authors: Aparicio-Lopez Cesar B. 
Published: March 2024

Abstract
Pancreatic cancer is a highly lethal malignancy with an urge for the exploration of novel treatments. One promising approach is microwaved-induced hyperthermia, which has shown great antitumor and synergistic effects when combined with other therapies. The application of microwaves produces heat by dielectric hysteresis which depends on the dielectric properties of molecules. Ionic liquids (ILs) are compounds composed of ions with &lt;100 °C melting point and have strong dielectric properties. In short, we propose the creation of microwave-sensitive nanoparticles using IL, enabling precise hyperthermia induction with low-powered microwaves in localized areas. To achieve this, we stabilize a core composed of 1-butyl-methylimidazolium bromide or 1-butyl-3-methylimidazolium hexafluorophosphate using Span 80, Tween 20, and Triton-X as surfactants, along with phosphatidylcholine lipids as “cosurfactants”. Employing a double emulsion procedure for fabrication, nanoparticles are characterized using dynamic light scattering, Fourier-transform infrared spectroscopy, and transmission electron microscopy. Furthermore, we assess microwave sensitivity by comparing thermal changes between liposomes loaded with 120 mM and 250 mM NaCl solutions. Subsequently, we evaluate biocompatibility and heat effects by incubating IL nanoparticles with BXPC3 and KPC cells, monitoring cell viability through MTT assays. We aim to confine the ILs within the nanoparticle core rather than incorporating them into the membrane. We anticipate increased microwave sensitivity, translating to reduced off-target effects and enhanced precision in hyperthermia treatment. This research holds promise for improving the therapeutic outcomes of pancreatic cancer treatment.
Citation Format: Cesar B. Aparicio-Lopez. Microwave responsive thermosensitive lipid nanoparticles for spatiotemporal delivery of chemotherapeutics [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 5747.
Abstract 5756: Silver graphene quantum dots as drug delivery platforms for anti-cancer application
Authors: Villanueva Rafael A. , Cole Tori , Medina Nataniel , Morell Dr. Gerardo , Weiner Brad 
Published: March 2024

Abstract
Prostate cancer (PCa) stands as the most frequently diagnosed cancer and the third leading cause of cancer-related deaths among men in the United States (2019). Various cancer treatments, including Rehabilitation therapy, Immunotherapy, Hormone therapy, Stem Cell Therapy, and Chemotherapy, are available. However, chemotherapy has notable limitations due to its tendency to harm healthy cells, resulting in side effects such as nausea, vomiting, alopecia, diarrhea, anemia, bleeding, and sterility. In response to these challenges, we developed nanoparticle (NP) drug delivery platforms for cancer treatment. These platforms utilize silver graphene quantum dots nanocomposites (AgGQD), known for their ability to enhance drug therapies. Silver nanoparticles (AgNPs) exhibit toxicity towards both normal and cancer cells by impacting mitochondrial function, reactive oxygen species (ROS) production, lactate dehydrogenase (LDH) release, cell cycle dysregulation, induction of apoptotic genes like Bax, micronucleus formation, chromosome aberration, and DNA damage. Additionally, AgNPs demonstrate antiangiogenic and antiproliferative properties by inhibiting PI3K phosphorylation of Akt, disrupting the signaling pathway, ultimately halting angiogenesis, depriving cells of oxygen, and causing tumor cell death. To mitigate the toxicity of AgNPs in healthy cells and enhance their performance as drug delivery platforms, graphene quantum dots (GQDs) were introduced in this study. Moreover, GQDs may contribute to improving the solubility of drugs with low water solubility. The NPs were synthesized using graphene quantum dots as reducing agents. The study involved identifying the IC50 value, conducting validation tests on AgGQD and AgGQD doped, and comparing their toxicity on cells. Confocal microscopy was employed to identify the intracellular location of the drug.
Citation Format: Rafael A. Villanueva, Tori Cole, Nataniel Medina, Dr. Gerardo Morell, Brad Weiner. Silver graphene quantum dots as drug delivery platforms for anti-cancer application [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 5756.
Abstract 5772: Structural insights and rational design, optimization of highly potent and selective novel GRK5/6 inhibitors for cancer therapy
Authors: Chen Yueyi , Sonawane Amol D. , Manda Rajesh , Gadi Ranjith K. , Ghosh Arun K. , Tesmer John J. 
Published: March 2024

Abstract
G protein-coupled receptor kinases (GRKs) regulate cell signaling by triggering receptor desensitization via phosphorylation on G protein-coupled receptors (GPCRs). There are seven human GRKs (GRK1−GRK7) where GRK5 and GRK6 are structurally similar. GRK5 is ubiquitous and required for cancer progression in various cancer types. Knock-down of GRK5 has been shown to suppress prostate cancer and non-small-cell lung cancer growth. GRK6 is highly abundant in immune cells and is overexpressed in multiple myeloma (MM). Knocking down GRK6 has been shown to cause apoptosis of MM cells. Therefore, targeting GRK5 or 6 is a potential chemotherapeutic strategy. Currently, we are developing a series of inhibitors for GRK5/6 based on a lead compound derived from sunitinib and utilizing Cys474 residue unique in GRK5/6 to enhance selectivity by covalent capture. We tested a series of novel inhibitor warheads to improve potency and selectivity without potentially toxic functional groups. So far, we have identified several inhibitors with low nanomolar IC50 for GRK5 and more than 100,000-fold selectivity over GRK2, another closely related member expressed in the heart. I have developed a pipeline of X-ray crystallography of GRK5 available for soaking various ligands and have solved several structures of novel inhibitor-bound GRK5. The structure elucidated the binding mode of this new class of GRK5 inhibitors, where the core interacts with the adenine site, a fluorophenyl group stabilizes the P loop and density suggests in some cases covalent bond forming between the reversible covalent warhead and Cys474. Our ongoing studies focus on further compound optimizations based on SAR. Overall, the discovery of the inhibitors can significantly facilitate understanding and treatment and cancers.
Citation Format: Yueyi Chen, Amol D. Sonawane, Rajesh Manda, Ranjith K. Gadi, Arun K. Ghosh, John J. Tesmer. Structural insights and rational design, optimization of highly potent and selective novel GRK5/6 inhibitors for cancer therapy [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 5772.
Abstract 5773: Multi-omics profiling of chemotactic characteristics of brain microglia and astrocytoma
Authors: Chen Chih-Yi , Huang Yu-Ching , Su Wen-Hsiu , Liu Yi-Ting , Chen Chi-Sheng , Li Chia-Yang , Chang Kun-Che , Dai Chia-Yen , Wang Shu-Chi 
Published: March 2024

Abstract
Brain cancer is a deadly disease with low survival rates for over 70 % of patients. Therefore, there is a critical need to develop better treatment methods and strategies to improve patient outcomes. In this study, we explored the tumor microenvironment and discovered unique characteristics of microglia to interact with astrocytoma cells and promote proliferation and migration of collisions. The conditioned medium from the collisions expressed cell chemoattraction and anti-inflammatory responses. To further understand the interactions between microglia and astrocytoma cells, we used flow sorting and protein analysis found that the protein alterations were related to biogenesis in the astrocytoma cells and metabolic processes in the microglia. Both types of cells were involved in binding and activity in cell-cell interactions. Using STRING to demonstrate the protein cross-interaction between the cells. Furthermore, PHB and RDX interact with oncogenic proteins, which were significantly expressed in patients with Glioblastoma Multiforme (GBM) and low-grade glioma (LGG) according to GEPIA. To study the role of RDX in chemoattraction, the inhibitor-NSC668394 suppressed collision formation and migration in BV2 cells in vitro by down-regulating F-actin. Additionally, it suppressed macrophage infiltration in infiltrating islands in vivo of intracranial tumor-bearing mice. These findings provide evidence for the role of resident cells in mediating tumor development and invasiveness and suggest that potential interacting molecules may be a strategy for controlling tumor growth by regulating the infiltration of tumor-associated microglia in the brain tumor microenvironment.
Citation Format: Chih-Yi Chen, Yu-Ching Huang, Wen-Hsiu Su, Yi-Ting Liu, Chi-Sheng Chen, Chia-Yang Li, Kun-Che Chang, Chia-Yen Dai, Shu-Chi Wang. Multi-omics profiling of chemotactic characteristics of brain microglia and astrocytoma [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 5773.
Abstract 5778: Determining the structure and function relationship of the oxysterol-binding protein (OSBP) to guide drug development
Authors: Bayimenye Ruth Fiona , Berrios-Rivera Jorge L. , Nimmo Susan , Bourne Christina R. , Burgett Anthony W. 
Published: March 2024

Abstract
The human Oxysterol Binding Protein Structure and function relationship remains elusive, yet the anti-cancer and antiviral molecules library targeting OSBP and OSBP-Related proteins (ORPs) continues to grow. OSBP is a ubiquitously expressed protein in most eukaryotes, functioning as a master lipid sensor and cholesterol regulator in cells. OSBP and its closely related protein ORP4 are also reported to be essential in several human diseases, including viral infection and cancer cell proliferation. Our lab has shown that the natural product OSW-1 has potential anti-viral and anti-cancer activity through targeting OSBP and ORP4, as confirmed with protein-ligand interactions that showed binding with high affinity. Moreover, several anti-cancer molecules targeting the ORPs provoke different protein conformation changes and, therefore, lead to varying OSBP functions. However, the structure of full-length OSBP is still unknown, which leaves a gap in knowledge regarding the compounds’ mechanism of action or how OSBP could be established as a molecular anti-cancer target. Our goal is to determine the structure and function relationship of OSBP with emphasis on the effect of small molecule ligands on cellular OSBP levels and function. In pursuit of this research goal, we aim to determine the in vitro activity of OSW-1 analogs (OA) isolated in our lab, as well as determine their interaction with OSBP and ORP4 proteins in multiple cancer cell lines. We mainly seek to determine the structure and ligand interaction with the OSBP-ligand binding domain (LBD) and full-length OSBP to shed light on the conformation changes that occur upon ligand binding. Preliminary data indicate that the tested OA compounds are active in multiple cancer cell lines with reduced OSBP levels effect, suggesting a similar mechanism of action to OSW-1. A transient expression of full-length OSBP and LBD showed that the truncated OSBP (LBD) was mostly found in the pellet, which could imply low solubility, while the full-length OSBP showed sufficient solubility. Our efforts are currently focused on purifying full-length OSBP. We are also working towards purifying full-length OSBP with a cleavage site that allows cutting out the LBD, thus solving the insolubility issue. Once obtained, the full-length OSBP and the ligand binding domain will be used for both binding and structure determination studies.
Citation Format: Ruth Fiona Bayimenye, Jorge L. Berrios-Rivera, Susan Nimmo, Christina R. Bourne, Anthony W. Burgett. Determining the structure and function relationship of the oxysterol-binding protein (OSBP) to guide drug development [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 5778.
Abstract 5780: Simultaneous targeting existing proteins and nascent proteins for synergistic anticancer activity
Authors: Li Bingbing X. , Wang Jian , Chao Bo , Piesner Jake , Kelly Felice , Petrie Stefanie Kaech , Xiao Xiangshu 
Published: March 2024

Abstract
Protein synthesis and subsequent delivery to the target locations in cells are essential for their proper functions. Newly synthesized proteins and existing protein have differential properties that can potentially be exploited for targeting to maximize therapeutic potentials. Methods to label and distinguish newly synthesized proteins from existing ones are critical to assess their differential properties, but such methods are lacking. We describe the first chemical genetics-based approach for selective labeling of existing and newly synthesized proteins that we termed as CG-SLENP. Using HaloTag in-frame fusion with lamin A (LA), we demonstrate that the two pools of proteins can be selectively labeled using CG-SLENP in living cells (https://doi.org/10.1101/2023.11.02.565346). We further employ our recently developed selective small molecule ligand LBL1 for LA to probe the potential differences between newly synthesized and existing LA. Our results show that LBL1 can differentially modulate these two pools of LA. We further extend our CG-SLENP strategy to evaluate the differences of the two pools for BRD4 (bromodomain containing 4). These observed differences motivated us to investigate the synergistic anticancer properties of BRD4 degraders and inhibitors in triple negative breast cancer. Our results show that simultaneous targeting newly synthesized proteins and existing proteins display strong synergistic anticancer activities.
Citation Format: Bingbing X. Li, Jian Wang, Bo Chao, Jake Piesner, Felice Kelly, Stefanie Kaech Petrie, Xiangshu Xiao. Simultaneous targeting existing proteins and nascent proteins for synergistic anticancer activity [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 5780.
Abstract 5792: Rapid and efficient generation of panels of T cell engaging (TCE) multispecific antibodies via complementary technologies
Authors: Ahonen Cory , Sharkey Nathan , Durkin Melissa , Avery Andrew , Battles Michael , Sharkey Beth , Barlow Kyle , Sivasubramanian Arvind , Stein Caitlin , Lunde Bradley , Schutz Kevin , Prinz Bianka , Pejchal Rob , Widboom Paul , Krauland Eric 
Published: March 2024

Abstract
A goal of immunotherapy is to induce an anti-tumor response that is potent and specific. However, there is increasing understanding that currently approved monospecific checkpoint inhibitors are not effective for all patients and/or indications. Thus, investigators are increasingly pursuing multispecific antibody treatments in an attempt to enhance clinical outcomes. These treatments may either take the form of mixtures (administered simultaneously or in series) of multiple monospecific antibodies, or as single entity, multispecific antibodies (‘multispecifics’). In the case of multispecifics, the large number of possible topologies and complexity of manufacture necessitate the development and application of a robust set of complementary technologies. We have developed an exemplary set of such technologies. Herein, we demonstrate the ability to direct desired antibody chain pairing (HC-HC and HC-LC), isolate and engineer single-domain antibodies, as well as generate large (&gt;100) panels of multispecific antibodies with diverse topologies from a limited number of input molecules. These technologies can be leveraged in combination with our affinity and developability-optimized TCE αCD3 and αCD28 antibody panels to achieve desired potency without the need for additional discovery or engineering.
Citation Format: Cory Ahonen, Nathan Sharkey, Melissa Durkin, Andrew Avery, Michael Battles, Beth Sharkey, Kyle Barlow, Arvind Sivasubramanian, Caitlin Stein, Bradley Lunde, Kevin Schutz, Bianka Prinz, Rob Pejchal, Paul Widboom, Eric Krauland. Rapid and efficient generation of panels of T cell engaging (TCE) multispecific antibodies via complementary technologies [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 5792.
Abstract 5796: A HER3 antibody that uniquely blocks the HER3 heterodimerization interface effectively inhibits tumor growth in pre-clinical models with potentially oncogenic HER3 mutations
Authors: Toy Weiyi , Thakkar Dipti , Magallanes Roberto , Wu Sharon , Poi Ming , Mas Alejandro , Paszkiewicz Konrad , Ingram Piers , Boyd-Kirkup Jerome 
Published: March 2024

Abstract
HER3 activation, via NRG1 ligand-dependent and -independent heterodimerization with HER2 or EGFR, has been associated with tumor progression and acquired resistance to therapies in multiple indications. HER3 mutations, detected in around 3% of cancer cases, may drive oncogenic signaling, leading to rapid tumor growth. Currently, there are no approved targeted therapies for HER3 mutations. Through analysis of real-world data and structural modelling of HER3 heterodimers, we identified four common HER3 mutations located within or close to the dimerization interface of HER3, suggesting a potential impact on HER3 heterodimerization. Immunoprecipitation assays confirmed that all four mutations increased the heterodimerization of HER3 with both HER2 and EGFR. Further, conversion of an endogenous HER3 mutation to wild type via CRISPR editing significantly reduced the growth of KYSE-150, a HER3 mutant cell line. HMBD-001 is a clinical-stage anti-HER3 antibody rationally developed to uniquely block the HER3 dimerization interface to potently inhibit HER3 heterodimerization. Through structural analysis and FACS binding on HER3 mutation cell lines, we confirmed that the binding epitope of HMBD-001 does not overlap with the selected HER3 mutations and therefore may be a good therapeutic option for patients with HER3 mutations. In vitro, HMBD-001 suppressed HER3 mutation-driven PI3K/AKT signaling, as demonstrated by the reduction of phosphorylated HER3 and AKT levels. In multiple cell- and patient-derived xenograft models with HER3 mutations HMBD-001 response achieved &gt;80% tumor growth inhibition. Based on this encouraging preclinical data, a Phase Ib clinical trial (NCT05919537) has been initiated, evaluating HMBD-001 in patients with aberrant HER3 signaling, including HER3 mutations.
Citation Format: Weiyi Toy, Dipti Thakkar, Roberto Magallanes, Sharon Wu, Ming Poi, Alejandro Mas, Konrad Paszkiewicz, Piers Ingram, Jerome Boyd-Kirkup. A HER3 antibody that uniquely blocks the HER3 heterodimerization interface effectively inhibits tumor growth in pre-clinical models with potentially oncogenic HER3 mutations [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 5796.