bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1917: HER2-FGFR1 interaction induced by bispecific molecules: A novel strategy for treating breast cancer
Authors: Krzyscik Mateusz Adam , Hristova Kalina 
Published: March 2024

Abstract
Breast cancer poses a significant global health challenge, demanding effective therapies targeting specific receptors. In our prior study, we engineered molecules capable of binding to both HER2 and FGFR1, pivotal receptors in breast cancer progression. By combining the high-affinity Affibody ZHER2:2891 for HER2 with a modified, stable form of FGF2 binding to FGFR1, we created the bispecific protein (AfHER2-lFGF2). This innovative molecule could simultaneously recognize HER2 and FGFR1, exhibiting enhanced cell penetration. When coupled with the potent cytotoxic agent monomethyl auristatin E (MMAE), it demonstrated exceptional efficacy in eliminating cancer cells expressing HER2, FGFR, or both receptors. Our current investigation focused on quantifying the interaction between HER2 and FGFR1 receptors on the cell surface upon treatment with these bispecific molecules. Leveraging fully quantified spectral imaging FRET (FSI-FRET), a technique utilizing spectrally resolved two-photon microscopy. We directly monitor the association of HER2 and FGFR1 in the plasma membrane. Our findings revealed that the bispecific AfHER2-lFGF2 molecule forces interaction between HER2 and FGFR1 on the cell surface. Furthermore, we analyzed the activation of the HER2-FGFR1 complex and subsequent downstream signaling pathways using western blotting. In summary, our research uncovers the ability of the AfHER2-lFGF2 bispecific protein to foster direct interaction between HER2 and FGFR receptors on the cell membrane. By employing state-of-the-art techniques like FSI-FRET, we elucidated the mechanisms governing this interaction and, by western blotting, downstream signaling pathways. These insights emphasize the potential of AfHER2-lFGF2 as a promising therapeutic agent for targeting HER2, FGFRs, and HER2/FGFRs-positive cancers. This approach paves the way for targeted therapies in addressing the prevalent global health challenge of breast cancer.
Citation Format: Mateusz Adam Krzyscik, Kalina Hristova. HER2-FGFR1 interaction induced by bispecific molecules: A novel strategy for treating breast cancer [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 1917.
Abstract 1928: Targeting FAK to improve the therapy of KRAS G12C mutant cancers
Authors: Liu Shuang , Shi Junfen , Lu Chang , Zhang Miao , Xin Ying , Zhu Yan , Li Jijun , Luo Hong , Sun Yinghui 
Published: March 2024

Abstract
Despite the pivotal role of KRAS G12C in tumor initiation and progression, currently available KRAS G12C inhibitors have relatively modest activity compared to other approved therapies targeting other classic oncogenic drivers. Fortunately, efforts to improve the anti-tumor response to KRAS G12C targeted therapy have benefited from the use of combination approaches. Here, we found that treatment with KRAS G12C inhibitors induces sustained activation of focal adhesion kinase (FAK) in KRAS G12C mutant cell lines from various cancer types, including non-small cell lung cancer, colorectal cancer, and pancreatic cancer. These results suggest a potential role for FAK in adaptive resistance to KRAS G12C inhibition and encourage us to explore the anticancer effects of combining the KRAS G12C inhibitor SY-5933 with a FAK inhibitor, CT-707. The cell viability and clonogenic assays using various KRAS G12C mutant cancer cell lines showed that the combination of SY-5933 and CT-707 synergistically inhibited cell growth. Mechanistically, this enhanced anti-proliferative effect is associated with a significant decrease in FAK activity and a more pronounced induction of cell cycle arrest and apoptosis. In vivo efficacy studies in multiple cell line derived xenograft (CDX) models, the combination of SY-5933 plus CT-707 consistently induced a more potent anti-tumor response than either monotherapy alone. In conclusion, our results demonstrate that CT-707 has the potential to enhance the efficacy of SY-5933 by suppressing adaptive FAK activation under KRAS G12C inhibition. This provides a rationale for an innovative combination therapy to improve outcomes in patients with KRAS G12C mutated cancers.
Citation Format: Shuang Liu, Junfen Shi, Chang Lu, Miao Zhang, Ying Xin, Yan Zhu, Jijun Li, Hong Luo, Yinghui Sun. Targeting FAK to improve the therapy of KRAS G12C mutant cancers [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 1928.
Abstract 1948: Resistance to RAS inhibition promotes remodeling of the immunosuppressive microenvironment of pancreatic cancer
Authors: Tiriac Herve 
Published: March 2024

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, largely due to acquired chemotherapy resistance. MRTX-1133, a promising KRAS-G12D inhibitor, has demonstrated initial efficacy; however, resistance analogous to that seen with KRAS-G12C inhibitors is an emerging challenge. The tumor microenvironment (TME) is increasingly recognized as a contributor to resistance, often fostering tumor survival and immune evasion.
Methods: To elucidate the resistance mechanisms to KRAS-G12D inhibition, we established resistant mouse and human PDAC cell lines derived from mouse and human models. These models were analyzed using flow cytometry and single cell RNA sequencing to define TME dynamics as resistant is acquired and after is has been established. We also analyzed cytokines released by resistant tumor cells using protein arrays and RNA sequencing.
Results: Our investigation revealed significant TME alterations associated with acquired resistance. Notably, there was a marked increase in the population CD4+ Tregs and neutrophil while activated CD8+ T cells are decreased in the resistant tumors. Concurrently, an increased secretion of chemokines such as CXCL1 and CXCL2 was observed in resistant tumor cells relative to their parental counterparts.
Conclusions: The adaptation of PDAC to circumvent KRAS inhibition involves a distinct reprogramming of the TME, attenuating immune surveillance and potentially facilitating tumor progression. Current efforts are directed towards delineating the key pathways implicated in these TME modifications to pioneer new therapeutic approaches for managing KRAS inhibitor resistant PDAC.
Citation Format: Herve Tiriac. Resistance to RAS inhibition promotes remodeling of the immunosuppressive microenvironment of pancreatic cancer [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 1948.
Abstract 1974: Discovery of TRX-211-399, a potent, CNS-penetrant, highly selective inhibitor of EGFR exon 20 insertion mutations
Authors: Chun Kwangwoo , Lim Sumin , Lee Joohyun , Choi Seulgi , Kim Seongrak , Choi Youngil , Park Areum , Kim Bohee , Park Yongseo , Choi Eunhyun , Lee Sungwon , Lee Koo 
Published: March 2024

Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for approximately 2 million new cases and 1.8 million deaths annually. Various types of EGFR-activating mutations are one of the most important oncogenic drivers in non-small cell lung cancer (NSCLC). Among NSCLC patients with EGFR mutations, 5-10% of patients have EGFR exon 20 insertion (ex20ins) mutations that are insensitive to clinically available EGFR tyrosine kinase inhibitors (TKIs). Recently, as mobocertinib (EXKIVITY®) failed to improve progression-free survival in Phase 3 clinical trial, there remains a high unmet medical need to develop new drugs with wider therapeutic window to treat NSCLC harboring EGFR ex20ins mutations. Herein, we report a novel EGFR-TKI, TRX-211-399, specifically designed to target ex20ins mutations. TRX-211-399 potently inhibited the proliferation of not only Ba/F3 cells overexpressing near-loop (A767dupASV, S768dupSVD) and far-loop (H773insNPH, H773dupH) mutations but also patient-derived NSCLC cell line. In particular, TRX-211-399 demonstrated high selectivity against wild-type EGFR. With favorable DMPK profiles, once-daily oral administration of TRX-211-399 showed significant tumor regression in multiple Ba/F3 xenograft models carrying different EGFR exon20ins mutations. Furthermore, in a PC-9-luc cell intracranial xenograft model, TRX-211-399 induced substantial anti-tumor effects and prolonged survival without body weight loss. TRX-211-399 is currently undergoing further preclinical evaluation as a potential candidate for clinical development for patients with EGFR exon20ins mutations.
Citation Format: Kwangwoo Chun, Sumin Lim, Joohyun Lee, Seulgi Choi, Seongrak Kim, Youngil Choi, Areum Park, Bohee Kim, Yongseo Park, Eunhyun Choi, Sungwon Lee, Koo Lee. Discovery of TRX-211-399, a potent, CNS-penetrant, highly selective inhibitor of EGFR exon 20 insertion 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 1974.
Abstract 1994: Drug-induced cancer cell secretome promotes resistance in colon cancer
Authors: Satapathy Shakti Ranjan , Ghatak Souvik , Sjölander Anita 
Published: March 2024

Abstract
Colorectal cancer (CRC) is the third most common cancer in the world, with a projection of increased lethality in the upcoming years. Adjuvant chemotherapy with biological agents is the most practiced standard of care today. However, patients with metastatic CRC (mCRC) do not benefit from the wide range of therapies available for CRC, which either owe to unresectability or co-morbidity or more importantly resistance to therapy. 5-fluorouracil (5-FU) combined with leucovorin, oxaliplatin, or irinotecan (FOLFOX or FOLFIRI) has been routinely employed as the first-line therapy in colon cancer, but patients often develop resistance to 5-FU. Additionally, tumor cell dormancy plays a major role in tumor relapse which leads to poor prognosis in the patients. Despite many advances, the understanding of therapy-induced resistance is still in its infancy. Here, we show that 5-FU-induced tumor cell secretome helps in the outgrowth and metastasis of 5-FU-resistant clones in colon cancer. We used parental and 5-FU-resistant colon cancer cell lines, and transgenic zebrafish embryos to test the hypothesis and perform the colon cancer cell-based functional assays. We observed that 5-FU resistant (5-FU-R) colon cancer cells showed an increase in proliferation and survival when cultured with the secretome of 5-FU exposed colon cancer cells compared to the DMSO-induced secretome. Interestingly, we also noted elevated migration and invasion in the 5-FU-R colon cancer cells exposed to 5-FU-induced secretome compared to the DMSO counterpart. Additionally, in zebrafish xenograft, we found that 5-FU-R colon cancer cells cultured with 5-FU-induced secretome showed higher tail-vein metastatic burden compared to the 5-FU-R cells cultured with DMSO-induced secretome. This provides a background to further study in detail the therapy-induced resistance as well as dormancy in colorectal cancer which will help to develop approaches to prevent or reverse chemoresistance in patients who receive systemic therapy for mCRC.
Citation Format: Shakti Ranjan Satapathy, Souvik Ghatak, Anita Sjölander. Drug-induced cancer cell secretome promotes resistance in colon cancer [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 1994.
Abstract 2020: Determination of parameters to understand the metabolism in the tumor microenvironment by in vivo microdialysis
Authors: Heins Mariette Suzan , Flik Gunnar 
Published: March 2024

Abstract
The tumor microenvironment presents a unique surrounding with more favorable conditions for the cancer cells to growth thrive and interact than for the host cells. To obtain a better understanding of cancer biology and pathophysiology, information about the physiological state of the tumor microenvironment is crucial. By using the in situ microdialysis technique we can quantitate relevant modulators in the interstitial space of the tumor.
The current set of experiments demonstrates the benefits of the use of microdialysis in freely-moving awake tumor-bearing animals. Following inoculation, growth was monitored continuously and upon an average tumor volume of 400 mm3, the animals underwent surgical implantation of microdialysis probes. The next day, the sample collection was initiated by perfusion of the implanted probes with dialysate fluid. Samples were continuously collected over several hours and stored at -80C. Levels of analytes indicative of metabolic and physiological conditions of the tumor microdialysis were quantified by EIA and/or LC-MS/MS analysis.
The microdialysis technology combined with sensitive analytical methods allows us to quantify several analytes from the tumor microenvironment simultaneously and monitor changes over time. Metabolic activity is an important indicator of tumor growth speed. Depletion of energy can lead to increases in lactate levels and acidification of the tumor microenvironment. Resulting in a reduction of host immunological efficacy. Elucidation of the status of the tumor environment during tumor growth and treatment allows for better translational models.
Citation Format: Mariette Suzan Heins, Gunnar Flik. Determination of parameters to understand the metabolism in the tumor microenvironment by in vivo microdialysis [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 2020.
Abstract 204: Quantitative evaluation of biomarkers for TGF-β-induced epithelial-mesenchymal transition in biochemical, cellular, and 3D spheroid model systems
Authors: Wood Antony W. , Heimsath Ernest 
Published: March 2024

Abstract
Epithelial-mesenchymal transition (EMT) is a cellular differentiation process whereby epithelial cells lose epithelial features and acquire mesenchymal, fibroblast-like properties, leading to reduced cell-cell contacts and increased motility. EMT is a fundamental biological process required for normal embryonic development, but may be co-opted by malignant epithelial tumors to facilitate metastatic spread. A known driver of EMT is the TGF-β superfamily of growth factor ligands, which elicit receptor-mediated responses in cells, primarily via TGF-β/SMAD signaling pathways. In these pathways, receptor-mediated SMAD (R-SMAD) proteins serve as the primary downstream effector molecules, the activities of which are regulated through receptor-mediated phosphorylation. The magnitude and duration of ligand-induced receptor activation influences the level of SMAD phosphorylation, which in turn influences the magnitude of the downstream cellular response(s). In this study, we describe high-throughput methods to quantitatively evaluate the biochemical and cellular responses to TGF-β/SMAD pathway activation in a cellular model of TGF-β-induced EMT. Effects of pathway activation are examined at different levels of biological complexity (biochemical, cellular, and multicellular), using 2D and 3D (spheroid) models. Collectively, these approaches enable a comprehensive evaluation of TGF-β/SMAD pathway activation that is amenable to high-throughput analysis platforms.
Citation Format: Antony W. Wood, Ernest Heimsath. Quantitative evaluation of biomarkers for TGF-β-induced epithelial-mesenchymal transition in biochemical, cellular, and 3D spheroid model systems [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 204.
Abstract 2049: Novel preclinical models for PROTAC evaluation: And beyond
Authors: xu yuzhou , Zhang Jichuan , Tian Ye , Chen Ziyu , Wang Amy , Ma Ting , Chen Qikuan , Yin Yinfei 
Published: March 2024

Abstract
Proteolysis-targeting chimeras (PROTACs) are a novel class of small molecules that induce the degradation of target proteins. Unlike conventional inhibitors that disable target proteins by direct binding, PROTACs are event-driven, meaning that a single PROTAC molecule can induce the degradation of multiple target protein molecules. This catalytic mechanism allows PROTACs to achieve complete inhibition of target proteins at lower concentrations compared to conventional inhibitors, making them a promising therapeutic approach for previously considered "undruggable" targets.Despite their promise, the development of PROTACs faces several challenges. The large molecular weight of PROTACs can lead to poor cell permeability and bioavailability. Additionally, the lack of high-throughput, quantitative assays for evaluating PROTAC efficacy hinders structure-activity relationship (SAR) studies. The formation of the Protein-PROTAC-E3 ternary complex is crucial for PROTAC function, and reliable methods for assessing this interaction are essential for PROTAC development.In this poster, ChemPartner showcases a comprehensive suite of preclinical models for PROTAC evaluation, encompassing both in vitro and in vivo approaches. Using low-cost, high-throughput biochemical assays, we can provide valuable insights into PROTAC efficacy, facilitating SAR studies and elucidating the relationship between molecular structure and activity. Followed by in cell and in vivo function assays, we can test PROTAC PK/PD, toxicity, and efficacy. This suite of assays provides a powerful tool to speed up PROTAC development and reduce the fail rate.
Citation Format: yuzhou xu, Jichuan Zhang, Ye Tian, Ziyu Chen, Amy Wang, Ting Ma, Qikuan Chen, Yinfei Yin. Novel preclinical models for PROTAC evaluation: And beyond [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 2049.
Abstract 2090: The GNAQ T96S mutation enhances the oncogenic properties of breast cancer
Authors: Wu Ming-Hsi , Wang Hsiang-Ching , Wang Wei-Hsin , Lin Yen-Ju , Chen Wan-Ru , Chen Shih-Ta , Fu Chih-Wei , Chuang Eric 
Published: March 2024

Abstract
Breast cancer (BC) is the most commonly diagnosed cancer in the world, and metastatic breast cancer (mBC) remains responsible for the majority of breast cancer deaths. In this study, we collected 615 cases of Taiwanese BC patient's tumor samples and used whole exome sequencing (WES) to clarify the genetic mutation landscape of this population. We have compared with various BC genomic databases such as TCGA, COSMIC, and MSKCC to identify 29 novel variants in 18 genes that were predicted to have a pathogenic effect. In these pathogenic variants, we found that the GNAQ T96S mutation (threonine 96 to serine alteration of the Gαq protein) was presented in 116 out of 615 BC patients (18.9%). To examine the effect of the GNAQ T96S mutation on BC, we transfected the MCF-7 and MDA-MB-231 cell lines with the wild-type or the mutant GNAQ T96S expression vector. Transfection with the GNAQ T96S expression vector enhanced cell proliferation, colony formation, migration, and activation of the MAPK pathways compared to wild-type GNAQ expression MCF-7 cells. We also found that the tumorigenicity, and tumor growth were significantly increased in the GNAQ T96S expressed MCF-7 xenograft model, and exhibited higher rates of lung metastasis in GNAQ T96S expressed MDA-MB-231 cells. Our data suggest that the GNAQ T96S mutation may play an oncogenic role in BC by potentiating the GNAQ signaling pathway. In this study, we also found several compounds that can inhibit in vitro cell proliferation and in vivo tumor growth of GNAQ T96S expressed MCF-7 cells. These compounds showed the potential to treat the mBC patients who have GNAQ T96S mutation.
Citation Format: Ming-Hsi Wu, Hsiang-Ching Wang, Wei-Hsin Wang, Yen-Ju Lin, Wan-Ru Chen, Shih-Ta Chen, Chih-Wei Fu, Eric Chuang. The GNAQ T96S mutation enhances the oncogenic properties of breast cancer [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 2090.
Abstract 2153: The impact of socioeconomic and racial segregation on cancer stage at diagnosis, treatment and mortality among patients with small cell lung cancer
Authors: Bekele Bayu B. , Lian Min , Liu Ying 
Published: March 2024

Abstract
Background: Although studies have revealed the adverse impact of residential segregation on early detection, treatment, and survival of non-small cell lung cancer―a predominant type of lung cancers, it remains unknown regarding the role of residential segregation in treatment and outcomes of small cell lung cancer (SCLC)―a rare type of lung cancer characterized by rapid growth and poor prognosis. Therefore, we examined the associations of racialized socioeconomic segregation with risks of extensive-stage diagnosis, non-adherence to guideline-recommended treatment, and mortality among non-Hispanic White (NHW) and non-Hispanic Black (NHB) patients with SCLC.
Methods: This population-based retrospective cohort study included patients who were diagnosed with SCLC as a first primary malignancy at age 20 and older between January 2007 and December 2015, followed through December 2016, and identified from the Surveillance, Epidemiology, and End Results. County-level racialized socioeconomic segregation was measured using the Index of Concentration at the Extremes (ICE). Multilevel logistic regression accounting for county-level clustering was used to estimate odds ratios (ORs) for extensive-stage diagnosis and non-adherence to guideline-recommended treatment. Hazard ratios (HRs) for lung cancer-specific mortality and all-cause mortality were computed using multilevel Cox regression.
Results: Among 38,393 patients, 90.1% were NHW and 9.9% were NHB. Patients dwelling in the counties with the highest concentration of low-income NHB households (highest ICE quartile) had higher risks of non-adherence to guideline-recommended treatment (OR=1.23, 95% CI: 1.08-1.40; Ptrend &lt;0.01), lung cancer-specific mortality (HR=1.08, 95% CI: 1.04-1.12; Ptrend &lt;0.01), and all-cause mortality (HR=1.13, 95% CI: 1.09-1.17; Ptrend &lt;0.0001) as compared with patients dwelling in the counties with the highest concentration of high-income NHW households (lowest ICE quartile). These associations were comparable between NHB and NHW patients. Racialized economic segregation was not significantly associated with extensive-stage diagnosis.
Conclusions: Residing in the segregated, low-income NHB counties had adverse impacts on stage-appropriate treatment for SCLC and survival outcomes. Future research on the pathway(s) linking residential segregation to SCLC treatment underutilization and poor outcomes is warranted.
Citation Format: Bayu B. Bekele, Min Lian, Ying Liu. The impact of socioeconomic and racial segregation on cancer stage at diagnosis, treatment and mortality among patients with small cell lung cancer [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 2153.