tbuckley/cabot-search huggingface dataset:
Abstract 246: Innovative use of a fluorescent probe and 3D spheroids to study A3 adenosine receptor-targeted compounds in cancer cell lines
Authors: Katerina Jecmenova, Alžběta Srovnalova, Marián Hajdúch, Petr Džubák
Journal: Cancer Research (2025)

Abstract Introduction: The A3 adenosine receptor (A3AR) is a promising cancer therapy targeted due to its role in tumor progression, immune regulation, and apoptosis. Its selective expression in tumors like the liver and pancreas makes it ideal for therapies with minimal off-target effects. However, live-cell imaging techniques to study A3AR, including receptor expression, membrane localization, and interactions with AR modulators, are limited. Here, we present CELT-228, an A3AR-specific fluorescent probe, as a tool for visualization and functional analysis in live cells and 3D spheroid cultures. This method also enables competitive binding assays to identify and validate new A3AR agonists and antagonists. Material and methods: The reporter cell line ES-012-A, overexpressing A3AR, was treated with the CELT-228 (Celtarys, Spain) and imaged via spinning disc confocal microscopy (Yokogawa CV7000). Fluorescent signal localization and intensity were analyzed using Signal Image Artist (Revity). Competitive binding assays using CELT-228 were developed for High Content Screening (HCS) of newly synthesized nucleoside-based compounds and for studying A3AR interactions in cancer cell lines of diverse origins. Additionally, CELT-228 staining was applied to 3D spheroids from Hep-3B cells to investigate receptor localization under varying microenvironmental conditions. Results: In 2D and 3D models, CELT-228 predominantly localized to cell membranes of reporter and cancer cell lines. Competitive assays showed that new compounds bind to the orthosteric site, competing effectively with CELT-228. In 3D spheroids, staining revealed A3AR distribution across different regions, including cell membranes and intracellular compartments. A3AR expression patterns varied in hypoxic, nutrient-deprived, and proliferative regions, providing insights into microenvironmental influences on A3AR regulation. Conclusion: CELT-228 is a versatile tool for studying A3AR in 2D and 3D models, enabling receptor localization, competitive binding assays, and receptor mapping in spheroids. This approach holds great potential for A3AR-targeted drug discovery and advancing cancer therapies. Supported by the MEYS Czech Republic: CZ-OPENSCREEN (LM2023052), EATRIS-CZ (LM2023053), SALVAGE (811100711/37), National Institute for Cancer Research (Program EXCELES, ID Project No. LX22NPO5102) and IGA_LF_2024_038. Citation Format: Katerina Jecmenova, Alžběta Srovnalova, Marián Hajdúch, Petr Džubák. Innovative use of a fluorescent probe and 3D spheroids to study A3 adenosine receptor-targeted compounds in cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 246.
Abstract 38: Augmenting drug responses to PARP inhibitors in high grade serous cancer with inhibitors of the anti-apoptotic protein Bcl-XL
Authors: Alla Buzina, Wiebke Schormann, Lilian Gien, Helen MacKay, David W. Andrews
Journal: Cancer Research (2025)

Abstract While most patients with high grade serous ovarian cancer (HGSC) respond to platinum-based chemotherapy, the response is rarely durable and recurrence almost inevitable. A characteristic of HGSC is defective DNA repair. A class of drugs called PARP inhibitors (PARPi) exploit this vulnerability and have proven useful in delaying recurrence. However, resistance is inevitable. In models of HGSC a protein that frequently confers resistance is called Bcl-xL, a member of the Bcl-2 family of proteins that prevent apoptosis. If treating the patients with a PARPi makes cancer cells dependent on Bcl-xL then adding an inhibitor of Bcl-xL to their treatment might overcome resistance to Olaparib and cause the cancer cells to die. To test this, we have initiated companion studies for a clinical trial in which patients that have had a recurrence after receiving platinum-based therapy will first be treated with the PARPi Olaparib and then, an inhibitor of Bcl-xL, Navitoclax, will be added to their course of treatment. Navitoclax has a well-known on-target side effect of thrombocytopenia. We show that with continuous dosing of Navitoclax, platelet counts recover and are maintained. Our preliminary data from the first few patients enrolled in the trial suggest that the combination is well tolerated and for several participants there was a reduction in tumor burden. However, Bcl-xL is only one of the five known inhibitors of apoptosis. To identify which women will benefit most from adding Navitoclax to their treatment we need a biomarker(s). Our hypothesis is that patient derived organoids can be used as a pragmatic way to identify for patient cohorts which Bcl-2 protein inhibitor will synergize with a PARPi to optimize treatment. By combining novel methods for cell aggregation and hydrogel based synthetic ECM supports we can reproducibly generate HGSC patient-specific tumor organoids models in weeks with greater than 90% success. Organoids grown 384 well format are stained with novel non-toxic dyes enabling live cell painting of chemoresponses to drugs alone and in combination with drugs targeting anti-apoptotic proteins. Our data suggest that this approach captures the inherent heterogeneity of the disease, albeit local to the sampled site. We are employing deep learning AI algorithms to enable automated analyses of 3D confocal image stacks of organoids to infer drug responses that will be compared to patient responses in ongoing clinical trials. Citation Format: Alla Buzina, Wiebke Schormann, Lilian Gien, Helen MacKay, David W. Andrews. Augmenting drug responses to PARP inhibitors in high grade serous cancer with inhibitors of the anti-apoptotic protein Bcl-XL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 38.
Abstract 788: QT prolongation induced by CDK-4/6 inhibitors in breast cancer: A prospective cohort study utilizing 12-hour continuous ECG monitoring
Authors: Chia-Lun Chang, Wan-Chen Hsieh, Wei-Wen Chang, Ping-Kun Hsiao, Mao-Chih Hsieh, Tzeon-Jye Chiou, Tzu-Yao Liao, H-Eugene Liu, Hsin-Hsien Yu, Chih-Hsin Lee
Journal: Cancer Research (2025)

Abstract CDK 4/6 inhibitors improve survival in HR+ and HER2 breast cancer patients but carry risks of QT prolongation. Single ECG readings may be unreliable. This study assesses QT prolongation via 12-hour ECG monitoring for three CDK 4/6 inhibitors. Methods: A prospective cohort study (Apr 2023-Aug 2024) included HR+, HER2- breast cancer patients receiving CDK 4/6 inhibitors. Exclusions were QTc &amp;gt;500 msec and persistent Af. Ribociclib/Palbociclib followed a 21/7 regimen; Abemaciclib was continuous. ECG monitoring occurred pre-treatment and on day 14 (Ribociclib/Palbociclib) or day 14 only (Abemaciclib). ECGs were recorded from 8 PM-8 AM and stored on the PCA 500 cloud. Drug blood concentrations were measured on day 8, with dose adjustments as needed. Results: From July 16, 2023, to July 31, 2024, 33 patients were included: Ribociclib (N=19), Abemaciclib (N=9), and Palbociclib (N=5). Case 36 underwent testing at 600 and 400 mg Ribociclib due to QT prolongation. • Ribociclib: Median baseline QTcF was 422 msec, rising to 431 msec (400 mg, N=7) and 440 msec (600 mg, N=13) post-treatment. QTcF Max &amp;gt;500 msec increased from 23% to 54% in the 600 mg group. • Palbociclib: Median QTcF rose from 431 msec (washout) to 439 msec (100 mg, N=4) and decreased to 421 msec (125 mg, N=4). QTcF Max &amp;gt;500 msec rose from 20% to 40% post-treatment. • Abemaciclib: Post-treatment QTcF medians were 425 msec (100 mg, N=1), 433 msec (150 mg, N=5), and 434 msec (alternative 150 mg, N=3). QTcF Max &amp;gt;500 msec increased to 56% post-treatment. Conclusions: Ribociclib and Abemaciclib prolonged QTcF Max &amp;gt;500 msec, especially at higher doses. Palbociclib had less QT prolongation and reduced QTcF at 125 mg. 12-hour ECG monitoring underscores the need for closer cardiac safety measures. Citation Format: Chia-Lun Chang, Wan-Chen Hsieh, Wei-Wen Chang, Ping-Kun Hsiao, Mao-Chih Hsieh, Tzeon-Jye Chiou, Tzu-Yao Liao, H-Eugene Liu, Hsin-Hsien Yu, Chih-Hsin Lee. QT prolongation induced by CDK-4/6 inhibitors in breast cancer: A prospective cohort study utilizing 12-hour continuous ECG monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 788.
Abstract 377: Mechanistic and phenotypic insights into temporal and dosage-dependent responses to PARP inhibition in advanced prostate cancer
Authors: Love A. Moore, Akshaya Karthikeyan, Bryan Correa Gonzalez, Anamitra Bhaumik, Ethan Sandoval, Alan Paul Lombard
Journal: Cancer Research (2025)

Abstract Background: Poly ADP-ribose polymerase (PARP) inhibition effectively treats prostate cancer (PCa) by inducing replication stress and cell death through synthetic lethality. However, PARP inhibitor (PARPi) resistance inevitably develops, necessitating the study of short- and long-term effects. Responses to PARP inhibition in PCa vary from cytostasis to cell death, with the impact of different dosages and durations underexplored. This study examines how temporal and dosage variations of Olaparib (Ola) influence PCa cell phenotypes and identifies mechanisms underlying treatment response and putative therapeutic strategies to address vulnerabilities following PARP inhibition. Methods: C4-2B cells were treated with 0, 1, and 5 µM Olaparib for 1 and 5 days. RNA sequencing (RNA-seq), gene set enrichment analysis (GSEA), cell growth assays, microscopy, and western blotting were used to identify pathway alterations and putative vulnerabilities. Results: C4-2B cells respond well to clinically relevant doses of olaparib. Morphological assessment at 1 and 5 days suggests significant differences in response based on duration and intensity of treatment. After 1 day, RNA-seq and western blots support a dominant p53-associated cell cycle checkpoint response which may be driven by ATM. By day 5, surviving cells exhibited significant morphology changes indicating epithelial-mesenchymal transition (EMT) and suggesting acquisition of a stress-induced phenotype. RNA-seq and GSEA support phenotypic shifts including EMT and significant changes in fatty acid metabolism. These findings suggest that prolonged PARP inhibition leads to adaptations in surviving cells. Strategies to either co-target cell cycle checkpoint activation or putative survival adaptations show promise in combination with olaparib. Conclusion: PARP inhibition induces distinct cellular and metabolic changes based on dosage and duration. Acute exposure may trigger p53-mediated cell cycle arrest, while prolonged exposure results in phenotypic shifts which may promote cell survival. Our study underscores the need for the design of rational combination therapies to address both immediate and long-term effects of treatment. Citation Format: Love A. Moore, Akshaya Karthikeyan, Bryan Correa Gonzalez, Anamitra Bhaumik, Ethan Sandoval, Alan Paul Lombard. Mechanistic and phenotypic insights into temporal and dosage-dependent responses to PARP inhibition in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 377.
Abstract 2293: <i>KLRC2</i> gene deletion is associated with active cytomegalovirus infection and risk of head and neck cancer
Authors: Heather H. Nelson, DeVon Hunter-Schlichting, Rondi Butler, Anna Prizment, Bharat Thyagarajan, Karl Kelsey
Journal: Cancer Research (2025)

Abstract Human cytomegalovirus (CMV) is a common infection that can have a profound impact on the immune system which, in turn, has the potential to impact cancer risk. Natural Killer (NK) cells are the front-line defense against viral infection and CMV seropositive individuals develop a specialized subset of NK cells, the adaptive NK (aNK), in response to CMV reactivation. A defining feature of aNK is surface expression of the NKG2C receptor, encoded by the KLRC2 gene. There is a polymorphic 15.5 kb deletion of the KLRC2 gene and approximately 5% of the Caucasian population completely lacks the NKG2C receptor due to this polymorphism. KLRC2 gene copy number has been shown to influence steady-state levels of aNK cells in CMV seropositive individuals, and deletion of the gene is associated with both early life CMV infection and CMV viremia after transplantation. Here, we have evaluated whether the polymorphic KLRC2 gene deletion is associated with active CMV infection and risk of head and neck squamous cell carcinoma (HNSCC) using the resources of the CoHANDS epidemiology study. KLRC2 deletion was measured using PCR with gel visualization in 1, 096 cases and 1, 179 controls. Among a subset of the controls (n=207) we measured CMV DNAemia, the presence of cell free CMV DNA in serum, which is an established biomarker of active CMV infection. KLRC2 deletion was associated with the presence of CMV DNAemia: among those with one copy of KLRC2 the risk of active infection was 2.74 (95% CI 1.30 - 5.78), and among those with homozygous deletion of KLRC2 the risk was 5.17 (95% CI 1.56 - 17.16). These results from a healthy population are consistent with prior reports that the KLRC2 gene is important in the control of CMV reactivation. We then evaluated KLRC2 as a risk factor for HNSCC. Homozygous deletion of the KLRC2 gene was strongly associated with increased risk of HNSCC after adjusting for age and sex (OR 3.99; 95% CI 2.62 - 6.10). Collectively, these data support the hypothesis that active CMV infection may be a risk factor for HNSCC. Citation Format: Heather H. Nelson, DeVon Hunter-Schlichting, Rondi Butler, Anna Prizment, Bharat Thyagarajan, Karl Kelsey. KLRC2 gene deletion is associated with active cytomegalovirus infection and risk of head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2293.
Abstract 1317: Lung-specific CRISPR/Cas9 delivery using sulfonium lipid nanoparticles effectively suppresses lung metastases by targeting ATAD3A
Authors: Fanghui Chen, David O. Popoola, Fan Yang, Wei Zhen, Yamin Li, Yong Teng
Journal: Cancer Research (2025)

Abstract Metastasis is the leading cause of cancer-related morbidity and mortality. The lung is the second most common site of metastasis. It is estimated that 20 to 54% of malignant tumors that develop elsewhere in the body will have pulmonary metastases. However, limiting metastatic tumor growth and progression in the lung remains a significant bottleneck. ATAD3A, a mitochondrial-localized protein, has been shown to play a critical role in maintaining the growth and survival of metastatic tumors in the lung. The current challenge lies in genetically depleting ATAD3A in lung metastatic tumors. Among various mRNA delivery systems, lipid nanoparticles (LNPs) are the most advanced for clinical use. While clinical trials mainly focus on mRNA/LNP therapies for liver diseases, the potential for gene editing therapies extends far beyond this and remains underexplored. In our previous work, we developed lung-specific sulfonium lipid nanoparticles (sLNPs) for selective mRNA delivery to the lung. Building on this, we have now created CRISPR-based ATAD3A-targeting nanodrugs, termed ltLNP3AKO, which encapsulate Cas9 mRNA and anti-ATAD3A sgRNA in the lung-specific sLNPs. In an experimental mouse model of lung metastasis, intravenous administration of ltLNP3AKO efficiently and specifically delivered Cas9 mRNA and anti-ATAD3A sgRNA to the lung, where it successfully depleted the ATAD3A gene. Most notably, ltLNP3AKO induced significant regression of lung metastatic tumors without causing lung or systemic inflammation or toxicity in major organs. These groundbreaking results not only highlight the safety and efficacy of the lung-targeted sLNP platform, but also provide a novel approach to selectively inhibit ATAD3A in lung metastases. Our study further demonstrates the great potential to advance gene editing therapies for patients with lung metastases. Citation Format: Fanghui Chen, David O. Popoola, Fan Yang, Wei Zhen, Yamin Li, Yong Teng. Lung-specific CRISPR/Cas9 delivery using sulfonium lipid nanoparticles effectively suppresses lung metastases by targeting ATAD3A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1317.
Abstract 273: Decipher actionable tumor suppressor defects in prostate cancer for precision medicine
Authors: Feiyu Chen, Di Zhao
Journal: Cancer Research (2025)

Abstract Chromatin remodeling proteins contribute to DNA replication, transcription, repair, and recombination. The chromodomain helicase DNA-binding (CHD) family of remodelers plays crucial roles in embryonic development, neurogenesis, and carcinogenesis. As the founding member, CHD1 is capable of assembling nucleosomes, remodeling chromatin structure, and regulating gene transcription. Dysregulation of CHD1 at genetic, epigenetic, and post-translational levels is common in prostate cancer and other malignancies. Through interacting with different genetic alterations, CHD1 possesses the capabilities to exert oncogenic or tumor-suppressive functions in context-dependent manners. In the past decade, my study uncovered the novel cell-intrinsic and -extrinsic roles of CHD1 during prostate cancer development, progression, and therapy resistance (Nature 2017, Cancer Discover 2020, Cancer Research 2022, Nature Cancer 2024). Cancer genome studies have uncovered a unique subtype of prostate cancer characterized by speckle-type BTB/POZ protein (SPOP) mutations, which stabilize AR and its co-activators and have been associated with prolonged responses to androgen deprivation therapies and favorable prognoses. Loss of CHD1 frequently co-occurs with SPOP mutations; however, how concurrent CHD1 loss impacts SPOP-mutated prostate cancer remains unclear. Most recently, by generating the first-in-the-field genetically engineered mouse models, we provided genetic evidence supporting that CHD1 loss accelerates SPOP-mutated prostate cancer progression and confers resistance to castration in this context. We uncover a non-canonical epigenetic function of CHD1 and demonstrate that CHD1 reprograms lipid metabolism by governing SREBPs. CHD1 loss-induced lipid reprogramming supplies intratumoral androgen biosynthesis and retains AR transcriptional activity in SPOP-mutated prostate tumors upon castration. Furthermore, the mechanistic studies facilitate the development of a novel biomarker-driven combinatorial therapy for castration-resistant prostate cancer harboring CHD1 loss and SPOP mutations. These findings advance our understanding of an emerging prostate cancer subtype and mechanism of action and provide novel therapeutic strategies for men with advanced prostate cancer. Citation Format: Feiyu Chen, Di Zhao. Decipher actionable tumor suppressor defects in prostate cancer for precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 273.
Abstract 2949: LX-101, a novel, clinical stage, payload-bearing targeted therapy directed to the insulin-like growth factor receptor (IGF-1R), demonstrates potent preclinical anti-tumor activity against multiple cancer types with elevated IGF-1R expression
Authors: Matt Hoberman
Journal: Cancer Research (2025)

Abstract Objective: LX-101 is a next-generation, targeted therapy directed to IGF-1R. LX-101 consists of a proprietary IGF-1 variant coupled to a cytotoxic methotrexate payload. LX-101 was previously evaluated in Phase 1 trials of adult patients with advanced, pretreated cancers, where it was well-tolerated and demonstrated single agent activity. Neither a dose limiting toxicity, nor a maximum tolerated dose was reached, leaving potential room for additional dose and schedule optimization. Multiple aggressive cancers of unmet need harbor alterations affecting the IGF-1R pathway, including gene fusions and/or high IGF-1R expression, that correlate with poor outcomes, including certain subsets of cancers of the breast, head and neck, esophagus, stomach, and lung, as well as Ewing’s sarcoma, osteosarcoma, and others. Prior attempts at targeting IGF-1R with non-payload bearing naked monoclonal antibodies or small molecules produced a range of clinical outcomes including some partial and complete responses. None of these agents, however, were ultimately approved, potentially due to redundant signaling, escape pathways, and/or the lack of enrichment for select tumor types with strong ties to the IGF-1/IGF-1R pathway. Herein, we investigated the anti-tumor activity of the payload-bearing agent LX-101 against IGF-1R-expressing cancer cell lines to overcome these past shortcomings. Methods: Cell lines known to highly express IGF-1R were incubated with LX-101 (∼1.6 - 2500nM). Cell viability was assessed by CellTiter-Glo after 4 days. IC50s were calculated using GraphPad PRISM software. Results: LX-101 displayed high levels of potency against lung cancer (A549, IC50 = 29 nM; NCI-H2122, IC50 = 10 nM; NCI-H526, IC50 = 23 nM), esophageal cancer (TE-1, IC50 = 16 nM; KYSE-70, IC50 = 7 nM), and stomach cancer (MKN74, IC50 = 19 nM; NUGC-4, IC50 = 30 nM). Conclusion: These results demonstrate that LX-101 has potent preclinical anti-tumor activity against multiple cancer cell lines expressing IGF-1R. These data support further clinical development of LX-101 in IGF-1R-involved cancers. New clinical trials are planned. Citation Format: Matt Hoberman. LX-101, a novel, clinical stage, payload-bearing targeted therapy directed to the insulin-like growth factor receptor (IGF-1R), demonstrates potent preclinical anti-tumor activity against multiple cancer types with elevated IGF-1R expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2949.