tbuckley/cabot-search huggingface dataset:
Abstract 5591: Development of a BCR-ABL degrader overcoming resistance by BCR-ABL1 kinase domain mutations in chronic myeloid leukemia
Authors: Ye Seul Lim, Na-rae Jeong, Sun-Mi Yoo, Han Wool Kim, So Hyuk Kim, Hyun-Hwi Kim, Yongdae Kwon, Heejung Moon, Hohyun Lee, Jungmin Ahn, Jihye Lee, Je Ho Ryu, Song Hee Lee
Journal: Cancer Research (2025)

Abstract Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by the presence of the BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML, yielding remarkable responses in patients. However, resistance mutations within the BCR-ABL1 kinase domain can arise, leading to treatment failure and disease progression. In this study, we report the identification of potent, orally efficacious BCR-ABL1 PROTACs. UBX-362 exhibits strong degradation activity against BCR-ABL1 proteins in CML cell lines. Consistently, it effectively suppresses cell viability in these cell lines, with low nanomolar IC50 values. Additionally, we evaluated the effects of single and combination therapies with TKIs (Asciminib or Ponatinib) using cell proliferation assays in K562 and Ba/F3 BCR-ABL1 mutant cell lines. Co-treatment of UBX-362 with Asciminib or Ponatinib resulted in a synergistic anti-proliferative effect in K562 cells. Notably, the combination of UBX-362 and Asciminib showed synergistic growth-inhibitory effects in Ba/F3 cell lines harboring BCR-ABL1 mutations. Oral administration of UBX-362 significantly reduced BCR-ABL1 protein levels in tumor tissue and robustly inhibited tumor growth in a CML CDX mouse model. These preclinical findings suggest the potential for the clinical development of a BCR-ABL1 degrader. Furthermore, UBX-362 demonstrates the ability to overcome resistance in CML patients with BCR-ABL1 mutations and shows promise as a candidate for combination therapy with other BCR-ABL1 inhibitors, providing new therapeutic possibilities for CML patients. Citation Format: Ye Seul Lim, Na-rae Jeong, Sun-Mi Yoo, Han Wool Kim, So Hyuk Kim, Hyun-Hwi Kim, Yongdae Kwon, Heejung Moon, Hohyun Lee, Jungmin Ahn, Jihye Lee, Je Ho Ryu, Song Hee Lee. Development of a BCR-ABL degrader overcoming resistance by BCR-ABL1 kinase domain mutations in chronic myeloid leukemia [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 5591.
Abstract 2726: A circadian regulator drives tumor lineage plasticity through chromatin bivalency resolution
Authors: Yatian Yang, None Xiong zhang, None hongye zou, Eva Corey, Ronald M. Evans, Amina Zoubeidi, Hongwu Chen
Journal: Cancer Research (2025)

Abstract Chromatin bivalency plays an important role in cell lineage specification during development. Cancer therapy resistance involves an extensive reprogramming of gene expression resulting in tumor lineage plasticity (LP). However, the underlying mechanisms are poorly understood. Rev-erb-alpha, a member of the nuclear receptor transcription factor family, plays a key role in regulation of circadian rhythm and metabolism primarily through repression of its target genes. We performed sequential ChIP-seq epigenome profiling of tumor tissues from the clinic and PDX models of prostate cancer and integrated analysis of tumor epigenome and transcriptome. We also treated the PDX models with small-molecule inhibitors of the receptor. We found that most of the tumor LP genes, including those in programs of neurodevelopment, neural signaling, stemness and EMT, are controlled by bivalent promoters with concurrent marking of H3K27me3 and H3K4me3. Our further studies revealed that the bivalent chromatin state resolves during the development of cancer therapy resistance. Interestingly, Rev-erb-alpha plays a critical role in promoting the bivalency resolution and activation of the LP programs. Its pharmacological targeting effectively reverses the bivalency resolution and diminishes the LP in anti-AR therapy-resistant tumors. Therefore, our study establishes that resolution of chromatin bivalency is a major epigenetic mechanism of tumor LP and demonstrates that therapeutic targeting of Rev-erb-alpha represents a novel treatment of advanced prostate cancer. This work was supported by NIH and UC Davis comprehensive cancer center and U.S. Department of Defense. Citation Format: Yatian Yang, Xiong zhang, hongye zou, Eva Corey, Ronald M. Evans, Amina Zoubeidi, Hongwu Chen. A circadian regulator drives tumor lineage plasticity through chromatin bivalency resolution [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 2726.
Abstract 3618: Biosocial determinants of health disparities among racial/ethnic minorities with chronic liver disease and liver cancer
Authors: Tagari Samanta, Jun Hyoung Park, Panagiotis Katsonis, Benny Abraham Kaipparettu
Journal: Cancer Research (2025)

Abstract Background: Metabolic disorders and chronic liver disease (CLD) play crucial roles in the development and progression of liver cancer (LC) like hepatocellular carcinoma (HCC). Previous studies suggest that the ethnic minority population increasingly suffers from CLD and LC. Thus, the impact of biosocial factors contributing to CLD and LC among minority populations requires further investigation. Using the All of Us database, this study aimed to understand the biosocial factors contributing to CLD and LC among racial subgroups. Methods: Using All of Us Researcher Workbench, we analyzed in a cohort of 33767 CLD [non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and Hepatitis B and C] patients among different ethnic groups. We investigated the impact of various social determinants of health (SDOH) factors and genetic variations in key liver disease genes (PNPLA3, TM6SF2, MBOAT7, GCKR, and HSD17B13). Additionally, we explored metabolic pathways contributing to LC progression were analyzed using MACdb, GENT2, and TCGA databases and publicly available RNASeq data. Results: Several confounding factors associated with CLD in Hispanic (HA) and African American (AA) populations compared to the non-Hispanic White (NHW) populations were identified in this study. HA and AA CLD patients suffer more from high socioeconomic status (SES) barriers. While genetic variations in the aforementioned genes were associated with CLD risk, their impact varied across ethnic groups. Metabolomic data of urinary metabolites from LC patients and healthy volunteers suggest hypoxanthine is upregulated in LC patients. TCGA analysis of hypoxanthine-related genes in the LC tumors confirmed that xanthine dehydrogenase (XDH), which converts hypoxanthine to uric acid, is down-regulated in the tumors of Asian patients. Survival analysis confirmed poor overall survival among the Asian and AA LC patients with lower XDH expression in their tumors. Conclusions: Our study highlights the complex interplay of social, genetic, and metabolic factors in CLD and LC disparities. Further research is needed in a larger cohort to eliminate the root causes of these SES and cancer signaling disparities to obtain a more equitable survival outcome from CLD and LC in minority populations. Citation Format: Tagari Samanta, Jun Hyoung Park, Panagiotis Katsonis, Benny Abraham Kaipparettu. Biosocial determinants of health disparities among racial/ethnic minorities with chronic liver disease and liver 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 3618.
Abstract 1882: Development of hit compounds targeting STAT3 for autoimmune diseases and cancers using a chemoproteomics-driven approach
Authors: Heejung Yang, Hojin Yoo, Sang-Jun Han, Sijin Kim, Donggyun Hong, Jeongyeon Kang, Birang Jeong, Go-Yeon Jung, Namgil Lee, Hoguen Kwak, Byung-Seok Kim
Journal: Cancer Research (2025)

Abstract Signal transducer and activator of transcription 3 (STAT3) is a critical regulator of immune responses, cellular proliferation, and survival, positioning it as a promising therapeutic target in autoimmune diseases and cancer. In this study, we present a chemoproteomics-based approach for the discovery and optimization of small-molecule inhibitors targeting STAT3. A series of novel small molecules capable of selectively modulating STAT3 activity were identified. By integrating structure-based design with our chemoproteomics platform, we not only validated the interactions of these compounds with STAT3 but also elucidated their downstream signaling effects in disease-relevant autoimmune models. Our chemoproteomics platform facilitates the unbiased identification of drug targets and off-target effects at a proteome-wide scale, significantly accelerating the lead optimization process. These findings highlight the potential of our STAT3 inhibitors as a novel class of therapeutics for autoimmune diseases. Ongoing studies are focused on optimizing these compounds for clinical trials by using the chemoproteomics platform to identify their molecular mechanisms of action and to predict potential off-target effects. Citation Format: Heejung Yang, Hojin Yoo, Sang-Jun Han, Sijin Kim, Donggyun Hong, Jeongyeon Kang, Birang Jeong, Go-Yeon Jung, Namgil Lee, Hoguen Kwak, Byung-Seok Kim. Development of hit compounds targeting STAT3 for autoimmune diseases and cancers using a chemoproteomics-driven approach [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 1882.
Abstract 3647: Validation of a computational reasoning model for precision oncology with large-scale patient-derived xenograft data
Authors: Robert Doczi, Akos Takacs, Anna Dirner, Dora Lakatos, Maria Kocsis-Steinbach, Barbara Vodicska, Dora Tihanyi, Eniko Kispeter, Reka Szalkai-Denes, William T. Beck, Petak Istvan
Journal: Cancer Research (2025)

Abstract Comprehensive tumor molecular testing is key in precision oncology. However, interpretation of complex molecular profiles in clinical practice can be challenging and subjective. The Digital Drug Assignment (DDA) system is a computational reasoning model that scores treatment options based on full tumor genomic data. This approach was predictive of relative benefit of the agents as used in the SHIVA01 trial (DOI: 10.1038/s41698-021-00191-2). Here, we analyzed patient-derived xenograft (PDX) data from Gao et al. (DOI: 10.1038/nm.3954). Molecular profiles of 179 solid tumors were processed by DDA, the resulting personalized drug scores were evaluated with treatment outcome data in PDX models for 1151 molecularly targeted agent (MTA) monotherapies, using 23 MTAs, targeting key oncogenic signaling pathways. In the PDX avatar system, multiple treatments can be tested for the same tumor, and outcomes can be measured in clinical metrics, enabling direct evaluation of drug ranking. To this end, cohorts were formed based on DDA ranking positions for each MTA-tumor pair. DDA ranking position was predictive of relative treatment benefit (Table, upper panel). Because the difference between neighboring ranks is probably minor, and to increase group sample sizes, larger cohorts were formed by combining neighboring rank groups. Here, a clear pattern of gradual decrease of treatment benefit with ranking distance from the top cohort was demonstrated (Table, lower panel). In this study, utilizing the unique advantages of the PDX system, we could demonstrate the predictive power of DDA treatment ranking. Digital drug assignment can serve as a practical and economic in silico avatar system for treatment planning and can potentially address challenges with complex molecular profiles in routine clinical settings. Citation Format: Robert Doczi, Akos Takacs, Anna Dirner, Dora Lakatos, Maria Kocsis-Steinbach, Barbara Vodicska, Dora Tihanyi, Eniko Kispeter, Reka Szalkai-Denes, William T. Beck, Petak Istvan. Validation of a computational reasoning model for precision oncology with large-scale patient-derived xenograft data [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 3647.
Abstract 6186: HPV vaccine hesitancy and uptake: A conceptual analysis using Rodgers' evolutionary approach
Authors: Grace Kwakyewaa Kyei, Evans F. Kyei, Rockson Ansong
Journal: Cancer Research (2025)

Abstract Aim: This study examines the factors contributing to HPV vaccine hesitancy through Rodgers's evolutionary concept analysis, with a focus on the role of uncertainties surrounding the vaccine's impact on preventing HPV-related diseases despite its availability.Design: Rodgers's evolutionary concept analysis was employed to investigate factors influencing HPV vaccine hesitancy. The analysis considered studies published in English within the past five years (2019 - 2024), excluding those older than five years, non-English publications, and studies focused on other vaccines. Data Sources: To ensure a thorough review, a comprehensive literature search was conducted across key databases, including PsycINFO, CINAHL, MEDLINE, and PubMed. Relevant keywords such as “HPV” and “vaccine hesitancy” were used. Review Methods: Following PRISMA guidelines, 29 articles were selected for analysis: 19 quantitative studies, 8 qualitative studies, and 2 mixed-methods studies. The analysis explored factors related to HPV vaccine hesitancy, examining antecedents, attributes, and consequences. Results: Key antecedents identified included cultural beliefs, educational level, knowledge, and vaccine availability, along with factors like insurance status, perceived risk, and decision-making processes. Significant attributes influencing hesitancy involved media coverage, environmental and community influences, social factors, trust in healthcare, efficacy rates, and safety concerns. Consequences of hesitancy were noted as lower vaccine uptake, increased HPV-related diseases, and the persistence of misinformation. Conclusion: This study underscores the complex interaction of factors contributing to HPV vaccine hesitancy. Addressing these factors is essential to overcoming vaccine hesitancy challenges and creating effective intervention strategies. Impact: This analysis's findings provide valuable insights into public health strategies for enhancing vaccine uptake and reducing HPV-related diseases. Targeted efforts to address misinformation and build vaccine trust can improve public health outcomes. Patient or Public Contribution: This concept analysis was conducted without the direct involvement of patients, service users, caregivers, or members of the public. Citation Format: Grace Kwakyewaa Kyei, Evans F. Kyei, Rockson Ansong. HPV vaccine hesitancy and uptake: A conceptual analysis using Rodgers' evolutionary approach [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 6186.
Abstract 3053: SHP2 inhibition with RMC4630 demonstrates antitumor efficacy and potentiates nanoparticle-paclitaxel response in pancreatic cancer
Authors: Nicola Grimaldi, Lily Darman, Mitchel Ramos, Margaret Schwarz, Niranjan Awasthi
Journal: Cancer Research (2025)

Abstract Objective: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a grim prognosis. The combination of nab-paclitaxel and gemcitabine (NPT-GEM) remains the standard treatment for advanced and metastatic PDAC, achieving a median survival of approximately 8.5 months. An activating mutation in the KRAS gene is central to PDAC pathogenesis, driving cancer cell proliferation, survival, and tumor progression through downstream pathways, including PI3K/AKT/mTOR and RAS-RAF-MEK-ERK. Despite being a critical target, KRAS has long been considered "undruggable" due to its small size and the lack of accessible binding sites. The SHP2 inhibitor RMC4630, targeting a key coactivator of KRAS signaling, represents a promising therapeutic approach for PDAC. Methods: In vitro cell proliferation assays were performed using the colorimetric WST-1 method. Protein expression levels were assessed by immunoblotting. In vivo tumor growth studies were conducted in 4-6-week-old female NOD/SCID mice bearing AsPC-1 subcutaneous xenografts. Results: In vitro assays demonstrated dose-dependent inhibition of proliferation in PDAC-associated cell lines treated with RMC4630 and NPT-GEM. A synergistic effect was observed with the combination therapy. In KRASG12DAsPC-1 cells, NPT-GEM, RMC4630, and their combination inhibited proliferation by 33%, 13%, and 74%, respectively. Similarly, in KRASG12C MIA PaCa-2 cells, inhibition rates were 46%, 20%, and 78%, while in KRASwt BxPC-3 cells, inhibition was 63%, 26%, and 73%. PDAC Stromal cell proliferation was inhibited by 48%, 25%, and 60% with NPT-GEM, RMC4630, and their combination, respectively. Immunoblot analysis of KRAS G12D-mutant cells revealed that RMC4630 treatment decreased phosphorylation of PI3K/AKT and RAS-RAF-MEK-ERK pathway proteins, while increasing apoptosis marker proteins cleaved-PARP-1 and cleaved-caspase-3. In vivo, RMC4630 and NPT-GEM significantly delayed tumor growth, with the combination demonstrating synergistic effects. Tumor weights were reduced from 0.22g in controls to 0.09g with NPT-GEM, 0.077g with RMC4630, and 0.06g with the combination. No significant body weight changes were observed, indicating minimal toxicity. Conclusion: These findings underscore the therapeutic potential of RMC4630, especially in combination with standard chemotherapy, as a promising approach for managing KRAS-mutant PDAC. Citation Format: Nicola Grimaldi, Lily Darman, Mitchel Ramos, Margaret Schwarz, Niranjan Awasthi. SHP2 inhibition with RMC4630 demonstrates antitumor efficacy and potentiates nanoparticle-paclitaxel response in pancreatic 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 3053.
Abstract 1504: Harnessing the power of mangifera indica: Activation of Nrf2 by leaf-derived oxylipins
Authors: Atif Ali Khan Khalil, Min Seok Woo, Jung-Hwan Kim
Journal: Cancer Research (2025)

Abstract Mangifera indica L., a member of the Anacardiaceae family, is grown all over the world and is known for its therapeutic properties because of its abundance of bioactive chemicals. In the current study, we investigated the effect of mango leaf extract on oxidative stress in HeLa cells. At a concentration of 100 µg/mL, the n-hexane fraction (MLHx) significantly increased antioxidant response element (ARE)-luciferase activity, surpassing other fractions. Furthermore, via raising nuclear NRF2 levels, MLHx enhanced the HO-1 mRNA expression. Increased phosphorylation of ERK1/2 and stability of NRF2 are the fundamental mechanisms. Through bioactivity-guided isolation, six oxylipins were identified: 13(R)-hydroxy-octadeca-(9Z, 11E, 15Z)-trienoic acid (C-1), 9(R)-hydroxy-octadeca-(10E, 12Z, 15Z)-trienoic acid (C-2), 13(R)-hydroxy-(9Z, 11E)-octadecadienoic acid (C-3), 9(R)-hydroxy-(10E, 12Z)-octadecadienoic acid (C-4), 9-oxo-(10E, 12E)-octadecadienoic acid (C-5), and 9-oxo-(10E, 12Z)-octadecadienoic acid (C-6). Their structures were confirmed by advance spectroscopic methods, such as 1H NMR and MS. Additionally, the structures of compounds C-7 (9-oxo-(10E, 12Z, 15Z)-octadecatrienoic acid) and C-8 (13-oxo-(9E, 11E)-octadecadienoic acid) were characterized via LC-MS/MS mass fragmentation. This work is the first to disclose the isolation of components 1-6 from M. indica. In HeLa cells, compounds 3, 5, and 6 showed significant, dose-dependent stimulation of ARE-luciferase activity when tested for their impact on NRF2 activity Citation Format: Atif Ali Khan Khalil, Min Seok Woo, Jung-Hwan Kim. Harnessing the power of mangifera indica: Activation of Nrf2 by leaf-derived oxylipins [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 1504.
Abstract 3074: Sorafenib resistance and cholesterol metabolism in hepatocellular carcinoma
Authors: Veerababu Nagati, Dennis Kwabiah, Yamile Abuchard Anaya, Manish K. Tripathi
Journal: Cancer Research (2025)

Abstract Hepatocellular carcinoma (HCC) is among the most prevalent cancers and a leading cause of cancer-related deaths worldwide. Sorafenib, a multikinase inhibitor, serves as a key first-line treatment for HCC when surgical intervention is not an option. However, primary and acquired resistance to sorafenib has significantly limited its effectiveness, reducing the disease control rate. Dysregulation of numerous genes that influence cancer cell proliferation, survival, and drug resistance contributes to this challenge. Identifying the molecular drivers of sorafenib resistance remains critical to improving treatment outcomes. Several factors, including activation of oncogenic pathways (e.g., Akt/mTOR), hypoxia, cholesterol metabolism, multidrug resistance, and autophagy, play pivotal roles in driving resistance. RNA/DNA binding proteins, such as Y-box binding protein 1 (YBX1), are central to cancer progression, metastasis, and drug resistance. Elevated YBX1 expression correlates with poor prognosis in HCC. Our preliminary data indicate that YBX1 overexpression enhances oncogenic phenotypes such as proliferation, migration, and colony formation. Additionally, it upregulates oncogenic markers like CD44, PDL1, SNAIL, and TWIST, further promoting HCC progression. Conversely, YBX1 inhibition increases sensitivity to sorafenib, as evidenced by the downregulation of drug resistance markers in HCC cell lines. Kinases also play a critical role in drug resistance, and activation of Akt/mTOR-associated genes was observed in YBX1 overexpression models. Moreover, cholesterol metabolism pathways appear to be significantly impacted by YBX1. Specifically, sterol regulatory element-binding transcription factors (SREBF1 and SREBF2) and downstream lipid metabolism genes, such as COL1A1, are positively correlated with YBX1 expression and are activated in HepG2 and Huh7 sorafenib-resistant cells. Notably, YBX1 knockdown reversed the effects of SREBF2-associated lipid metabolism genes, reducing their role in drug resistance. Collectively, these findings suggest that YBX1 contributes to sorafenib resistance in HCC through cholesterol metabolism and oncogenic signaling. This research highlights YBX1 as a potential therapeutic target, with the promise of sensitizing sorafenib-resistant HCC cells and improving treatment outcomes. Citation Format: Veerababu Nagati, Dennis Kwabiah, Yamile Abuchard Anaya, Manish K. Tripathi. Sorafenib resistance and cholesterol metabolism in hepatocellular carcinoma [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 3074.