tbuckley/cabot-search huggingface dataset:
Abstract 1696: Combination therapy of cell cycle inhibitor and HDAC inhibitor induces metabolic alterations in pancreatic cancer
Authors: Shraddha P. Bhutkar, Anjali Yadav, Vikas V. Dukhande
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC), characterized by several multigene mutations, is one of the lethal solid cancers accounting for several drug treatment challenges. NCI statistics show that the overall 5-year survival rate of PDAC remains at 12.8%. The tumor aggressiveness and invasive-metastatic potential of the cancer, along with drug resistance issues, demand the development of novel and effective multi-drug therapies. Our initial results show that combination therapy of a cell cycle inhibitor Abemaciclib (Abe), and histone deacetylase inhibitor Panobinostat (Pan) effectively decreases pancreatic cancer cell proliferation and growth and causes apoptotic cell death. Cell cycle and epigenetic changes drive tumor progression by rewiring metabolic signaling pathways of pancreatic cancer cells. Therefore, we hypothesized that co-treatment of pancreatic cancer with Abe and Pan modulates cancer cell metabolism, developing energy imbalance leading to cell death. Our Seahorse metabolic experiments depicted a reduced oxygen consumption rate upon combination treatment in pancreatic cancer cells with upregulation of extracellular acidification rate. We also performed metabolomic profiling upon combination treatment in pancreatic cancer cells, revealing alterations in the levels of metabolites involved in carbohydrate, lipid, and amino acid metabolism in the combination treatment group compared to control pancreatic cells. We also observed a moderate increase in mitochondrial membrane potential upon combination treatment, suggesting altered mitochondrial metabolic signatures compared to control and individual drugs along with combination treatments. These results suggest that mitochondrial dysfunction may underlie the Abe and Pan combination treatment, impairing metabolic homeostasis and energy balance. Our future studies include deciphering the in-depth mechanism of alterations in mitochondrial dynamics and metabolic signaling pathways upon combining cell cycle and HDAC inhibitor treatment in pancreatic cancer cells by performing transcriptomic profiling on PDAC cells and in vivo xenograft studies. This study is funded by the College of Pharmacy and Health Sciences at St. John’s University, New York, and is also supported by the National Institute of General Medical Sciences (Award Number R16GM145557). Citation Format: Shraddha P. Bhutkar, Anjali Yadav, Vikas V. Dukhande. Combination therapy of cell cycle inhibitor and HDAC inhibitor induces metabolic alterations 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 1696.
Abstract 4297: Targeting metabolic dysfunction in prostate cancer: the anti-proliferative effects of ql47 through inhibition of dlat
Authors: Grace Nirmala Jesuthankaraj, August John, Huanyao Gao, Arun Kanakkanthara, Richard Weinshilboum, Liewei Wang
Journal: Cancer Research (2025)

Background: Prostate cancer is the most common cancer in men in the United States with an estimated 288,300 new cases diagnosed in 2023. The treatment strategies include androgen deprivation therapies (ADTs) for metastatic prostate cancer (mPC) but 10-20% of patients eventually progress to castration-resistant prostate cancer (CRPC). However, nearly all patients develop primary and acquired resistance overtime, and developing therapies and identifying novel molecular targets are essential in enhancing the clinical outcomes of patients with prostate cancer. In this study, we report a small molecule that belongs to a class of tricyclic quinolones, QL47 that was previously screened among various other compounds in prostate PDX organoid models and showed a potent anti-proliferative activity. Methods: QL47 was tested on prostate cancer cell lines (22Rv1, 22RV1 abiraterone-resistant and DU145) for its anti-proliferative potential. Further, we used the biotinylated QL47 (QL47B) to pulldown its potential targets and we identified the targets through immunoprecipitation-mass spectrometry (IP-MS) technique followed by Western blot analysis. Cell cycle and cell death analyses were performed after staining the cells with propidium iodide and Annexin V followed by flow cytometry analysis. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) was investigated using the Seahorse assay. Results: The initial screening of QL47 in prostate cancer cell lines showed that it inhibits the proliferation at an IC50 of 50-200 nM. Through IP-MS and Western blot analysis, we identified a member of the pyruvate dehydrogenase complex dihydrolipoamide S-acetyltransferase (DLAT) as a direct target of QL47. Mechanistically, we found that QL47 does not increase cell death or affect cell cycle, but inhibits metabolic function, with a decrease in both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Conclusion: We have identified a novel mechanism of action of QL47 on the pyruvate dehydrogenase complex, and we plan to further validate the safety and efficacy for the treatment of prostate cancer. Citation Format: Grace Nirmala Jesuthankaraj, August John, Huanyao Gao, Arun Kanakkanthara, Richard Weinshilboum, Liewei Wang. Targeting metabolic dysfunction in prostate cancer: the anti-proliferative effects of ql47 through inhibition of dlat [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 4297.
Abstract 1703: Molecular drivers of enzalutamide resistance in prostate cancer: insights into CYP3A5 and associated pathways
Authors: Imran Khan Mohammed, Ranjana Mitra
Journal: Cancer Research (2025)

Abstract Prostate cancer (PC) disproportionately affects Black/African American (AA) men, who experience higher incidence rates, more aggressive disease, and worse outcomes compared to non-Hispanic White Americans (NHWA). CYP3A5, a cytochrome P450 enzyme, is expressed at higher levels in individuals carrying the *1 variant, prevalent in AAs, compared to the *3 variant, more common in NHWA. Elevated CYP3A5 expression in AAs has been associated with aggressive prostate cancer phenotypes, potentially due to its role in activating androgen receptor (AR) signaling and promoting crosstalk with Wnt signaling pathways. Resistance to AR-targeted therapies, such as enzalutamide, remains a major challenge in metastatic castration-resistant prostate cancer (mCRPC), particularly in aggressive disease subtypes. To investigate mechanisms underlying enzalutamide resistance, we generated resistant PC cell lines of NHWA origin (low CYP3A5-LNCaP) and AA origin (high CYP3A5-MDAPCa2b). In resistant MDAPCa2b cells, RT2 androgen receptor profiler arrays revealed upregulation of MME, SGK1, SNAI, and STEAP, genes implicated in Wnt pathway regulation (SGK1), epithelial-to-mesenchymal transition (SNAI), and enhanced proliferation and migration (STEAP). Additionally, tumor suppressors and regulatory genes, including ADAMTS1, KLK4, MT2A, NDRG1, and TIPARP, were significantly downregulated, suggesting reduced ECM remodeling, oxidative stress responses, and DNA repair capacity in resistant cells. Importantly, CYP3A5 expressions were significantly elevated in resistant MDAPCa2b cells but remained unchanged in resistant LNCaP cells, highlighting a potential link between high CYP3A5 expressions and resistance mechanisms. The upregulation of SGK1, SNAI, and STEAP, alongside the downregulation of ADAMTS1, KLK4, MT2A, NDRG1, and TIPARP, suggests that resistance to enzalutamide involves AR and Wnt signaling, EMT, and loss of tumor suppressive functions. These findings support the hypothesis that the *1 CYP3A5 variant in AAs drives aggressive disease and therapeutic resistance, providing a molecular basis for observed clinical disparities and potential pathways for targeted intervention. Citation Format: Imran Khan Mohammed, Ranjana Mitra. Molecular drivers of enzalutamide resistance in prostate cancer: insights into CYP3A5 and associated pathways [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 1703.
Obstetrician and Gynecologist Physicians’ Practice Locations Before and After the <i>Dobbs</i> Decision
Authors: Becky Staiger, Valentin Bolotnyy, Sonya Borrero, Maya Rossin-Slater, Jessica Van Parys, Caitlin Myers
Journal: JAMA Network Open (2025)

Importance State abortion policies may influence the practice locations of obstetricians and gynecologists (OBGYNs), having potentially significant implications for access to and quality of reproductive health care. Objective To explore changes in OBGYN practice locations from before to after the Dobbs v Jackson Women’s Health Organization US Supreme Court decision in June 2022. Design, Setting, and Participants National Plan &amp;amp;amp; Provider Enumeration System data files were used in a descriptive cohort study assessing the association between state abortion policy environments and OBGYN practice locations in the US from January 1, 2018, to September 30, 2024, for all OBGYNs listed in the data files during the study period. Main Outcome and Measures The number of OBGYNs practicing in states with differing abortion laws and the movement of OBGYNs between these states before and after the Dobbs decision. Results The sample included 60 085 OBGYNs (59.7% women), of whom 3.8% were maternal-fetal medicine specialists and 12.9% were recent residency graduates. The mean increase in the per-quarter number of OBGYNs from before to after Dobbs was 8.3% (95% CI, 6.6%-10.1%) in states with total abortion bans, 10.5% (95% CI, 8.1%-13.0%) in states with gestational age limits or threatened bans, and 7.7% (95% CI, 5.9%-9.4%) in states with abortion protections. From the quarter immediately before Dobbs to the end of the study period, 95.8% of OBGYNs remained in protected states, 94.8% (95% CI, 94.3%-95.2%) remained in states threatening bans, and 94.2% (95% CI, 93.7%-94.7%) remained in states with abortion bans. Conclusions and Relevance In this descriptive cohort study, there were no significant differences in trends in OBGYNs’ practice locations across states with different abortion-related policy environments after the Dobbs decision. Although these findings do not provide insight into changes in the quality of care provided, they suggest that there are no major changes in the supply of OBGYNs associated with the Dobbs decision.
Abstract 2916: DNA polymerase theta inhibitor, ART6043, potentiates the efficacy of 177Lu- and 225Ac-based radioligand therapies in vitro and in vivo
Authors: Marco Ranzani, Alessandro Cicconi, Joseph Barlow, Paula Costales, Elias Elias, Alessandro Galbiati, Jayesh B. Majithiya, Silvia Peripolli, Eeson Rajendra, Marina Roy-Luzarraga, Nan Shao, Martin L. Stockley, Asmita Thapa, Robert A. Heald, Graeme C. Smith, Helen M. Robinson
Journal: Cancer Research (2025)

Abstract DNA polymerase theta (Polθ) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Loss or inhibition of Polθ has been shown to potentiate external beam radiation in a tumour-specific manner1,2. However, the ability of Polθ inhibitors to potentiate open source radiation has not been explored. This potential is pertinent to cancer therapy, as radioligand therapy (RLT), where a radionuclide is targeted to tumour cells by linking to peptides binding tumour-specific receptors, has had recent clinical success, in particular with 177Lu-PSMA-617 for prostate cancer. Hence, we investigated the ability of the clinical Polθ inhibitor, ART60433, to potentiate different forms of RLT. Here, we show that ART6043 treatment significantly potentiate the cell killing activity of 177Lu-RLT and 225Ac-RLT in different prostate cancer cell models. Mechanistic studies show that the combination of ART6043 with 177Lu-RLT caused a significant activation of DNA damage response pathways, accumulation of DNA damage and an increase in apoptosis compared to RLT or ART6043 alone. Key findings were confirmed for the combination of ART6043 with 225Ac-RLT.Furthermore, in vivo studies in mouse prostate cancer xenografts showed that the combination of ART6043 with 177Lu-RLT induced significant tumour growth inhibition and a significant improvement in median survival with regimens that were well tolerated. This work supports the clinical development of the combination of ART6043 with RLT to improve the clinical efficacy of RLT. References: 1 Rodriguez-Berriguete G, Ranzani M, et al., Clin Cancer Res. 2023. 2 Higgins GS, et al., Cancer Res. 2010. 3 NCT05898399. Citation Format: Marco Ranzani, Alessandro Cicconi, Joseph Barlow, Paula Costales, Elias Elias, Alessandro Galbiati, Jayesh B. Majithiya, Silvia Peripolli, Eeson Rajendra, Marina Roy-Luzarraga, Nan Shao, Martin L. Stockley, Asmita Thapa, Robert A. Heald, Graeme C. Smith, Helen M. Robinson. DNA polymerase theta inhibitor, ART6043, potentiates the efficacy of 177Lu- and 225Ac-based radioligand therapies in vitro and in vivo [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 2916.
Abstract 1707: Characterization of egfr ectodomain mutation in acquired resistance to cetuximab in colorectal cancer
Authors: Neeraj Joshi, Hidenori Tanaka, Galina Bogatcheva, Ramona Graves Deal, Claudia Wahoski, Sarah Harmych, Claiborne Tydings, Marisol Ramirez, James Higginbotham, Maria J. Irudayam, Jeffrey L. Franklin, Qi Liu, Jens Meiler, Robert J. Coffey, Eben L. Rosenthal, Bhuminder Singh
Journal: Cancer Research (2025)

Abstract Colorectal cancer (CRC) remains the second leading cause of cancer-related deaths in the United States (US), and individuals with surgically unresectable stage four CRC have a five-year overall survival of 13%. Targeting of the receptor tyrosine kinase (RTK), EGF receptor (EGFR) with therapeutic monoclonal antibodies (cetuximab, panitumumab) is approved for use in wild-type KRAS/NRAS/BRAF (RAS/RAF) advanced CRC. However, these antibodies as a single agent have response rates of 12-17% and expected progression-free survival of only 3-4 months. Accordingly, resistance may be present at the outset (de novo resistance) or develop during treatment (acquired resistance). To model and understand drug resistance, we cultured CRC lines in a defined 3D matrix (type 1 collagen) with anti-epidermal growth factor receptor (EGFR) antibody cetuximab. Here, we report the identification of an EGFR ectodomain missense mutation acquired in vitro in response to cetuximab treatment. Using 2D and 3D drug sensitivity assays, we demonstrate that this EGFR ectodomain mutation, in addition to being resistant to cetuximab and panitumumab, also could not be targeted by the oligoclonal anti-EGFR antibody cocktail MM-151. To determine whether this EGFR ectodomain mutation is necessary and sufficient to impart cetuximab resistance, (i) we engineered stable cell lines that inducibly overexpress mutant EGFR and (ii) demonstrated the sufficiency of mutant EGFR overexpression in conferring cetuximab resistance under both in vitro and in nude mouse xenografts. Further, our structural, functional, and biochemical studies implicate reduced binding of EGFR mutant to cetuximab and sustained downstream signaling activity as a cause of cetuximab resistance. Collectively, this mutation necessitates additional treatment strategies for a subset of subjects with advanced CRC who do not respond to treatment with current anti-EGFR biologics. Citation Format: Neeraj Joshi, Hidenori Tanaka, Galina Bogatcheva, Ramona Graves Deal, Claudia Wahoski, Sarah Harmych, Claiborne Tydings, Marisol Ramirez, James Higginbotham, Maria J. Irudayam, Jeffrey L. Franklin, Qi Liu, Jens Meiler, Robert J. Coffey, Eben L. Rosenthal, Bhuminder Singh. Characterization of egfr ectodomain mutation in acquired resistance to cetuximab in colorectal 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 1707.
EEG-Guided Titration of Sevoflurane and Pediatric Anesthesia Emergence Delirium
Authors: Kiyoyuki W. Miyasaka, Yasuyuki Suzuki, Emery N. Brown, Yasuko Nagasaka
Journal: JAMA Pediatrics (2025)

Importance Pediatric anesthesia emergence delirium (PAED) is a common complication of general anesthesia and has unknown etiology. Exposure to volatile anesthetics may contribute to PAED, and excessive exposure may occur frequently during routine pediatric anesthesia. Objective To examine whether use of electroencephalography (EEG) monitoring can reduce PAED by minimizing exposure to sevoflurane while maintaining a state of unconsciousness under anesthesia. Design, Setting, and Participants A single-center, parallel-group, 2-arm, superiority randomized clinical trial with a 1:1 allocation ratio was conducted from October 13, 2021, to March 18, 2023, at an academic tertiary pediatric hospital in Japan. The follow-up period was 24 ± 6 hours postoperatively or uneventful discharge to home, whichever came first. The observer for the primary outcome was blinded to patient assignment. The trial included a convenience sample of children aged 1 to younger than 6 years undergoing general anesthesia for procedures for which reliable antinociception can be provided. Data analysis was performed in March 2023. Intervention EEG-guided titration of anesthesia to minimize sevoflurane exposure (EEG-guided group) vs standard 1.0–minimum alveolar concentration (MAC) sevoflurane anesthesia (control group). Main Outcomes and Measures Proportion of patients who developed PAED, defined by a maximum PAED score of 10 or higher. Results Of the 177 participants who completed follow-up, 125 (71%) were male and 52 (29%) were female. The EEG-guided group included 91 participants (mean [SD] age, 2.9 [1.5] years), and the control group included 86 participants (mean [SD] age, 2.8 [1.6] years). In the EEG-guided group, sevoflurane exposure was reduced by 1.4 MAC-hours (96.65% CI, 1.1 to 1.6 MAC-hours). A total of 30 (35%) in the control group and 19 (21%) in the EEG-guided group developed PAED (difference, 14%; 96.65% CI, −0.0019% to 28%; 95% CI, 0.92% to 27%; P = .04). Children in the EEG-guided group emerged a mean of 21.4 minutes (96.65% CI, 15.4 to 27.4 minutes) earlier from general anesthesia and spent a mean of 16.5 minutes less (96.65% CI, 10.8 to 22.3 minutes less) in the postanesthesia care unit. Conclusions and Relevance EEG-guided management of general anesthesia reduced sevoflurane exposure and pediatric anesthesia emergence delirium in children, with faster emergence and shorter postanesthesia care unit stays. The findings suggest that high concentrations of sevoflurane for induction followed by routine use of 1.0-MAC sevoflurane for maintenance may be excessive. Trial Registration Japan Registry of Clinical Trials Identifier: jRCTs032210248
Abstract 5251: Anergic response of NK cells mediated by killer cell lectin-like receptor C1 and tumoral HLA-E interaction in pleural metastasis of lung adenocarcinoma
Authors: Ying-Ming Tsai, Kuan-Li Wu, Ya-Ling Hsu
Journal: Cancer Research (2025)

Abstract The presence of effusion is negatively correlated with prognosis in lung cancer. Despite the advent of novel therapies, clinical outcomes remain unsatisfactory. Pleural metastasis and malignant pleural effusion (MPE) result from tumor-host interactions involving mechanisms such as pleural inflammation, angiogenesis, and vascular hyperpermeability. Natural killer (NK) cells are potent immune effectors capable of responding to cancer. However, several aspects of NK cell biology remain under investigation. Understanding their role will aid in identifying effective therapeutic targets. Effusion samples from patients with congestive heart failure (designated as HP) and lung cancer pleural metastasis (LCP) were collected. Cells were harvested to delineate the functional phenotype of NK cells using single-cell RNA sequencing (scRNA-seq). Additionally, changes in NK cells were validated using immunohistochemistry and cell marker identification. The results revealed six subsets of NK cells: CD16+/CD56- NK cells, CD16-/CD56+/XCL2+ NK cells, CD16-/CD56+/RUNX2+ NK cells, CD16+/CD56+/BCL11B+ NK cells, CD16+/CD56+/CCL3+ NK cells, and CD16-/CD56- NK cells. Most NK cell subclusters dominated in the LCP group, except for CD16+/CD56- NK cells, which were prevalent in the HP group. These NK cell subsets exhibited different expression patterns of inhibitory receptors (KLRC1 and KLRD1) and activating receptors (HCST and KLRK1). Notably, CD16-/CD56+/RUNX2+ NK cells were present exclusively in MPE and absent in effusions from HP. Compared to other NK cell subsets, CD16-/CD56+/RUNX2+ NK cells exhibited lower expression of activating receptors and higher expression of inhibitory receptors, particularly KLRC1, suggesting an immunosuppressive phenotype. Cell-cell interaction analysis using CellChat indicated that HLA-E in pleural tumors interacted with RUNX2+/CD16-/CD56+ NK cells, resulting in decreased NK cytotoxicity. This interaction was further validated through higher expression of HLA-E in pleural tumor cells by immunohistochemistry and the presence of CD16-/CD56+/RUNX2+ NK cells in malignant effusions of lung cancer by a flow cytometry. These findings imply that the presence of the inhibitory ligand HLA-E from tumor cells supports the formation of pleural metastasis by evading NK cell-mediated cytotoxicity. Further investigation into these cell groups may aid in the prevention and treatment of MPE in lung cancer. Citation Format: Ying-Ming Tsai, Kuan-Li Wu, Ya-Ling Hsu. Anergic response of NK cells mediated by killer cell lectin-like receptor C1 and tumoral HLA-E interaction in pleural metastasis of lung adenocarcinoma [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 5251.