bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4560: Assessing cancer drug combination efficacy across 900+ PRISM cell lines in a multiplexed screening assay
Authors: George Ashish Bino , Nair Shiker , Kocak Mustafa , Nguyen Ellen , Kalathungal Alvin , Fazio Anthony , Ponsi Cole , Golabi Aydin , Ronan Melissa A. , Rees Matthew G. , Roth Jennifer A. 
Published: March 2024

Abstract
Combination therapies are crucial in cancer care, yet identifying which combination will benefit a specific patient is challenging. The vast array of clinical, investigational, and tool anticancer agents and diverse cancer contexts makes investigating many drug combinations over a large number of cell lines infeasible. Here, we describe a multiplexed screening approach using the PRISM assay, where drug combinations are screened on &gt;900 DNA-barcoded cancer cell lines. We analyze cell viability data in drug combinations and single agents using established metrics to describe the combined effects such as additivity, synergy, and antagonism. Quantifying and classifying combined effects will help prioritize specific combinations for follow-up investigations and provide biological and mechanistic insights, thus enabling rationally designed combination therapies. We illustrate our methodology through data from three drug combinations that exemplify synergy and antagonism. In the first combination, temozolomide+O6-benzylguanine (alkylating agent + MGMT inhibitor), we found that cell lines expressing MGMT were sensitized to temozolomide in the presence of O6-benzylguanine, thus illustrating synergy. In the second combination, we screened two anti-apoptosis compounds A-1331852+AZD5991 (BCL-xL + MCL1 inhibitor) and found that BCL-xL and MCL1 inhibition were also synergistic. In the third combination, ML210+ferrostatin-1 (GPX4 inhibitor inducing ferroptosis + ferroptosis inhibitor), we found that ferrostatin-1 antagonized the effects of ML210. Our analysis also reveals the importance of appropriate dose selection and analytical metrics for reliably measuring combined effects. In conclusion, the PRISM platform's multiplexed cell line screening is a robust method for characterizing rationally designed drug combinations, offering a systematic approach to enhance the precision of combination therapy development in cancer care.
Citation Format: Ashish Bino George, Shiker Nair, Mustafa Kocak, Ellen Nguyen, Alvin Kalathungal, Anthony Fazio, Cole Ponsi, Aydin Golabi, Melissa A. Ronan, Matthew G. Rees, Jennifer A. Roth. Assessing cancer drug combination efficacy across 900+ PRISM cell lines in a multiplexed screening assay [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 4560.
Abstract 4575: FGFR3 altered bladder cancer exhibits a lineage-dependent vulnerability
Authors: Koleilat Mohamad Karim , Zhu Yan , Kwong Lawrence 
Published: March 2024

Abstract
Fibroblast Growth Factor 3 (FGFR3) genomic alterations are oncogenic drivers in ~15% of bladder cancer patients. A novel FGFR inhibitor, Erdafitinib, was FDA approved in 2019 based off a Phase II trial with an overall response rate of 40%. However, the majority of patients rapidly relapse at a median of 6 months, requiring combination therapies to prevent drug resistance. We hypothesized that a genome-wide CRISPR screen would identify Erdafitinib-sensitizing co-targets. We screened UM-UC-14, an S249C FGFR3 mutated bladder cancer cell line, and identified Cyclin C as a top hit in addition to known MAPK effectors such as ERK2 and SHP2. Cyclin C is a non-cell cycle related cyclin and part of the CDK8/19 kinase module of Mediator. Pharmacological validation in 4 FGFR3 altered cell lines confirmed a high degree of synergy between Erdafitinib and the CDK8/19 inhibitor Sel120, while no effect was seen in 2 wildtype cell lines, suggesting strong specificity. Moreover, the synergy in FGFR3-mutant cells was superior to that of SHP2 inhibitor SHP099 or the ERK inhibitor BVD-523. Similarly, GATA3 and PPARG also scored highly in our CRISPR screen. These transcription factors have been shown to be sufficient to enforce a luminal identity but not necessarily to maintain it. We validated these 3 genes as sensitizers and show in luminal cells that loss of either GATA3 or PPARG leads to loss of luminal markers and gain of basal markers. In contrast, cells treated with Sel120 showed, on RNAseq, an increase in basal markers without loss of luminal markers. Interestingly, our data suggests that the gain of basal markers, commonly associated with a worse prognosis, is associated with a strong sensitization to FGFR inhibition in FGFR3 alteration driven bladder cancer. We conducted a xenograft experiment confirming that mice responded well to single agent Erdafitinib, but without frank tumor regression. By contrast, Sel120+Erdafitinib induced complete responses in 8/10 mice compared to 6/10 mice for SHP099+Erdafitinib. Remarkably, after 60 days of daily drugging and a 20-day washout, the tumors did not grow back in the complete responders. Importantly, no loss of body weight or other signs of morbidity were found. Our results suggest an immediate and promising benefit in combining either CDK8/19 or SHP2 inhibitors with Erdafitinib in treating patients with FGFR3 alteration driven bladder cancers. Furthermore, we identified a strategy in targeting lineage modulators as sensitizers to existing therapies.
Citation Format: Mohamad Karim Koleilat, Yan Zhu, Lawrence Kwong. FGFR3 altered bladder cancer exhibits a lineage-dependent vulnerability [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 4575.
Abstract 4583: Development of selective HDAC6 inhibitors to improve cancer immunotherapy
Authors: Gajendran Nithya , Suresh Manasa , Quiceno David , Li Xintang , Durr Marie , Tan Karen , Noonepalle Satish Kumar Reddy , Villagra Alejandro 
Published: March 2024

Abstract
Histone Deacetylases (HDACs) are enzymes that modify histones and non-histone proteins. Our group has previously demonstrated that HDAC6 inhibitors (HDAC6is) modulate multiple immune pathways, including those that suppress the antitumoral M2 phenotype, leading to improved antitumor immunity. Despite the potential of HDAC6is, current inhibitors have poor selectivity and off-target effects and only work at micromolar concentrations. In this work, we designed a screening pipeline of HDAC6i, considering selectivity, potency, capacity to prevent the protumoral phenotype of macrophages, and low cytotoxicity on macrophages and other immune cells. This approach has not been tested before, as the standard screening method for antitumoral HDACis has focused on its cytotoxic effect on cancer cells. We initially designed in silico 980 compound derivatives from previously reported HDAC6i, such as SS208, Nexturastat A, and Suprastat. Twenty-four compounds with a high capacity to bind HDAC6 and chemical stability were screened by their ability to inhibit HDAC6 in cell-free conditions. Sixteen compounds demonstrated high potency and were further evaluated in murine macrophages by their cytotoxic effect using CellTox. The capacity to impede tubulin deacetylation was assessed by western blot and deacetylase activity by HDAC-Glo. The top six candidates were then evaluated by their selectivity compared to other HDAC members and by their effect on repressing the expression of protumoral M2 macrophages Arginase 1 and Fizz1, and activation of antitumoral markers TNFa and iNOS by western blot and qRT-PCR. The best three candidates were then evaluated at nanomolar concentrations to explore their immunomodulatory potential of M1 against M2 by performing antigen presentation (SIINFEKL presentation) and phagocytic capacity using microscopy. Two of these compounds, SM-06-09 and SM-05-947, will be further tested in syngeneic murine melanoma models for their ability in tumor regression and antitumor immunity. This study has yielded important insights into developing new and improved HDAC6is with minimal cytotoxicity, and we believe our work will help advance cancer research and ultimately lead to better patient outcomes.
Citation Format: Nithya Gajendran, Manasa Suresh, David Quiceno, Xintang Li, Marie Durr, Karen Tan, Satish Kumar Reddy Noonepalle, Alejandro Villagra. Development of selective HDAC6 inhibitors to improve cancer immunotherapy [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 4583.
Abstract 459: Exosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysisExosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysis
Authors: Tien Sui-Chih , Chang Chin-Chun , Chen I-Chih , Huang Ching-Hsuan , Peng Hsuan-Yu , Chang Yu-Ting , Chang Ming-Chu , Hu Chun-Mei , Lee Wen-Hwa 
Published: March 2024

Abstract
Over 80% of the patients with pancreatic ductal adenocarcinoma (PDAC) have cachexia, which is associated with reduced survival, decreased quality of life, and higher rates of metastatic disease. To date, the diagnostic and therapeutic options of PDAC-associated cachexia remain limited due to the lack of a complete understanding of the underlying pathological mechanism. Here, we demonstrate that fat loss is the earliest feature of cachexia induced by PDAC through its secreted exosomes. By analyzing exosomal components of normal and cancer-derived exosomes through small RNA-seq, we identify miR-16-5p, miR-21-5p, miR-29a-3p and miR-125b-5p enriched in pancreatic cancer-derived exosomes and in the exosomes from sera of mice or patients with pancreatic tumor. Among these, miR-16-5p and miR-29a-3p play a key role in fat loss by inhibiting adipogenesis through decreasing Erlin2 and CMPK1 expression leading to C/EBPβ and PPARγ downregulation. Synergistically, miR-29a-3p increases ATGL expression to facilitate lipolysis by suppressing MCT1 expression. Furthermore, PDAC-derived exosomes deprived of miR-16-5p and miR-29a-3p fail to induce fat loss, suggesting that these two exosomal miRs are required for PDAC-induced fat loss. These findings unravel a precise mechanism of how PDAC causes adipose atrophy via exosomal miRs and may provide new diagnostic and therapeutic strategies for PDAC-induced cachexia.
Citation Format: Sui-Chih Tien, Chin-Chun Chang, I-Chih Chen, Ching-Hsuan Huang, Hsuan-Yu Peng, Yu-Ting Chang, Ming-Chu Chang, Chun-Mei Hu, Wen-Hwa Lee. Exosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysisExosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysis [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 459.
Abstract 4613: Tumor-derived interleukin 35 facilitates the gemcitabine resistance in pancreatic adenocarcinoma by mediating the dissemination of chemoresistance among PDAC cells
Authors: Huang Chongbiao , Sun Huizhi , Chang Antao , Hao Jihui 
Published: March 2024

Abstract
Rapid drug resistance after chemotherapy is a key cause of treatment failure in human pancreatic ductal adenocarcinoma (PDAC). Here, we found that tumor-derived interleukin 35 (IL-35) mediated the rapid resistance of PDAC to gemcitabine (GEM). The role of IL-35 in GEM resistance was determined by molecular and cell biology approaches in PDAC cells and in patient-derived tumor xenograft (PDX) models. We used whole genome RNA sequencing, molecular cloning and other molecular biological methods to study the molecular mechanism of IL-35 mediated GEM resistance. An anti-IL-35 neutralizing antibody was used in mouse models to investigate the feasibility of targeting IL-35 to overcome drug resistance in pancreatic cancer. We observed the phenomenon that GEM resistance could spread from GEM resistant PDAC cells to GEM sensitive ones. The results of sequencing and experiments confirmed that the IL-35 secretion is responsible for the dissemination of chemoresistance. IL-35 secreted from GEM resistant cells activated the IL35 expression in GEM sensitive cells and upregulated SOD2 expression via GP130-STAT1 signaling, which scavenges reactive oxygen species (ROS) and then leads to GEM resistance.Furthermore, we found that a neutralizing antibody against IL-35 significantly enhanced the tumor suppressive effect of GEM. These findings collectively reveal that IL-35 plays crucial roles in mediating GEM resistance in pancreatic cancer. Moreover, IL-35 might serve as a promising therapeutic target for combating PDAC chemoresistance.
Citation Format: Chongbiao Huang, Huizhi Sun, Antao Chang, Jihui Hao. Tumor-derived interleukin 35 facilitates the gemcitabine resistance in pancreatic adenocarcinoma by mediating the dissemination of chemoresistance among PDAC cells [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 4613.
Abstract 4683: Suppression of ARL6ip1 inhibits malignant phenotypes of human colorectal cancer cells in vivo and &gt; in situ
Authors: Lin Yinzhi , Karnan Sivasundaram , Ito Hideaki , Umezawa Kazuo 
Published: March 2024

Abstract
Introduction: Conophylline is an alkaloid isolated from the leaves of the Thai plant, Ervatamia microphylla. We isolated conophylline as an inhibitor of K-Ras functions and an activator of pancreatic β-cell differentiation. It ameliorates various disease models in animals, including cancer, diabetes mellitus, NASH, and hepatic cirrhosis. On the other hand, its molecular target was determined to be ADP-ribosylation factor-like 6-interacting protein 1 (ARL6ip1) using a conophylline-biotin conjugate. ARL6ip1 is located in the endoplasmic reticulum (ER) membrane, and conophylline binds to the cytoplasmic portion of ARL6ip1. Known functions of ARL6ip1 include inhibition of apoptosis, inhibition of glutamate transporter, and modulation of the ER structure. Previously, we knocked out ARL6ip1 in human colon carcinoma cells by CRISPR-Cas9 and found that either deletion of ARL6ip1 or addition of conophylline inhibited migration, invasion and tumorigenicity in cultured cancer cells. In the present research we have studied the in vivo anticancer effect of conophylline and ARL6ip1 knockout, and the mechanism of anticancer activity in cultured cells.
Materials and Methods: Conophylline was isolated from the leaves of Ervatamia microphylla. We employed HCT116 and DLD1 cell lines as human colorectal cancer cells. Cellular migration was measured by a wound-healing assay. The activity of Akt was measured by the phospho-Akt antibody. BALB/cSlc-nu/nu mice were used for the animal experiment.
Results: Colon adenocarcinoma tissue microarray comparing tumor and adjacent normal tissues revealed that ARL6ip1 expression was significantly higher in cancer than in normal tissues. Intraperitoneal administration of conophylline and knockout of ARL6ip1 both inhibited the growth of HCT116 in mice. Neither influenced the bodyweight of animals. Conophylline and deletion of ARL6ip1 both inhibited the migration. Rescue of ARL6ip1 canceled the effect of ARL6ip1 deletion on migration in HCT116 and DLD1 cells. As the mechanism, either conophylline or ARL6ip1 knockout inhibited the Akt activity, which was canceled by the rescue of ARL6ip1 in both cell lines.
Conclusion: ARL6ip1 was found to be highly expressed in the tumor tissue in colorectal cancer. CRISPR-Cas9 knockout of ARL6ip1 showed a similar anticancer activity as treatment with conophylline in the animal experiment. It is likely that the anticancer activity of conophylline would be mediated by Akt. Thus, ARL6ip1 would be a useful molecular target for the treatment of cancer.
Citation Format: Yinzhi Lin, Sivasundaram Karnan, Hideaki Ito, Kazuo Umezawa. Suppression of ARL6ip1 inhibits malignant phenotypes of human colorectal cancer cells in vivo and &gt; in situ [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 4683.
Abstract 4718: Reclaiming a dirty drug: What is the context of vulnerability to arsenic trioxide in glioblastoma
Authors: Shaffer Charles , Tang Nanyun , Hao Yue , Fink Karen , Snipes George , Mickey Bruce , Berens Michael 
Published: March 2024

Abstract
Glioblastoma (GBM) is the most prevalent type of malignant tumor within the central nervous system. There is a growing demand to develop and adapt new therapeutic options in order to combat the five-year survival rate of 6.8% and improve patient quality of life. Arsenic trioxide (ATO) is the standard of care for myelodysplasia and relapsed or refractory acute promyelocytic leukemia. While currently being classified to have an idiopathic mechanism of action, two specific cytotoxic consequences of ATO have emerged: MNK1 activity and oxidative stress. Across six GBM PDX models a 20-fold difference in sensitivity manifests, indicative of underlying innate sensitivity or resistance to ATO. To correlate this to the proposed mechanisms of action, we observed ATO’s effect on MNK1 activity through eIF4E phosphorylation and glutathione (GSH) levels following treatment. A subset of GBM models exhibited a marked upregulation of eIF4E phosphorylation following treatment with 2 uM ATO. Of the six models, three were chosen to undergo further testing to observe whether this upregulation showed a consistent dose-dependent relationship across the models and correlated with vulnerability to ATO. Combination therapy with the MNK1 inhibitor, ETC-206, displayed mild to moderate synergy on overall cell viability and strong synergy when observing its effects on the glioma stem cell population. This preferential effect on the GSC populations suggests that MNK1i based combination strategies may show greater effectiveness in vivo than indicated by our previous in vitro studies. Nutraceuticals targeting GSH synthesis, Chrysin and Silibinin, displayed a 0.95 to 1.4-fold decrease in ATO IC50 values across all 6 models. To observe whether each nutraceutical impacted GSH levels consistently across all of the tested models, we measured GSH levels following treatment for each individual compound and their combination treatments. These findings further implicate MNK1 activity and cellular response to oxidative stress as markers of ATO sensitivity, however they are not the sole determinates of response. Understanding of the mechanism of action for idiopathic compounds may allow for the discovery of molecular signatures of sensitivity, improving patient selection for clinical trials and the development of new combination approaches to combat resistance in other tumor types.
Citation Format: Charles Shaffer, Nanyun Tang, Yue Hao, Karen Fink, George Snipes, Bruce Mickey, Michael Berens. Reclaiming a dirty drug: What is the context of vulnerability to arsenic trioxide in glioblastoma [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 4718.
Abstract 4797: Impact of COVID-19 pandemic on breast cancer screening and diagnosis stage in a large midwestern United States academic medical center
Authors: Johnson Kimberly J. , Waken RJ , O'Connell Caitlin P. , Brown Derek 
Published: March 2024

Abstract
Background: Access to breast cancer screening mammogram services decreased in association with the COVID-19 pandemic. There is also evidence for increases in late-stage breast cancer diagnoses. Our objectives were to determine: 1) the COVID-19-affected period on mammogram screening, 2) the proportion of pandemic-associated missed or delayed mammogram screening visits overall and by race/ethnicity and age group, and 3) evidence for pandemic-associated shifts in diagnosis stage.
Methods: Screening mammogram encounter data between 1-1-2019 and 12-31-2022 were extracted from EPIC for females ≥ 40 years old for the screening analysis. We used Bayesian state space models to describe weekly screening mammogram counts, modeling an interruption that phased in and out from 3-1-2020 to 9-1-2020. We used the posterior predictive distribution to simulate differences between a predicted, uninterrupted process and the observed screening mammogram counts. Breast cancer diagnoses at ≥ 21 years from the tumor registry between 12-1-2018 and 11-30-2021 were included in the stage analysis. We used logistic regression models to estimate late-stage diagnosis odds comparing matched three-month periods during the pandemic to before the pandemic.
Results: A total of 319,492 encounters among 146,644 women were included. Model-estimated screening mammograms dropped by 98.8% (95% CI 95.1 to 100) between 3-15-2020 and 5-24-2020, returning to pre-pandemic levels or higher after this period. Drops in screening mammogram encounters did not vary significantly by race/ethnicity or age group (p &gt; .75). Among 4,669 breast cancer diagnoses, we found no significant differences in the odds of late-stage diagnoses for any period vs. the same period before the pandemic (Table).
Conclusions: These data suggest a short-term pandemic effect on screening mammograms. Evidence for increases in late-stage diagnoses is limited. These results may inform future pandemic planning.
OR (95% CI) Period comparison 1.19 (0.74 to 1.91) 3/2020 to 5/2020 vs. 3/2019 to 5/2019 1.05 (0.69 to 1.60) 6/2020 to 8/2020 vs. 6/2019 to 8/2019 1.14 (0.73 to 1.78) 9/2020 to 11/2020 vs. 9/2019 to 11/2019 0.92 (0.60 to 1.41) 12/2020 to 2/2021 vs. 12/2019 to 2/2020 1.08 (0.71 to 1.65) 3/2021 to 5/2021 vs. 3/2019 to 5/2019 0.89 (0.59 to 1.33) 6/2021 to 8/2021 vs. 6/2019 to 8/2019 1.31 (0.84 to 2.04) 9/2021 to 11/2021 vs. 9/2019 to 11/2019
Citation Format: Kimberly J. Johnson, RJ Waken, Caitlin P. O'Connell, Derek Brown. Impact of COVID-19 pandemic on breast cancer screening and diagnosis stage in a large midwestern United States academic medical center [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 4797.