tbuckley/cabot-search huggingface dataset:
Abstract 234: Microfluidic chip for drug response studies in non-small cell lung carcinoma patient-derived organoids
Authors: Qiyue Luan, Ines Pulido, Angelique Isagirre, Jian Zhou, Takeshi Shimamura, Ian Papautsky
Journal: Cancer Research (2024)

Abstract Background. Organoids have been widely accepted as 3D tumor models for patient-specific drug response. However, research involving non-small cell lung cancer (NSCLC) organoids is hampered by the lack of appropriate platforms. Although dome cultures show promising results, the relatively large size variability of patient-derived organoids (PDOs) hinders their application in drug response studies. Here, we report a microfluidic chip for maintaining high uniformity and requiring miniscule sample volume for PDO drug screening. Methods. The microfluidic chip includes a bottom microwell layer and a top microchannel layer. Each chip has 5 channels for parallel treatment conditions, with 30 U-shaped microwells (400μm dia x 250μm deep) per channel. PDOs were loaded from side channels and trapped by filters adjacent to microwells. NSCLC PDOs F231/F671 (NCI PDMR) were cultured and treated by KRASG12C inhibitor adagrasib (0-2000nM, 72h). PDO drug response was assessed via viability using fluorescent dyes. Results. On-chip PDO size after one-week incubation exhibited the coefficient of variation (CV) of 28% for F231 and 36% for F671, which was notably lower than measurements obtained using Matrigel dome (126%, n=3) and low attachment plate (80%, n=4). The F231/F671 showed viability &amp;gt;81% after 1wk (n=20). On-chip cytotoxicity results showed that both KRASG12C PDOs exhibited sensitivity to adagrasib, matching the clinical response, with IC50 values of 830 nM (F231) and 1324nM (F671). When cultured with fibroblast (WI-38) supernatant, the cytotoxic effect was mitigated due to the fibroblast-induced resistance, with IC50 increasing ≥2 ×. No statistical difference was observed for the fibroblast effect in the open-format microwells and our microfluidic chip (69.6±16.9% to 80.2±9.0% vs. 69.0±12.2% to 82.2±4.1%, respectively, following 500nM adagrasib for 72h), further underscoring the reliability of our chip for PDOs’ drug response studies. Application of continuous perfusion at 70nL/min yielded no statistical difference in viability from static conditions. Conclusions. Our microfluidic chip offers uniform PDO growth with perfusion allowing drug screening in almost real time. The on-chip response to adagrasib was clinically relevant. Resistance due to tumor microenvironment (TME) can be readily assessed using fibroblast supernatant, and could be expanded to other TME components in future studies to investigate their impact on treatment resistance. Citation Format: Qiyue Luan, Ines Pulido, Angelique Isagirre, Jian Zhou, Takeshi Shimamura, Ian Papautsky. Microfluidic chip for drug response studies in non-small cell lung carcinoma patient-derived organoids [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 234.
Abstract 5280: Minimizes T cells DNA damage induced by PARP inhibitors and enhances its anti-tumor efficacy
Authors: Jiahao Liu, Xiaofei Jiao, Wei Mu, Huayi Li, Li Zhu, Xuejiao Zhao, Gordon B. Mills, Qinglei Gao, Yong Fang
Journal: Cancer Research (2024)

Abstract Background: Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising targeted therapies for ovarian and breast cancer. The sustained remission induced by PARP inhibitors largely depends on T cell activity. However, the direct effects of PARP inhibitors on T cells, as well as their precise impact on T cell DNA integrity and subsequent anti-tumor immune responses, have not been fully elucidated. Method &amp; Result: Following treatment with 25 μM olaparib or 15 μM niraparib for 48 hours, T cell viability decreased by 39.20% and 41.89%, respectively. Reduced proliferation and increased cell death were also observed, as indicated by reduced Ki-67 and elevated cleaved Caspase-3 levels. RNA sequencing further revealed a significant enrichment of DNA damage pathways in T cells after olaparib treatment, which was validated by elevated γH2AX levels in T cells using western blots and immunofluorescence. To assess PARP inhibitor-induced DNA damage in clinical settings, paired ovarian cancer samples pre- and post-niraparib monotherapy were obtained from the NANT trial (NCT04507841). Post-treatment tumor samples exhibited a higher number of γH2AX+ T cells compared to their pre-treatment counterparts. To identify the key protein mediating T cell inhibition induced by PARP inhibitors, a whole genomic CRISPR knock-out screening was conducted in human T cells, revealing an enrichment of sgRNAs targeting PARP1 after PARP inhibitor treatment. This outcome was further confirmed by the knockout of PARP1 in human T cells in vitro, leading to the restored viability and reduced levels of DNA damage after olaparib treatment. Importantly, following cytosine base editors (CBEs) of PARP1 in CAR-T cells, improved anticancer activity was observed both in vitro and in two ovarian cancer patient-derived xenografts (PDX) models when combined with PARP inhibitors. Conclusion: This study observed that PARP inhibitors can cause significant DNA damage in human T cells, resulting in cell death, inhibited proliferation, and impairment of anti-cancer immunity. PARP1 was identified as the target for PARP inhibitor-induced T cell death, and its knockout or point mutation led to improved anticancer efficacy of T cells when used in combination with PARP inhibitors. [JH Liu and XF Jiao contributed equally as co-first authors.] Citation Format: Jiahao Liu, Xiaofei Jiao, Wei Mu, Huayi Li, Li Zhu, Xuejiao Zhao, Gordon B. Mills, Qinglei Gao, Yong Fang. Minimizes T cells DNA damage induced by PARP inhibitors and enhances its anti-tumor efficacy [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 5280.
Abstract 1482: FKBP52 drives diverse HCC phenotypes through context-dependent targeting of p53
Authors: Xing Wang, Jingfeng Wu, Chengyan Tang, Xiang Li, Li Zhu, Yaoyu Liu
Journal: Cancer Research (2024)

Abstract p53 is notably the most frequently mutated protein in hepatocellular carcinoma (HCC), one of the major causes of cancer-related fatalities globally. These mutations often result in some of the most adverse outcomes in HCC, making p53 a prime target for therapeutic intervention. The concept of “hyperstability”of p53 is essential in understanding its gain-of-function and dominant-negative effects in tumorigenesis. However, the mechanisms driving this hyperstability are not completely understood. In this study, we have identified FKBP52, a member of the FK506-binding protein family, as a crucial factor in stabilizing and accumulating p53, irrespective of the type of mutation. Furthermore, our study suggests that FKBP52 could be a valuable biomarker for predicting HCC outcomes. We observed a notable link between FKBP52 levels and the histological differentiation in HCC samples. To corroborate these observations, we performed a series of in vitro and in vivo experiments using liver cancer models. These experiments highlighted the dual nature of FKBP52’s impact on hepatocytes, which varies according to cell type. Given its connection to HCC severity, FKBP52 seems to contribute negatively to the disease’s progression. The insights gained from this study on how FKBP52 influences p53 stabilization are critical. We suggest that targeting the processes upstream of FKBP52 could lead to more effective HCC treatments. These findings emphasize the importance of further investigating this pathway, potentially paving the way for new strategies in liver cancer therapy. Citation Format: Xing Wang, Jingfeng Wu, Chengyan Tang, Xiang Li, Li Zhu, Yaoyu Liu. FKBP52 drives diverse HCC phenotypes through context-dependent targeting of p53 [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 1482.
Abstract 1810: Development of new phthalic hydrazide scaffold for potent TNKS inhibitors
Authors: Hwani Ryu, Hye-Ran Seo, Ju Han Lee, Kyu Myung Lee, Jiyeon Ahn
Journal: Cancer Research (2024)

Abstract Tankyrase 1 and 2 (TNKS1/2) catalyze post-translational modifications of target proteins through poly-ADP-ribosylation. Inhibition of TNKS stabilizes AXIN and induces β-catenin degradation in adenomatous polyposis coli (APC)-mutated colorectal cancer (CRC) cells. Therefore, TNKS emerges as a therapeutic target for APC mutant CRC, and there is a critical need for drug development against it. Tankyrase 1 and 2 (TNKS1/2) catalyze the post-translational modification of target proteins through poly-ADP-ribosylation. Their inhibition stabilizes AXIN and induces β-catenin degradation. Therefore, TNKS is a therapeutic target for APC mutant colorectal cancer (CRC), and there is a need for drug development against it. However, reported TNKS inhibitors have serious limitations in that they cause intestinal toxicity. To address these issues and enhance efficacy, we synthesized 60 compounds based on the tetrahydrophthalazine scaffold using protein structure modeling-Al technology. Using an in vitro TNKS1 and TNKS2 enzyme assay and derivatizing Hit compounds, we confirmed that TI-61987 significantly inhibits TNKS enzyme activity at low nanomolar levels. TI-61987 stabilized AXIN2, reduced active β-catenin, and downregulated β-catenin target genes in COLO320DM, APC-mutated CRC cells. Additionally, TI-61987 exhibited excellent anticancer effects not only in COLO320DM cells but also in in vivo xenograft mouse models. Our findings demonstrate that TI-61987 is a therapeutic candidate targeting TNKS for the treatment of APC-mutated CRCs, and this anticancer drug may represent an effective therapy regimen for APC-mutated CRCs. Citation Format: Hwani Ryu, Hye-Ran Seo, Ju Han Lee, Kyu Myung Lee, Jiyeon Ahn. Development of new phthalic hydrazide scaffold for potent TNKS inhibitors [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 1810.
Abstract 5251: RNA primed SMAR-T cells against multiple driver mutations, all HLA's designed for first line therapy
Authors: Alfred E. Slanetz, Sriram Srivatsa, Farzona Muzaffar, Walter Barry, David Ryan, Salim Metri, Michael Slanetz
Journal: Cancer Research (2024)

Abstract Success of immune checkpoint inhibitors (e.g., anti-PD1 antibodies) have revolutionized cancer immunotherapy by demonstrating that a patient’s own T-cells recognize and treat cancer. The efficacy of PD-1 blockade is driven by recruitment of new T-cells from blood rather than via activation of pre-existing tumor infiltrating lymphocytes (Yost K.E., et al. Nat. Med. 2019). However, anti-PD1 therapy is most effective in ~5% of malignancies i.e., cancers with high mutational burden. Hence, the challenge of addressing most lower mutational burden cancers (the ~95%) needs an alternate treatment strategy. We address this challenge by using RNA to prime and expand peripheral T-cells to cancer-specific mutations ex-vivo. Using our proprietary, patented, and robust manufacturing method, we can generate T-cell populations reactive to as low as 8 and as high as 40 cancer-specific mutant proteins. In-vitro, these T-cells have cancer mutation-specific cytotoxicity and do not kill the normal cells. Further, the T-cells express homing receptors enabling them to infiltrate tumors and express high levels of TNFα and IFNγ, which are associated with effective tumor cytotoxicity and pro-inflammatory modification of tumor microenvironment (TME). Additional characterization shows these cells to be predominantly CD4+ and CD8+ T-cells bearing central and effector memory phenotypic with negligible regulatory or exhausted T-cells. We believe our T-cells can be used for cellular therapy in conjunction with, or as an alternative to, immune checkpoint inhibitors to treat lower mutational burden cancers present in most patients. Citation Format: Alfred E. Slanetz, Sriram Srivatsa, Farzona Muzaffar, Walter Barry, David Ryan, Salim Metri, Michael Slanetz. RNA primed SMAR-T cells against multiple driver mutations, all HLA's designed for first line therapy [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 5251.
Abstract 7258: Combinatorial effects of viral oncolysis and miRNA modulation as a novel therapeutic of pancreatic ductal adenocarcinoma
Authors: Monique Kanitz Ruschel, Isaiah Davis, Hannah Taylor Mills, Karthik Gourishetti, Deepak Bhere
Journal: Cancer Research (2024)

Abstract Pancreatic cancer is a devastating illness that affects numerous individuals each year. Unfortunately, pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of this disease that accounts for a disproportionate number of cancer-related deaths. Despite representing only 3.3% of all cancer cases in the United States, pancreatic cancer is responsible for a staggering 8.3% of cancer-related fatalities. In 2023, 64,050 patients were diagnosed with PDAC alone. Current treatment options, which are limited to surgery, radiation, and chemotherapy, have failed to improve clinical outcomes. Recent research has revealed miRNA (miR) as a contributor to the suppression and progression of various cancers, including PDAC. Specifically, dysregulation of miR-7 has been associated with PDAC. Downregulation of miR-7 is linked to more aggressive cases of the disease. Another potential therapeutic approach to treating cancer is the use of oncolytic viruses (OV). These viruses can replicate in cancerous cells while leaving healthy cells unharmed, making them an attractive treatment option. In this study, we utilized exosomes isolated from human Umbilical Cord stem cells (hUCs) enriched with miR-7 and combined with OHSV to examine their effect on established PDAC cell lines. We utilized cell viability assays, microscopy, and western blot analysis to evaluate the impact of the combinatorial approach on the underlying molecular mechanisms. Our findings suggest that the successful transfer of miR cargo and treatment with oHSV into the target PDAC cells arrested cell proliferation by targeting apoptotic pathways. Citation Format: Monique Kanitz Ruschel, Isaiah Davis, Hannah Taylor Mills, Karthik Gourishetti, Deepak Bhere. Combinatorial effects of viral oncolysis and miRNA modulation as a novel therapeutic of pancreatic ductal adenocarcinoma [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 7258.
Abstract 1808: Discovery of highly selective novel MTA-cooperative PRMT5 inhibitors for the treatment of cancers
Authors: Wen-Lian Wu, Taishan Hu, Zhilin Deng, Honghai Li, Quanrong Shen, Lei Zhang, Xiaochu Ma, Peihua Sun, Cindy Cheng, Fang Liu, Xin Chen, Ye Hua, Bryan Huang
Journal: Cancer Research (2024)

Abstract Protein arginine methyltransferase 5 (PRMT5), a type II PRMT catalyzing the formation of symmetric dimethylation of arginine residues on histone and non-histone proteins, regulates many biological pathways in mammalian cells, including cell growth and differentiation. Methylthioadenosine phosphorylase (MTAP) is required for the methionine salvage pathway, deletion of MTAP leads to the accumulation of inhibitory PRMT5 cofactor methylthioadenosine (MTA). MTAP gene is adjacent to and frequently co-deleted with CDKN2A gene, the most commonly deleted tumor suppressor gene in human cancers. The increase in MTA significantly reduced PRMT5 activity in MTAP-deficient cancer cells, rendering them more vulnerable to PRMT5 inhibition than normal cells. Selective Inhibitors of PRMT5-MTA complex (MTA-cooperative) are supposed to exhibit an increased therapeutic index compared to first generation PRMT5 inhibitors for the treatment of MTAP-deleted (MTAP-del) cancer patients. Guided by computation-aided drug design (CADD), binding mode analysis of known PRMT5 inhibitors has led to the design and synthesis of a novel series of MTA-cooperative PRMT5 inhibitors. Many compounds within this series were found to inhibit PRMT5/MEP50 complex with single digit nM of IC50 in enzymatic assay. Cell based activity of these compounds was assessed by measuring the symmetric demethylarginine (SDMA) and 10-day cell proliferation assays. Several compounds exhibited low double-digit nM of cellular potency in HCT116 MTAP-del cells, the inhibition of SDMA and anti-proliferation activities in HCT116 MTAP-del cells over HCT116 MTAP-WT cells have excellent selectivity (80 - 400 fold). Further optimization of in vitro and in vivo pharmacokinetic properties has yielded candidate compounds suitable for evaluation of pharmacodynamic effect in the LU99 MTAP-del NSCLC xenograft model. Tumor growth inhibition (TGI) was observed in a dose-dependent manner, accompanied by a reduction of PRMT5-mediated SDMA levels in both the tumor and bone marrow. In summary, we have identified compounds with novel scaffolds that are potent and highly selective MTA-cooperative PRMT5 inhibitors. Further development of the second-generation PRMT5 inhibitors for treatment of cancers is also planned. Citation Format: Wen-Lian Wu, Taishan Hu, Zhilin Deng, Honghai Li, Quanrong Shen, Lei Zhang, Xiaochu Ma, Peihua Sun, Cindy Cheng, Fang Liu, Xin Chen, Ye Hua, Bryan Huang. Discovery of highly selective novel MTA-cooperative PRMT5 inhibitors for the treatment of cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1808.
Abstract 1641: Clobetasol differentially effects the vulvar cancer cell line, UMSCV-4, causing both increases in apoptosis while maintaining a subpopulation in quiescence
Authors: Jani E. Lewis, Mack Ogden, Gianna Minnuto, Kia Haering, Luke North
Journal: Cancer Research (2024)

Abstract Vulvar cancer is a rare but aggressive form of cancer that remains understudied. Our results show that treatment of the vulvar cancer cell line, UMSCV-4, with the glucocorticoid, clobetasol, increases apoptosis. Clobetasol is often used to treat a common inflammatory disease of the vulva known as vulvar lichen sclerosus (VLS) and up to 65% of vulvar carcinomas arise in the background of VLS. This would indicate clobetasol may also decrease the progression of vulvar cancer, if our observations reflect what is happening in vivo. However, our studies also show that apoptosis is not universal for the clobetasol treated UMSCV-4 cells. A subpopulation appears to enter a state of quiescence as evidenced by the return of some of the cells to normal cell proliferation upon removal of clobetasol. We previously showed that p27Kip1 is upregulated in the clobetasol treated cells. Cells that were incubated in clobetasol for three months and then removed from clobetasol (UMSCV-4 LT), allowing them to reenter the cell cycle, no longer expressed high levels of p27Kip1 upon re-exposure to clobetasol. We are now examining the differential phosphorylation states of p27Kip1 in the untreated and treated cells as well as identifying other genes important to clobetasol induced quiescence using RNAseq. Citation Format: Jani E. Lewis, Mack Ogden, Gianna Minnuto, Kia Haering, Luke North. Clobetasol differentially effects the vulvar cancer cell line, UMSCV-4, causing both increases in apoptosis while maintaining a subpopulation in quiescence [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 1641.
Abstract 1749: Esophageal adenocarcinoma single-cell resolution ecotypes and subtypes mediate chemoradiation resistance
Authors: Rui Ye, Yawei Qiao, Shanshan Bai, Emi Sei, Min Hu, Jianzhong He, Nan Li, Yifan Wang, Pablo Lopez, Wei Zhang, Fei Ye, Brian Weston, Emmanuel Coronel, William Ross, Phillip Ge, Bhutani Manoop, Nicholas Navin, Steven Lin
Journal: Cancer Research (2024)

Abstract Esophageal adenocarcinoma (EAC) is an aggressive and lethal disease with a 5-year survival rate less than 20%. The current standard of care for locally advanced EAC patients is neoadjuvant chemoradiation (CRT) followed by surgery and the pathological response rate is low in clinic. An unresolved question is how the cancer cells and their tumor microenvironment (TME) mediate CRT resistance in EAC. To address this question, we performed single-cell RNA sequencing on 84 longitudinal samples from a cohort of patients (N=47) containing 20 good responders (GR) and 27 non-responders (NR). In total, we obtained 302,918 single cells which enabled us to delineate the phenotypic heterogeneity landscape in EAC at baseline, and identify reprogramming in both the immune and tumor cells during treatment that lead to CRT resistance. We identified 4 major cell type compartments in the EAC TME: lymphoid cells (T cells, NK cells, B cells, and plasma cells), myeloid cells (macrophages, neutrophils, dendritic cells, and mast cells), stromal cells (fibroblasts and endothelial cells) and epithelial cells. Our data shows that the TME enriched in lymphoid cells, including resident and effector memory CD8 T cells, follicular helper CD4 T cells, and B cells was associated with better CRT responses. Moreover, a significant myeloid cell infiltration was observed across most patients during CRT and the infiltrated macrophages from GR harbored a more pro-inflammation phenotype. In addition, we identified 4 major ecotypes of the TME cells and 4 major expression subtypes of the cancer cells. Notably, the interactions between TME ecotypes and cancer subtypes are significantly associated with CRT responsiveness. In summary, this study has provided valuable insights into the biology of EAC CRT response, and identified novel predictive biomarkers and actionable targets to enhance CRT efficacy. Citation Format: Rui Ye, Yawei Qiao, Shanshan Bai, Emi Sei, Min Hu, Jianzhong He, Nan Li, Yifan Wang, Pablo Lopez, Wei Zhang, Fei Ye, Brian Weston, Emmanuel Coronel, William Ross, Phillip Ge, Bhutani Manoop, Nicholas Navin, Steven Lin. Esophageal adenocarcinoma single-cell resolution ecotypes and subtypes mediate chemoradiation resistance [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 1749.