tbuckley/cabot-search huggingface dataset:
Abstract 521: Anticancer mechanisms of epigallocatechin gallate revealed via cellular and molecular profiling
Authors: Aria Panchal, Jacqueline H. Law, Clement Lo, Kenneth W. Yip
Journal: Cancer Research (2024)

Abstract Introduction: Epigallocatechin gallate (EGCG) is a polyphenol present in green tea that is known for its anti-oxidant, anti-inflammatory, anti-angiogenic, pro-apoptotic, and anti-cancer properties. However, EGCG has not been systematically evaluated on a large panel of cancer cell lines. We hypothesized that EGCG exhibits varying effects on specific cancer cell genetic backgrounds and types. This study aimed to provide a comprehensive analysis of EGCG on both cell viability and gene expression profiles. Methods: 750 cancer cell lines were cultured and seeded in 1536-well plates for cell viability studies (by the CTD2 Center at the Broad Institute). After 24 h, cells were treated with 16 two-fold serial dilutions of EGCG. After 72 h, cell viability was assayed using CellTiter-Glo. For gene expression profiling (with the Broad Institute and NIH), 8 cell lines were treated with 10 µM EGCG for 6 and 24 h, and transcriptomes were assessed using Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays. The CMap large-scale transcriptome dataset was used for comparisons. Results: EGCG had the highest potency in the non-Hodgkins B-cell lymphoma cell line DoHH2 (IC50=0.42 µM), the myeloid leukemia cell line Ku812 (IC50=3.76 µM), and the multiple myeloma cell line KMS-28BM (IC50=4.57 µM). Tissue-of-origin analysis showed that EGCG was most potent against lymphoid cancers, and least potent against prostate cancers. Bioinformatics-based analyses found that EGCG-treated cells resembled cells overexpressing CHEK2, DDP4, CBLC, ZNF350, and TRAF6, and cells underexpressing TRIM16. EGCG-induced gene expression resembled lapatinib and sulfasalazine treatment. Conclusions: This study provides a comprehensive examination of the differential impact of EGCG treatment on cancer cells. Subsequent research on the timing and duration of the changes, along with pathway enrichment analyses, will potentially guide the translational potential of EGCG and its chemical analogs in personalized cancer treatment approaches. Citation Format: Aria Panchal, Jacqueline H. Law, Clement Lo, Kenneth W. Yip. Anticancer mechanisms of epigallocatechin gallate revealed via cellular and molecular profiling [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 521.
Abstract 3202: Investigating the induction of ferroptosis by nano drug delivery system
Authors: Eden M. Jacob, Sarah Y. Kim, Parul Sirohi, Mu-En Wang, Meredith L. Davis, Alyssa R. Bawcom, Ashutosh Chilkoti, Mark R. Wiesner, Jiaoti Huang, Ming Chen
Journal: Cancer Research (2024)

Abstract Prostate cancer is the second leading cause of cancer-related death in U.S. men. Genomic and clinical associations have identified loss of RB function as a dominant mechanism driving prostate cancer lethality. We recently demonstrated that ferroptosis induction in vivo by ferroptosis inducers blocks RB1-deficient prostate tumor growth and metastasis and leads to improved survival of the mice. As all ferroptosis inducers are newly discovered, there is a great need to improve their therapeutic potential through different avenues, including innovative drug delivery systems. Poly Lactic-co-glycolic acid (PLGA) is an FDA-approved biodegradable polymer. Due to their strong biocompatibility and consistent release, PLGA-based nanotherapeutics are an attractive carrier for small molecule drugs. This study aims to further improve the efficacy of ferroptosis induction against lethal RB1-deficient prostate cancer through PLGA-based ferroptosis-induced nanoparticles (NPs). The PLGA NPs encapsulating JKE-1674 were synthesized using the solvent evaporation method. The NPs were characterized using dynamic light scattering (DLS) and scanning electron microscopy (SEM) to assess the physicochemical properties of the NPs. The cell-killing efficacy of free-form or PLGA NP encapsulated JKE-1674 was then evaluated in vitro. Our analyses showed that the particle size and polydispersity index (PDI) of JKE-1674 PLGA NPs were 160.8 nm and 0.049, respectively. SEM images of JKE-1674 PLGA NPs further validated the DLS data. These findings suggest that encapsulation of JKE-1674 within the PLGA NPs results in a stable and biocompatible formation. Critically, JKE-1674 encapsulated by PLGA NPs is as potent as JKE-1674 in its free form to induce ferroptosis and associated lipid peroxidation in various human prostate cancer cell lines. This study presents the first effort to develop and validate PLGA-based ferroptosis-induced nanotherapeutics. Based on our in vitro data, we will test the in vivo efficacy of JKE-1674 PLGA NPs against lethal RB1 deficient prostate cancer. Citation Format: Eden M. Jacob, Sarah Y. Kim, Parul Sirohi, Mu-En Wang, Meredith L. Davis, Alyssa R. Bawcom, Ashutosh Chilkoti, Mark R. Wiesner, Jiaoti Huang, Ming Chen. Investigating the induction of ferroptosis by nano drug delivery system [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 3202.
Abstract 3242: TNG917 is a clinical-grade, potent and selective inhibitor of EHMT1/2 for the treatment of immune cold tumors
Authors: Alvin Lu, Brian Haines, Ji Lei, Wenhai Zhang, Minjie Zhang, Douglas A. Whittington, Maria Lucia Ferdinez, Yi Yu, Samuel R. Meier, Ashley Choi, Alborz Bejnood, Madhavi Bandi, Katherine Lazarides, Xuewen Pan, Lina Gu, Alice W. Tsai, Sirimas Sudsakorn, Colin Liang, Jon Come, Brett Williams, Scott Throner, Joseph Vacca, John P. Maxwell, Jannik N. Anderson, Alan Huang, Chengyin Min, Yingnan P. Chen
Journal: Cancer Research (2024)

Abstract CRISPR-based functional genomics screening can be designed to identify novel cancer cell intrinsic targets that increase tumor immunogenicity. Using a FACS-based CRISPR sorting screen for PD-L1 expression, we identified Euchromatic histone-lysine-N-methyltransferase 1 and 2 (EHMT1/2) as negative modulators of the interferon signaling pathways. EHMT1 and EHMT2 are histone methyltransferases that mono- and di-methylate lysine 9 of histone H3 to repress gene transcription of defined target genes. Gene knockout or pharmacological inhibition of EHMT1/2 in cancer cells resulted in de-repression of gene promoters, upregulation of interferon-stimulated genes (ISGs), and secretion of pro-inflammatory cytokines. Here, we present the preclinical characterization of TNG917 - an oral and highly selective EHMT1/2 inhibitor with low nanomolar cellular potency, and favorable pharmacodynamic and pharmacokinetic properties. In humanized and syngeneic mouse models, treatment with TNG917 in combination with anti-PD1 promoted a T-cell-infiltrated tumor microenvironment, led to significant anti-tumor activity, and resulted in survival benefit. In summary, our in vitro and in vivo studies provide a rationale for the clinical development path of TNG917, in combination with checkpoint inhibition, in patients with immune cold tumors. Citation Format: Alvin Lu, Brian Haines, Ji Lei, Wenhai Zhang, Minjie Zhang, Douglas A. Whittington, Maria Lucia Ferdinez, Yi Yu, Samuel R. Meier, Ashley Choi, Alborz Bejnood, Madhavi Bandi, Katherine Lazarides, Xuewen Pan, Lina Gu, Alice W. Tsai, Sirimas Sudsakorn, Colin Liang, Jon Come, Brett Williams, Scott Throner, Joseph Vacca, John P. Maxwell, Jannik N. Anderson, Alan Huang, Chengyin Min, Yingnan P. Chen. TNG917 is a clinical-grade, potent and selective inhibitor of EHMT1/2 for the treatment of immune cold tumors [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 3242.
Abstract 3824: Efficacy of trastuzumab in combination with capecitabine and cisplatin vs 5-FU and cisplatin therapy for Korean patients with HER2-positive advanced gastric cancer Health Insurance Review and Assessment service (HIRA) data retrospective analysis
Authors: hyun woo Lee, Jang-Hee Kim, Seok Yun Kang, Tae Jun Park, Yong Won Choi
Journal: Cancer Research (2024)

Abstract The combinations of oral fluoropyrimidines and cisplatin such as capecitabine and cisplatin (XP) or 5-FU and cisplatin (FP) are regarded as a standard therapy against HER-2 positive advanced gastric cancer (AGC). Trastuzumab-XP(HXP) and trastuzumab-FP(HFP) is the most common regimen against AGC in Korea. The aim of the present study is to evaluate the effectiveness of trastuzumab-XP vs trastuzumab-FP. Patients with HER2-positive AGC were assigned to the trastuzumabXP or trastuzumabFP group. We then retrospectively compared the efficacy and safety between both groups. As a first-line chemotherapy, trastuzumab in combination with XP or FP was administered to 2,399 patients: 1,913 with HXP and 486 with HFP. In the HXP group vs HFP group, median progression-free survival (mPFS), and median overall survival (mOS) were 8.02 vs 6.08 months (p &amp;lt;0.0001) and 13.27 vs 9.89 months (p &amp;lt;0.0001). In HFP group, mPFS and mOS were 10.15 vs 5.36 months (p &amp;lt;0.0001) and 15.15 vs 8.90 months (p &amp;lt;0.0001) in comparison HFP-H maintenance to HFP group. In HXP group, mPFS and mOS were 10.64 vs 13.44 vs 5.03 months (p &amp;lt;0.0001) and 20.14 vs 22.18 vs 9.10 months (p &amp;lt;0.0001) in comparison HXP-H maintenance, HXP-HX maintenance, and HXP group. Trastuzumab in combination with XP and HX maintenance is a potential first-line therapeutic option for patients with HER2-positive AGC. Citation Format: hyun woo Lee, Jang-Hee Kim, Seok Yun Kang, Tae Jun Park, Yong Won Choi. Efficacy of trastuzumab in combination with capecitabine and cisplatin vs 5-FU and cisplatin therapy for Korean patients with HER2-positive advanced gastric cancer Health Insurance Review and Assessment service (HIRA) data retrospective analysis [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 3824.
Abstract 3221: Targeting ARID1A-mutated gastric cancer cells with synthetic lethal approaches
Authors: Menghan Fang, Youfen Lin, Chaorong Xue, Kaiqin Sheng, Zegeng Guo, Yuting Han, Hanbin Lin, Yuecheng Wu, Stephen B. Howell, Xu Lin, Xinjian Lin
Journal: Cancer Research (2024)

Abstract AT-rich interaction domain 1A (ARID1A) functions as a tumor suppressor gene, and its loss or inactivation is a common occurrence in various human malignancies, including around 30% of gastric cancers (GC). This study aimed to identify potential therapeutic targets for GC cells with ARID1A deficiency. After robust screening from a chemical library consisting of 551 diverse protein kinase inhibitors, we identified the AKT inhibitor AZD5363 as being the most potent lead compound in inhibiting viability of ARID1A−/− cells. A synthetic lethality between loss of ARID1A expression and AKT inhibition by AZD5363 was validated in both GC cell model system and xenograft model. Mechanistically, AZD5363 treatment induced pyroptotic cell death in ARID1A-deficient GC cells through activation of the caspase-3/GSDME pathway. Furthermore, ARID1A occupied the AKT gene promoter and regulated its transcription negatively, thus the GC cells deficient in ARID1A showed increased expression and phosphorylation of AKT. Our study demonstrates a novel synthetic lethality interaction and unique mechanism between ARID1A loss and AKT inhibition, which may provide a therapeutic and mechanistic rationale for targeted therapy on patients with ARID1A-defective GC who are most likely to be beneficial to AZD5363 treatment. Citation Format: Menghan Fang, Youfen Lin, Chaorong Xue, Kaiqin Sheng, Zegeng Guo, Yuting Han, Hanbin Lin, Yuecheng Wu, Stephen B. Howell, Xu Lin, Xinjian Lin. Targeting ARID1A-mutated gastric cancer cells with synthetic lethal approaches [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 3221.
Abstract 4461: Unveiling the links between methionine metabolism and epigenomic reprogramming in upper aerodigestive squamous cell carcinoma
Authors: Chehyun Nam
Journal: Cancer Research (2024)

Abstract Upper aerodigestive squamous cell carcinoma (UASCC) presents as a prevalent and aggressive malignancy, posing challenges in terms of effective therapeutic interventions. In this study, we explored the intricacies of amino acid metabolism within UASCC, revealing an unexpected observation that distinguishes UASCC among all human cancers, having the highest methionine levels, driven by the overexpression of its transporter LAT1. Notably, LAT1 exhibits peak expression levels in UASCC, regulated at the transcriptional level by UASCC-specific promoters and enhancers, co-regulated by SCC master regulators TP63/KLF5/SREBF1.Surprisingly, our unbiased bioinformatic screen identifies EZH2 as a pivotal downstream target of the LAT1-methionine pathway, establishing a direct link between methionine metabolism and epigenomic reprogramming. This cascade emerges as crucial for the survival and proliferation of UASCC patient-derived tumor organoids. Furthermore, we find that LAT1 expression closely correlates with cellular sensitivity to inhibition of the LAT1-methionine-EZH2 axis.Significantly, the newly discovered LAT1-methionine-EZH2 cascade emerges as a promising target for intervention, with effective outcomes achievable through both pharmacological approaches and dietary interventions in vivo. In summary, this research unveils a novel mechanistic crosstalk connecting epigenomic reprogramming with methionine metabolism, revealing its biological significance in UASCC. Moreover, it identifies a unique tumor-specific vulnerability, providing avenues for exploitation through both pharmacological and dietary strategies Citation Format: Chehyun Nam. Unveiling the links between methionine metabolism and epigenomic reprogramming in upper aerodigestive squamous cell carcinoma [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 4461.
Abstract 4667: HDAC9 as a potential regulator of lenvatinib resistance in hepatocellular carcinoma
Authors: Yunong Xie, Minghe Zhang, Yan Liu, Linglin Liu, Alfred Sze-Lok Cheng, Stephanie Ma, Man Tong
Journal: Cancer Research (2024)

Abstract Lenvatinib is used as the first-line therapy for advanced hepatocellular carcinoma (HCC) patients. However, poor response and compromised therapeutic effect with prolonged treatment are frequently observed in HCC patients. To elucidate the underlying mechanisms, lenvatinib responsive and non-responsive stages were modeled in liver tumor-bearing immunocompetent mice which were divided into lenvatinib and vehicle control treatment groups. Tumor tissues after short and prolonged lenvatinib treatment were harvested for single-cell RNA sequencing. Results from single-cell RNA sequencing revealed heterogenous tumor cell sub-populations associated with tumor differentiation and identified an upregulated expression of class IIa histone acetylase HDAC9 in lenvatinib-treated tumor at the non-responsive stage. Upregulation of HDAC9 was similarly observed in lenvatinib-resistant human patient-derived xenograft (PDX). Functional studies suggested that suppressing HDAC9 could re-sensitize lenvatinib response in both in vitro and in vivo models. In sum, we identified a potential regulator of lenvatinib treatment response in HCC. Citation Format: Yunong Xie, Minghe Zhang, Yan Liu, Linglin Liu, Alfred Sze-Lok Cheng, Stephanie Ma, Man Tong. HDAC9 as a potential regulator of lenvatinib resistance in hepatocellular carcinoma [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 4667.
Abstract 4620: Exploring the role of GHRH antagonist MIA-602 in overcoming doxorubicin resistance in acute myeloid leukemia
Authors: Simonetta I. Gaumond, Joel Costoya, Andrew V. Schally, Joaquin J. Jimenez
Journal: Cancer Research (2024)

Abstract Acute Myeloid Leukemia (AML) is characterized by the uncontrolled proliferation of immature hematopoietic progenitors, often associated with a poor prognosis. Conventional therapies involve chemotherapy and bone marrow stem cell transplantation. The growth hormone releasing hormone receptor (GHRH-R) antagonist MIA-602 has exhibited inhibitory effects on the growth of various human cancer cell lines, including AML cells. This study aimed to investigate the impact of MIA-602 alone and in combination with doxorubicin on three doxorubicin-resistant AML cell lines, K-562, U-937, and KG-1A. Initial examinations confirmed the presence of GHRH receptors in both wild-type and doxorubicin-resistant cell lines through western blot analysis. Doxorubicin was administered at concentrations of 0.005, 0.01, and 0.05 μg/ml, while MIA-602 was used at 5 μmol/L. Subsequent experiments involved culturing both wild-type and doxorubicin-resistant clones with MIA-602 at concentrations ranging from 0.05 μmol/L to 5 μmol/L for 24 and 48 hours. The results revealed a significant, dose- and time-dependent reduction in cell proliferation across all six cell lines. Both wild-type and doxorubicin-resistant clones exhibited a comparable decrease in cell proliferation when exposed to MIA-602 at concentrations greater than 0.05 μmol/L (p &amp;lt; 0.05) after 24 and 48 hours. In conclusion, our study demonstrates that these three AML cell lines and their doxorubicin-resistant clones remain susceptible to GHRH antagonist MIA-602. These findings may pave the way for the development of novel therapies or drug combinations using GHRH antagonists such as MIA-602 for treating AML. This is of particular interest for those who are resistant to conventional chemotherapy, further broadening the spectrum of treatment options available. Additional investigations are warranted to progress these findings to in vivo xenograft models. Citation Format: Simonetta I. Gaumond, Joel Costoya, Andrew V. Schally, Joaquin J. Jimenez. Exploring the role of GHRH antagonist MIA-602 in overcoming doxorubicin resistance in acute myeloid leukemia [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 4620.
Abstract 3209: Antibody mediated targeted drug delivery approach for pancreatic cancer
Authors: Nirnoy Dan, Saini Setua, Poornima Shaji, Sonam Kumari, Murali Mohan Yallapu, Sheema S. Khan, Subhash Chauhan
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinomas, originating from the epithelial cell lining of ducts, account for approximately 95% of tumors in this category, showcasing a survival rate of less than 5-7%. Unfortunately, little progress has been seen in the outcomes of patients with PDAC as tumor develops high desmoplasia and chemo-resistance to chemotherapeutic drugs, such as gemcitabine (Gem). The therapies are unable to penetrate to the fibrotic tumors leading to insufficient availability of the therapeutic drugs at the tumor site. We and others have shown that MUC13 is aberrantly expressed in pancreatic tumors but not in normal pancreas, which makes MUC13 as an excellent protein for specifically targeting pancreatic tumors. Herein, we demonstrate a unique ability of our in-house generated mouse and humanized monoclonal antibody of MUC13 to penetrate and target pancreatic cancer. These antibodies have been conjugated with our recently developed novel patented superparamagnetic iron oxide nanoparticles (SPIONS) to deliver therapeutics specifically to pancreatic tumors. In this study, we are using curcumin that depletes tumor microenvironment and gemcitabine to investigate the efficacy of the MUC13 conjugated SPION in delivery of therapeutic drugs. Our results demonstrate that enhanced uptake of MUC13-SPION formulation in MUC13 positive (MUC13+) PanCa cells, compared with MUC13 null (MUC13-) cells as demonstrated by immunofluorescence, Prussian blue staining and flow cytometry experiments. Interestingly, the formulation resulted in sustained delivery of curcumin (CUR), enhanced inhibition of cell proliferation, migration and invasion in MUC13+ cells as compared with MUC13- cells, which suggests the targeting efficacy of the formulation. In PanCa orthotopic mice model, MUC13-SPION efficiently targeted pancreatic tumors resulting in significant tumor accumulation. We observed inhibition of tumor volume, metastasis, gem resistance and improved survival in mice treated with the formulation. Additionally, the tumor tissues from treated mice showed extensive downregulation of PCNA and expression of key proteins in SHH pathway, such as SHH, Gli-1, Gli-2, Patched 1, SMO, which has been associated with cancer progression and drug resistance. In conclusion, the results indicate high therapeutic significance of MUC13-SPIONS for achieving pancreatic tumor specific delivery of drugs. Citation Format: Nirnoy Dan, Saini Setua, Poornima Shaji, Sonam Kumari, Murali Mohan Yallapu, Sheema S. Khan, Subhash Chauhan. Antibody mediated targeted drug delivery approach for pancreatic cancer [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 3209.