tbuckley/cabot-search huggingface dataset:
Abstract 4703: Automated 42 PDX 3D <i>in vitro</i> tumor models of the TME screen immuno-oncology and targeted compounds and biologics for antitumor effects and MOA
Authors: Bin Xue, Christopher Harrod, Long Le, Julia Schüler, Kolin C. Hribar
Journal: Cancer Research (2024)

Abstract High throughput screening has been widely utilized for its efficiency in testing novel therapeutic agents. However, the conventional screening using 2D culture of cancer cell lines lacks the biological complexity of the tumor microenvironment or the immune compartment which limits their application in testing immune-oncology therapies. Particularly with the passing of the FDA Modernization Act 2.0, it is critical to create more biologically relevant 3D in vitro models that can be used to reduce, refine and ultimately replace preclinical animal models. Here we have developed a highly automated 3D high throughput screening platform comprised of 42 patient-derived xenograft models in coculture with fibroblasts in engineered extracellular matrix hydrogels that resemble tumor stromal microenvironment. The PDX models cover a diverse range of tumor and histological types including NSCLC, CRC, gastric, TNBC, RCC, bladder, ovarian, melanoma, pancreatic, and others. Moreover, PBMCs or other immune cells can be incorporated into the system for evaluating immuno-oncology drugs. The panel has been tested against chemotherapy drug cisplatin and the immunotherapy biologic, Solitomab, an EpCAM/CD3 bispecific antibody. The endpoint analyses for antitumor effects include the dose response of tumor size and tumor cell death percentage based on high content imaging analysis. In addition, immune cells and supernatant in the IO assay can be recovered from the wells and used for flow cytometry profiling and cytokine assays. In summary, the novel 42-PDX panel described here offers a unique and powerful tool for rapidly generating preclinical data and a better understanding the drug activity at the pharmacology stages, opening the door for faster and more human relevant drug discovery for cancer patients. Citation Format: Bin Xue, Christopher Harrod, Long Le, Julia Schüler, Kolin C. Hribar. Automated 42 PDX 3D in vitro tumor models of the TME screen immuno-oncology and targeted compounds and biologics for antitumor effects and MOA [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 4703.
Abstract 5424: Respiratory function linked to <i>in vivo</i> metastatic lung cancer progression
Authors: Padmini Bisoyi, Yoshi Sei, Neal Bennett, Ken Nakamura, Jean L. Nakamura
Journal: Cancer Research (2024)

Abstract Metastases are a major cause of morbidity and mortality in patients with cancer. How metastatic tumors employ metabolic programs to successfully colonize diverse microenvironment is poorly understood. Using an orthotopic xenograft mouse model of lung cancer that develops metastases and recapitulates metastatic lung cancer spread, we injected GFP-LUC-expressing human H1975 lung tumor cells into the left lungs of mice. In vivo bioluminescence imaging was used to visualize tumor growth and metastatic spread for 30 days. Animals were then euthanized and primary and metastatic tumors were collected from different anatomical sites of the body (left lung, right lung, mediastinum, abdominal metastases). Tumor samples were analysed by RNA sequencing analysis. The transcriptomes of lung metastases demonstrated a significant reduction in the expression of genes encoding respiratory pathway protein as compared to the primary lung tumors, suggesting metabolic reprogramming of their respiratory metabolism. CRISPRi-mediated silencing of genes encoding components of respiratory function in human lung cancer cells was associated with significantly increased metastatic spread in vivo. These studies suggest the functional importance of respiratory metabolism on modulating in vivo disease spread. Citation Format: Padmini Bisoyi, Yoshi Sei, Neal Bennett, Ken Nakamura, Jean L. Nakamura. Respiratory function linked to in vivo metastatic lung cancer progression [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 5424.
Abstract 5904: Targeting NaV1.7 channels in pancreatic cancer: Implications for EF2K and P-Src/P-Fak/integrin β1 signaling pathways
Authors: Mumin Alper Erdogan, Ayse Caner
Journal: Cancer Research (2024)

Abstract Pancreatic cancer (PaCa) ranks as the fourth leading cause of cancer-related deaths in the United States and is among the top five worldwide. Its hallmark characteristics include early invasion, metastasis, resistance to chemotherapy and radiotherapy, and aggressive tumor progression. Evaluating new generation treatments with significant potential in this ongoing battle against cancer is crucial. Voltage-gated sodium channels (VGSC), long detected in various metastatic cell lines and tissue samples beyond breast, lung, and prostate cancer, are of particular interest. This study aimed to explore the therapeutic effects of inhibiting NaV1.7 and its neonatal variant, nNaV1.7, in pancreatic cancer cells. The study utilized human normal keratinocyte cell line HaCaT and pancreatic cancer cell lines PANC-1 and MiaPaCa-2. It investigated the roles and effects of adult and neonatal isoforms of the NaV1.7 channel in pancreatic cancer proliferation, invasion, and metastasis. The findings revealed significantly higher adult and neonatal NaV1.7 mRNA expressions in PANC-1 and MiaPaCa-2 cell lines compared to HaCaT cells. Specific siRNAs effectively downregulated channel mRNA and protein expressions. Notably, NaV1.7 siRNA treatments significantly inhibited cell proliferation and colony-forming capacity in PANC-1 and MiaPaCa-2 cells, without cytotoxic effects on HaCaT cells. Combining gemcitabine with specific NaV1.7 siRNAs enhanced drug efficacy in the PANC-1 cell line. Furthermore, NaV1.7 siRNAs significantly reduced cell invasion, migration, and wound healing in both cell lines. These siRNAs also induced apoptosis and G1 arrest in the cell cycle. They inhibited protein expressions involved in key signaling pathways, including P-Src/P-Fak/Integrin β1, EF2K, P-Akt, P-mTOR, PARP, Caspase-3/9, Cyclin D1/E1. This study is pioneering, as literature lacks research on the expression and function of NaV1.7 and nNaV1.7 in pancreatic cancer cells or tissue samples. In conclusion, NaV1.7 channel isoforms play a significant role in the development, progression, and metastasis of pancreatic cancer and present as a potential therapeutic target in PaCa. Citation Format: Mumin Alper Erdogan, Ayse Caner. Targeting NaV1.7 channels in pancreatic cancer: Implications for EF2K and P-Src/P-Fak/integrin β1 signaling pathways [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 5904.
Abstract 212: Repression of NKX2-1 promote epithelial-mesenchymal transition and tumor neutrophil recruitment in lung cancer progression
Authors: Shih-Hwa Chiou, Ping-Hsing Tsai, Mong-Lien Wang
Journal: Cancer Research (2024)

Abstract Background: Malignant transformation is associated with tumor aggressiveness and poor patient outcome. This cellular alteration is due to either activation of oncogenes or the silencing of tumor suppressor genes. NKX2-1 was identified as a lineage-specific gene downregulated in poorly differentiated lung adenocarcinoma (LUAD). However, the molecular mechanism and functional role of infiltrated immune cells in NKX2-1-negative tumors are not clearly understood. Methods: Clinical relevance of NKX2-1 expression and disease status were evaluated by immunohistochemical analysis of LUAD tissue arrays and the overall survival analysis of TCGA databases. In vitro and in vivo experiments were applied to confirm the role and mechanisms of NKX2-1 actions in transformed cells. The secretion of chemokines was evaluated by using chemokine array. Flow cytometry and single-cell RNA sequencing analysis of mouse tumor tissue were used to demonstrate the infiltration of neutrophils in mouse models. Results: Low expression of NKX2-1 was observed in high-grade LUAD tumors. LUAD patients who express a pattern of NKX2-1high/TGF-βlow had better survival outcomes than those with NKX2-1low/TGF-βhigh. Mechanistically, TGF-β induced the downregulation of NKX2-1 which led to enhanced epithelial-mesenchymal transition (EMT), cell motility, and CXC chemokine expression. The high release of these chemoattractants promoted the recruitment of neutrophils. Meanwhile, NKX2-1-dependent suppression of CXC chemokines gene expression may be via repressive histone methylation at the promoter region of CXC chemokines in lung cancer cells. In the in vivo syngeneic LUAD models, exacerbated neutrophil infiltration was noted. Single-cell RNA sequencing and flow cytometry both revealed that neutrophils were recruited via CXCLs/CXCR2 activation in LUAD tumors with NKX2-1 knockdown. Conclusion: Our data showed that NKX2-1 represses tumor growth, metastasis, and neutrophil recruitment via the CXCLs/CXCR2-dependent mechanisms. Notably, targeting CXCR2 in NKX2-1-negative tumors may improve LUAD patient outcomes. Citation Format: Shih-Hwa Chiou, Ping-Hsing Tsai, Mong-Lien Wang. Repression of NKX2-1 promote epithelial-mesenchymal transition and tumor neutrophil recruitment in lung cancer progression [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 212.
Abstract 5761: A nanoplatform based on an <i>in situ</i> tumor vaccine and activation of STING and TLR7/8 pathways for enhanced NSCLC immunotherapy
Authors: Haiyu Zhou, Hengliang Hou, Bin Xu, Yucheng Huang, Hongrui Qiu
Journal: Cancer Research (2024)

Abstract Background: Immunotherapy has emerged as a promising treatment for tumors following surgical, radiotherapy, and chemotherapy interventions. Therapeutic tumor vaccines are considered highly effective in eliminating tumors and preventing their recurrence and metastasis due to their ability to induce or enhance T cell-mediated immune responses. However, the therapeutic efficacy of these vaccines is impeded by the heterogeneity present both between and within tumors. In contrast, in situ tumor vaccines, prepared from autologous antigens in tumor patients, present another promising strategy for generating comprehensive immune responses. Methods: In this study, we designed a multifunctional nanopolymer, the transformable nanoassembly PEG-Ce6@PAEMA/R848. This assembly includes the photosensitizer polyethylene glycol-chlorin-e6 (PEG-Ce6), the tumor pH-sensitive polymer poly(2-azepane ethyl methacrylate) (PAEMA), and the immune adjuvant Resiquimod (R-848). The objective is to confirm the activation of bone marrow-derived dendritic cells (DCs) at the cellular level. Subsequently, we investigated the maturation of DCs in lymph nodes and tumor sites in vivo. Results: In the particle characterization process, successful synthesis of nanoparticles was achieved, along with the verification of their acid-responsive function and toxic effects. Furthermore, in vitro experiments demonstrated the activation of bone marrow-derived dendritic cells (DCs) (Figure 1).To further investigate the in vivo vaccine effects, C57BL/6 mice were euthanized, and lymph nodes were extracted to examine the accumulation of FITC-PAEMA. It can be observed that, due to the reduction in size of the particles in the tumor acidic environment, the immune adjuvant can easily enter the lymph nodes. Activation of the STING pathway in dendritic cells within the lymph nodes was detected through qPCR. The maturation of dendritic cells (DCs) in the lymph nodes was determined using flow cytometry (Figure 2). Conclusions: In this study, we developed a straightforward yet potent strategy focused on in situ tumor targeting. This approach effectively inhibits tumor growth while inducing immunogenic cell death and eliciting a systemic anti-tumor immune response against cancer cells. Additionally, we intend to validate the therapeutic efficacy of this strategy on metastatic and distal tumors in subsequent investigations. Citation Format: Haiyu Zhou, Hengliang Hou, Bin Xu, Yucheng Huang, Hongrui Qiu. A nanoplatform based on an in situ tumor vaccine and activation of STING and TLR7/8 pathways for enhanced NSCLC 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 5761.
Abstract 6917: Ba/F3 AKT engineering cell lines, a useful platform for novel drug discovery
Authors: Guoqian Wang, Yao Tang, Jingxiao Xu, Yao Peng, Yu Wang, Jingying Ning, Feng Hao
Journal: Cancer Research (2024)

Abstract AKT, also known as phosphoinositide 3-kinase (PI3K), plays a key role in various signaling cascades involved in cell growth and division, apoptosis inhibition, and angiogenesis. For AKT, which is at the central node of the PI3K/AKT/mTOR signaling pathway, the loss of PTEN, mutation, or amplification of AKT/PIK3CA can lead to the overactivation of the AKT signaling pathway, resulting in the occurrence and development of tumors. Recent studies have also found that AKT activation is associated with drug resistance in tumor therapy. Therefore, AKT has become a hot target for tumor therapy. The AKT family consists of three highly homologous isoforms, AKT1 (PKBα), AKT2 (PKBβ), and AKT3 (PKBγ), with more than 85% homology in their kinase regions. E17K is the most common and well-characterized activating mutation, accounting for approximately 15% of all AKT mutations. Rare mutations mainly include L52R, Q79K, and D323H. The failures of AKT inhibitors LY2780301 and Bayer's BAY1125976 demonstrate the significant challenges and complexities in developing inhibitors of the AKT pathway. Currently, the most advanced AKT inhibitor globally is AstraZeneca's capivasertib, which is primarily indicated for HR+ breast cancer and triple-negative breast cancer. Our group has generated 21 Ba/F3-AKT engineering cell lines, as useful models for novel drug discovery in vitro and in vivo, almost all clinically significant mutations were included, such as common mutations AKT1/2-E17K as well as rare mutations L52R, Q79K, D323H, and others. The Ba/F3-AKT engineering cell lines can be useful for developing and evaluating next-generation AKT inhibitors and exploring newly acquired resistance mutations in AKT. Citation Format: Guoqian Wang, Yao Tang, Jingxiao Xu, Yao Peng, Yu Wang, Jingying Ning, Feng Hao. Ba/F3 AKT engineering cell lines, a useful platform for novel drug discovery [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 6917.
txci-ATAC-seq: a massive-scale single-cell technique to profile chromatin accessibility
Authors: Hao Zhang, Ryan M. Mulqueen, Natalie Iannuzo, Dominique O. Farrera, Francesca Polverino, James J. Galligan, Julie G. Ledford, Andrew C. Adey, Darren A. Cusanovich
Journal: Genome biology (2024)

We develop a large-scale single-cell ATAC-seq method by combining Tn5-based pre-indexing with 10× Genomics barcoding, enabling the indexing of up to 200,000 nuclei across multiple samples in a single reaction. We profile 449,953 nuclei across diverse tissues, including the human cortex, mouse brain, human lung, mouse lung, mouse liver, and lung tissue from a club cell secretory protein knockout (CC16
Abstract 4704: Biochemical and cell-based assay platforms for development of RAF inhibitors against human cancers
Authors: Jianghong Wu, Yong Wan, Shuguang Liang, Peter Gallagher, Li Liang, Christian Loch, Haiching Ma
Journal: Cancer Research (2024)

Abstract The RAF protein kinases are key intermediates in cellular signal transduction, functioning as direct effectors of the RAS GTPases and as the initiating kinases in the ERK cascade. In human cancer, RAF activity is frequently dysregulated due to mutations in the RAF family members (ARAF, BRAF, and CRAF) or to alterations in upstream RAF regulators, including RAS and receptor tyrosine kinases. The first and second generations of RAF inhibitors have yielded dramatic responses in malignant melanomas containing BRAF mutations; however, their overall usefulness has been limited by both intrinsic and acquired drug resistance. In addition, cancers with hyperactive RAS exhibit intrinsic resistance to these drugs. In particular, issues related to the dimerization of the RAF kinases can impact the efficacy of these compounds and are a primary cause of drug resistance. We have established biochemical HotSpotTM kinase assay, NanoBRETTM and NanoBITTM cell assay platforms for High Through Screening of kinase inhibitors. Here, we demonstrate that the 3rd generation of pan-RAF inhibitors LY3009120, LXH254, and Belvarafenib inhibit ARAF, BRAF, CRAF, BRAF(V600E), and CRAF(R391W) kinase activity in biochemical HotSpotTM assay. Our NanoBRETTM target engagement and NanoBITTM cellular assay data show that LY3009120, LXH254, and Belvarafenib bind to KRAS(G12C) primed BRAF and CRAF, and block BRAF and CRAF dimerization. Furthermore, our results show these inhibitors can block the downstream ERK phosphorylation in cellular HTRF assay and induce caspase-3/7 activation in Western blot assay in the triple negative breast cancer MDA-MB-231 cells. Taken together, our results indicate the biochemical HotSpotTM kinase activity assay, and NanoBRETTM target engagement and NanoBITTM cellular assays can serve as great platforms to facilitate RAF drug discovery against human cancers. Citation Format: Jianghong Wu, Yong Wan, Shuguang Liang, Peter Gallagher, Li Liang, Christian Loch, Haiching Ma. Biochemical and cell-based assay platforms for development of RAF inhibitors against human 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 4704.
Proteomics of mouse brain endothelium uncovers dysregulation of vesicular transport pathways during aging
Authors: Katalin Todorov-Völgyi, Judit González-Gallego, Stephan A. Müller, Nathalie Beaufort, Rainer Malik, Martina Schifferer, Mihail Ivilinov Todorov, Dennis Crusius, Sophie Robinson, Andree Schmidt, Jakob Körbelin, Florence Bareyre, Ali Ertürk, Christian Haass, Mikael Simons, Dominik Paquet, Stefan F. Lichtenthaler, Martin Dichgans
Journal: Nature Aging (2024)
Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming
Authors: Xujia Wu, Huairui Yuan, Qiulian Wu, Yixin Gao, Tingting Duan, Kailin Yang, Tengfei Huang, Shuai Wang, Fanen Yuan, Derrick Lee, Suchet Taori, Tritan Plute, Søren Heissel, Hanan Alwaseem, Michael Isay-Del Viscio, Henrik Molina, Sameer Agnihotri, Dennis J. Hsu, Nu Zhang, Jeremy N. Rich
Journal: Nature Cancer (2024)
Abstract 7098: Identifying of potential therapeutic targets of Taiwanese breast cancer by functional proteomics
Authors: Chi-Cheng Huang, Wei-Chi Ku, Chi-Jung Huang, Ling-Ming Tseng
Journal: Cancer Research (2024)

Abstract The aim of the study is to conduct translational research of crucial breast cancer prognostic genes with functional proteomics. We have collected 61 breast cancer core biopsy samples, which were used for targeted sequencing for genetic variant analysis, mass-spectrometry analysis for protein expression and stain with H&amp;E for whole slide image with Aperio Scanncer. After analysis of variant (ANOVA) of LC-MS/MS data, we found 17 proteins with highly differential expression between these 5 molecular subtypes from 61 patients. We then search for the protein-protein interaction (PPI) network from STRING database and found the strong network including 6 proteins namely Collagen Type II Alpha 1 Chain (COL2A1), Collagen alpha-1(XI) chain (COL11A1), Collagen alpha-1(VI) chain (COL6A1), Collagen alpha-2(VI) chain (COL6A2), Thrombospondin 1 (THBS1) and Lumican (LUM). To further investigate on the expression of these 6 target proteins in literature, we used Oncomine for data mining to query their mRNA expression profiles. Intriguingly, we discovered the mRNA expression of these targets are intensively distributed in many cancer types. This finding suggested the high potency of COL2A1, COL11A1, COL6A1, COL6A2, THBS1 and LUM as potential targets in breast cancer treatment. Our study has the potential contributing to the knowledge of breast cancer susceptibility, early detection, surveillance, and potential actionable targets, developing optimized screening programs and treatment protocols for distinct molecular subtypes. Citation Format: Chi-Cheng Huang, Wei-Chi Ku, Chi-Jung Huang, Ling-Ming Tseng. Identifying of potential therapeutic targets of Taiwanese breast cancer by functional proteomics [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 7098.
Abstract 7109: Fasn inhibition enhances the efficacy of chemotherapy by inhibiting DNA damage response in colorectal cancer
Authors: Moumita Banerjee, Yekaterina Zaytseva, Sumati Hasani, Piotr Ryachahou, Tadahide Izumi, B. Mark Evers, Tianyan Gao
Journal: Cancer Research (2024)

Abstract Altered lipid metabolism plays a significant role in progression of colorectal cancer, however, its role in chemotherapy resistance remains poorly understood. We previously identified FASN, the rate limiting enzyme in de novo lipogenesis, as an important regulator of colorectal cancer progression. However, TVB-3664, a potent and specific small molecule inhibitor of FASN, showed limited effect in reducing tumor burden in pre-clinical studies as a stand-alone therapy. Therefore, the goal of this study is to evaluate the combinatorial efficacy of TVB-3664 in improving the therapeutic indices of standard chemotherapy in colorectal cancer. Using a combination of colon cancer cell lines and patient derived organoids we showed that TVB-3664 potentiates chemotherapy drug-induced double-strand DNA breaks (DSBs) and apoptotic cell death by altering histone acetylation levels. In addition, TVB-3664 treatment blocked DNA damage response (DDR) by decreasing ATM expression and Chk1/2 phosphorylation. Mechanistically, inhibition of FASN prevents the activation of both DSB repair pathways, namely homologous recombination (HR) and classical non-homologous end joining (NHEJ), by blocking BRCA1 and 53BP1 recruitment to γH2AX foci, respectively. Moreover, we found that the inhibitory effect of TVB-3664 on DNA repair requires ACLY-dependent acetylation as genetic or pharmacological inhibition of ACLY attenuates TVB-3664-inducded DNA damage. Functionally, combining TVB-3664 with irinotecan synergistically decreased xenograft tumor growth and significantly delayed tumor relapse after withdrawal of therapy. Taken together, we identified a novel mechanism by which FASN inhibitors improve the efficacy of conventional chemotherapy by blocking DNA damage response to delay tumor recurrence and overcome a major challenge in treating colorectal cancer patients. Citation Format: Moumita Banerjee, Yekaterina Zaytseva, Sumati Hasani, Piotr Ryachahou, Tadahide Izumi, B. Mark Evers, Tianyan Gao. Fasn inhibition enhances the efficacy of chemotherapy by inhibiting DNA damage response in colorectal 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 7109.