tbuckley/cabot-search huggingface dataset:
Abstract 4400: Transcriptional dysregulation of chromosomes localized into the micronucleus
Authors: Danguole Norkunaite, Duaa Al-Rawi, Samuel Bakhoum
Journal: Cancer Research (2024)

Abstract Chromosomal Instability (CIN) is a characteristic of the most aggressive and drug-resistant cancers. Chromosomally unstable cells form micronuclei (MN), a structure with an unstable nuclear membrane that spontaneously surrounds missegregating chromosomes upon mitotic exit. Several studies have demonstrated that CIN drives drug resistance and metastasis through the karyotypic diversity caused by copy number alterations. Beyond facilitating karyotypic diversity, CIN has recently been demonstrated to cause durable epigenetic alterations including reduction of the activating histone H3K27ac mark in chromosomes localized to micronuclei. This reduction in histone H3K27 acetylation persists after the relocalization of the missegregated chromosome to the primary nucleus (PN). Given the loss of transcription-associated epigenetic modifications, we hypothesized that MN would exhibit transcriptional impairment. Indeed, by using nascent RNA assays and immunofluorescence, we found that chromosomes localized into the MN are less transcriptionally active and exhibit lower levels of active RNA polymerase II (RNAP2). Transcriptional inhibitors targeting RNAP2 largely abrogate MN transcription. Conversely, class-specific histone deacetylase inhibitors (HDACi) cause increased hyperacetylation of the MN relative to the PN, which persists beyond MN reincorporation into the PN. We also hypothesized that transcription in MN depends on the manner of MN biogenesis. Preliminary data shows that MN formed from breakage-fusion-bridge (BFB) events may cause less transcriptionally active MN than ones generated from treatment with the MPS1 inhibitor, reversine. To better understand the mechanisms that regulate transcription in the MN, our ongoing work is focused on an unbiased investigation of the micronuclear transcriptome. Citation Format: Danguole Norkunaite, Duaa Al-Rawi, Samuel Bakhoum. Transcriptional dysregulation of chromosomes localized into the micronucleus [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 4400.
Abstract 625: Remodeling of the tumor microenvironment in esophageal squamous cell carcinoma by neoadjuvant immunochemotherapy and its impact on therapeutic efficacy
Authors: Rusidanmu Aizemaiti, Huifang Zhang, Changbin Zhu, Kun Zhou, Tao Hu, Shuang Lin, Xiao Teng, Jin Wang, Xing Li, Peng Ye
Journal: Cancer Research (2024)

Abstract Background: Patients with local advanced esophageal squamous cell carcinoma (ESCC) benefited from neoadjuvant immunochemotherapy (NAI) with 22%-55% of complete pathological responses (pCR). While unpredicted therapeutic resistance hampered prognosis of these patients. Thus, this study aimed to investigate tumor microenvironment (TME) remodeling pre- and post-NAI identifying predictive biomarkers and potential targets for patients with resistance to NAI. Methods: 65 patients with locally advanced ESCC, who were treated with neoadjuvant anti-PD-1 antibody and platinum-based chemotherapy at the First Affiliated Hospital of Zhejiang University School of Medicine between November 2019 and June 2020, were included in this study. Genomic DNA and RNA from paired pre-and post-treatment FFPE samples were harvested and subjected to targeted DNA and RNA sequencing. Pre- and post- therapeutic microenvironment and immune cell infiltration were dynamically assessed based on RNA sequencing data. Results: 37 of 65 patients responded to NAI(TRG0-1), while 28 of 65 patients displayed unfavored response (TRG2-3). Comparative analysis of TME characteristics before and after NAI revealed that, in the TRG2-3 group, LRRC15+ CAFs, and fibroblasts were significantly upregulated, while CD4 T cells and endothelium cells exhibited downregulation. Especially, TIGIT tended to be upregulated after NAI in the TRG 2-3 group. In the TRG0-1 group, significant upregulation of activated B cells, T-cells, myeloid dendritic cells, together with notable downregulations of immune suppressive features like Type 2 T helper cells, Tregs and LRRC15+ CAFs were observed in post-treatment samples. Conclusions: Our study indicates the dynamic remodeling of TME during-NAI treatment might influence therapeutic efficacy and disclose potentially targetable resistant mechanisms. These preliminary findings pave the way for further validation through prospective clinical studies. Citation Format: Rusidanmu Aizemaiti, Huifang Zhang, Changbin Zhu, Kun Zhou, Tao Hu, Shuang Lin, Xiao Teng, Jin Wang, Xing Li, Peng Ye. Remodeling of the tumor microenvironment in esophageal squamous cell carcinoma by neoadjuvant immunochemotherapy and its impact on therapeutic 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 625.
Abstract 56: Preclinical <i>in vivo</i> characterization underpinning LGR5-targeting CAR-T cells as a cancer immunotherapy
Authors: Jade Foeng, Timona Tyllis, Caitlin Abbott, Dylan McPeake, Emma Thompson, Veronika Bandara, Batjargal Gundsambuu, Silvana Napoli, Claudine Bonder, Iain Comerford, Tim Sadlon, Simon Barry, Shaun McColl
Journal: Cancer Research (2024)

Abstract Incidences of early-onset colorectal cancer (CRC) have been accelerating worldwide. To begin to address the lack of therapeutic options for CRC, we have developed a CAR-T cell therapy specific for leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5). LGR5 is known to potentiate Wnt/Β-catenin signaling and mark cells-of-origin in intestinal cancers. Extensive screening has demonstrated elevated expression of LGR5 in CRC, which is correlated with reduced patient survival. In CRC, LGR5 has been intimately linked with metastasis, cell survival and perturbation of chemotherapeutic interventions. We have developed a 9-day preclinical manufacturing method to generate LGR5-targeting CAR-T cells with a minimally differentiated T cell phenotype, which was concomitant with significant cytotoxic and activation marker expression. In human CRC xenograft mouse models, LGR5-targeting CAR-T cells eradicated tumors at doses as low as 800,000 CAR+ cells, and were capable of significantly inhibiting advanced tumor growth following delayed administration. Robust CAR-T cell-mediated immunological protection was observed in rechallenge experiments, in which secondary tumor growth was undetectable in mice which had tumors rejected following previous CAR-T cell administration. LGR5 protein and mRNA expression was also detected in a diverse range of cancer families, including ovarian, brain, liver and stomach, expanding upon the clinical indications with which LGR5-targeting CAR-T cells may be harnessed. These results contribute to a preclinical body of work that culminated in a Phase I/IIa clinical trial in metastatic colorectal cancer patients, which was approved for initiation by the FDA and commenced in 2023 (NCT05759728). Citation Format: Jade Foeng, Timona Tyllis, Caitlin Abbott, Dylan McPeake, Emma Thompson, Veronika Bandara, Batjargal Gundsambuu, Silvana Napoli, Claudine Bonder, Iain Comerford, Tim Sadlon, Simon Barry, Shaun McColl. Preclinical in vivo characterization underpinning LGR5-targeting CAR-T cells as a 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 56.
Abstract 2790: Hematopoietic stem cells tropism and conditioned media for targeting the triple negative breast cancer stem cells and associated mechanism: An in vitro study
Authors: Sumit Mallick, Sudheer Shenoy P, Bipasha Bose
Journal: Cancer Research (2024)

Abstract Triple-negative breast cancers are the most challenging to treat with targeted therapy because of their non-expression of cell surface receptors, unlike other types of breast cancer. However, conventional therapies such as chemotherapy, radiotherapy, and surgery are standard treatment modalities. Moreover, drug encapsulation strategies to deliver drugs at the targeted site have been sought-after alternatives. Hematopoietic Stem Cells (HSCs) have unique features to migrate towards inflammatory sites and other body organs during any injuries and release various cytokines, which lead to interaction with molecular pathways and results in reduced inflammation and tissue injuries. From this characteristic, we have hypothesized that hematopoietic stem cells can show tumor tropism and modulate the metabolic alteration in cancer and cancer stem cells, mainly focusing on Triple Negative Breast Cancer Stem Cells (TNBC CSCs). In this study, we have sorted both cancer stem cells and hematopoietic stem cells from TNBC and hematological cell lines, respectively. Sorted HSCs were cultured in specific conditions to prepare conditioned media. Then, both cell’ types were used for co-cultured assay and conditioned media cultured with TNBC-CSCs were performed. Metabolomics studies were performed to decipher the molecular interactions and TNBC-CSCs metabolic alterations. The result indicates that the HSCs are showing positive tropism towards TNBC stem cells. Furthermore, HSCs-derived conditioned media (CM) interact with the cell cycle pathway by downregulating the CDK genes and causing DNA breakage in the TNBC-CSCs. Moreover, the Metabolomics studies further confirmed that HSCs CM-derived cytokines interact with various pathways, dysregulating the TNBC-CSCs proliferation and altering the metabolic activities. Citation Format: Sumit Mallick, Sudheer Shenoy P, Bipasha Bose. Hematopoietic stem cells tropism and conditioned media for targeting the triple negative breast cancer stem cells and associated mechanism: An in vitro study [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 2790.
Abstract 2451: Investigation of SIRT6 usefulness as a novel biomarker for oral cancer
Authors: Haruka Yoshii, Ami Shimoda, Kenji Mitsudo, Mitomu Kioi
Journal: Cancer Research (2024)

Abstract Introduction: SIRT6 is one of the seven human sirtuin genes and is known to function as an onco-suppressor gene in colorectal and ovarian cancers, although it is up-regulated in other cancers. Thus, SIRT6 is considered performing both tumor-suppressing and promoting roles. However, the association of SIRT6 with oral squamous cell carcinoma (OSCC) and its role in OSCC pathogenesis are currently unclear. Currently, SCC or CYFRA are used as a tumor marker to assist in the diagnosis of OSCC in a clinical setting whereas its sensitivity is low. Therefor the development of a novel biomarker for early diagnosis and identification of new therapeutic targets is critical to resolve the pressing clinical issues related to the management of OSCC. This study aimed to investigate the expression and the relevance of SIRT6 in patients with OSCC and its potential as a biomarker for early detection and prognosis prediction. Materials and Methods: This study enrolled 78 patients with OSCC and 9 patients with carcinoma in situ (CIS). The OSCC patients had undergone surgery or chemoradiotherapy (51 surgery and 27 chemoradiotherapy). The CIS patients had undergone surgery. Samples were also obtained from 10 patients with oral potentially malignant disorders (OPMDs). Biopsied or surgical resected samples were used for the study. We obtained 21 noncancerous tissues as normal tissues from the adjacent noncancerous tissues after tumor resection. Immunohistochemistry, quantitative real-time RT-PCR, and microarray analyses were performed to determine SIRT6 expression and its association with clinicopathological features in OSCC, CIS, and OPMDs using clinical paraffin embedded specimens. Results: SIRT6 mRNA levels were higher in OSCC tissues than those in noncancerous tissues (p&amp;lt;0.05). And SIRT6 protein expression levels were higher in OSCC, CIS and OPMDs tissues than those in noncancerous tissues (p&amp;lt;0.05). SIRT6 expression was predominant in patients aged ≥65 years and significantly correlated with shorten overall survival. In the microarray analysis, some SIRT6-associated genes, such as ANXA2 was significantly up-regulated, and PIGC and RGPD4 were down-regulated in OSCC. Conclusion: SIRT6 plays a role in tumor homeostasis, leading to a poor prognosis in OSCC. SIRT6 may represent a novel target not only for the treatment, but also as a prognostic marker in OSCC. Citation Format: Haruka Yoshii, Ami Shimoda, Kenji Mitsudo, Mitomu Kioi. Investigation of SIRT6 usefulness as a novel biomarker for oral 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 2451.
Abstract 2443: Improved detection of low frequency mutations in ovarian and endometrial cancers by utilizing a highly accurate sequencing platform
Authors: Timothée Revil, Nairi Pezeshkian, Lucy Gilbert, Alexandra Sockell, Jiannis Ragoussis
Journal: Cancer Research (2024)

Abstract Ovarian and endometrial cancers come within the top-4 for incident cancers as well as deaths in North American women. Cure rates have not improved in 30 years as high-grade subtypes continue to be diagnosed in Stage III/IV. Attempts at early diagnosis have failed because high-grade cancer cells exfoliate and metastasize while the primary cancer is small and undetectable by existing tests based on imaging and blood-based tumor markers. DOvEEgene (Detecting Ovarian and Endometrial cancers Early using genomics) is a genomic uterine pap test developed by a McGill team to screen and detect these cancers while they are confined to the gynecologic organs and curable by surgery. The test identifies pathogenic somatic mutations in uterine brush samples. Here we tested the Onso system, a highly accurate sequencing technology from PacBio in order to potentially increase sensitivity while driving down sequencing costs by reducing required sequencing depth vs the current NGS standard. A highly sensitive, error-correcting capture technology (DOvEEgene-SureSelectHS) utilizing duplex error correction sequencing interrogated the exons of 23 genes involved in the development of sporadic and hereditary ovarian and endometrial cancers. We applied a combination of germline gene panel testing on saliva samples with deep duplex sequencing to detect somatic mutations at &amp;lt;0.1% VAF, interrogation of microsatellite loci for instability, and low coverage WGS for copy number analysis of uterine brush samples. We sequenced 20 duplex Illumina sequencing libraries produced using the DovEE assay at PE 100bp mode and compared Onso data in non- duplex sequencing mode as well as duplex sequencing mode to the original Illumina duplex sequencing method. Here, we present this comparison and highlight the benefits of high accuracy sequencing for the detection of very low frequency (&amp;lt;0.1%) somatic mutations. We observed improved mismatch rates for Onso data compared to Illumina, even after duplex error correction was applied. In addition, we found that more individuals are called as displaying microsatellite instablity from the Onso data, which may be due to improved sequencing performance in repetitive regions for Onso. Finally, we observed fewer potential false positive variant calls in the Onso data, highlighting the value of improved sequencing accuracy for rare variant detection. Citation Format: Timothée Revil, Nairi Pezeshkian, Lucy Gilbert, Alexandra Sockell, Jiannis Ragoussis. Improved detection of low frequency mutations in ovarian and endometrial cancers by utilizing a highly accurate sequencing platform [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 2443.
Abstract 5598: Combined loss of the chromosome 7 genes <i>CUX1</i> and <i>EZH2</i> promotes chemotherapy resistance
Authors: Matthew R. Jotte, Angela Stoddart, Tanner C. Martinez, Yuqing Xue, Molly K. Imgruet, Megan E. McNerney
Journal: Cancer Research (2024)

Abstract Monosomy 7 (-7) or del(7q) are recurrent in high-risk myeloid neoplasms, including up to 50% of myeloid neoplasms arising after prior exposure to chemotherapy and/or radiation. Although putative chromosome 7 tumor suppressor genes have been identified, the effects of combinatorial 7q gene loss remain unclear. A barrier to understanding the pathogenesis of -7/del(7q) is the challenge of modeling aneuploidy in animal models. To address this knowledge gap, we established an in vivo model of del(7q) clonal hematopoiesis and drug resistance using multiplex CRISPR-Cas9 to simultaneously target four 7q genes (Cux1, Ezh2, Kmt2c, and Kmt2e) in murine hematopoietic stem cells. After chemotherapy exposure, we observe significant myeloid expansion of clones edited for both Cux1 and Ezh2. Compared to the transcriptomes of control or single gene edited cells, Cux1;Ezh2-deficient cells fail to induce DNA damage response pathways after genotoxic stress. Cux1;Ezh2-deficient cells also display reduced deposition of γH2AX after DNA damage, as well as persistent, unrepaired DNA breaks, indicating perturbations to DNA damage recognition and repair. Collectively, our data support the concept of 7q as a contiguous gene syndrome region, in which combined loss of multiple genes drives drug resistance and disease development. This work reveals a genetic interaction between CUX1 and EZH2, and sheds light on how -7/del(7q) contributes to the development and inherent drug resistance characteristic of high-risk myeloid disease. Further, our CRISPR-based approach may serve as a framework for interrogating other recurrent aneuploid events in cancer. Citation Format: Matthew R. Jotte, Angela Stoddart, Tanner C. Martinez, Yuqing Xue, Molly K. Imgruet, Megan E. McNerney. Combined loss of the chromosome 7 genes CUX1 and EZH2 promotes chemotherapy 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 5598.
Abstract 7202: Strategy of targeting PKCβΙ protein to overcoming the acquired gemcitabine resistant pancreatic cancer cells
Authors: EunSeo Bae, Yijae Lim, Junhwa Hong, Woong Sub Byun, Simin Chun, Suckchang Hong, Sang Kook Lee
Journal: Cancer Research (2024)

Abstract Pancreatic cancer (PC) is one of the most malignant cancers with limitation of treatment options such as resection surgery, radiation therapy and gemcitabine-based chemotherapy. To treating PC patients, gemcitabine-based chemotherapy is common and effective for PC, acquired gemcitabine resistance is one of the major reasons for treatment failure. Therefore, there is a need to suggest effective strategies and novel therapeutic approach for gemcitabine-resistant PC. Protein Kinase C β1 (PKC β1) is known as involved in multiple signal transduction related to oncogenic functions in cancer. We suggested that PKC β as one of the novel biomarker of drug resistance and further investigated the molecular mechanism. Among the natural products as small molecule inhibitor, we found that evodiamine has potent antitumor activity and various biological activities. Based on various biological activities of evodiamine, the scaffold was synthesized and investigated for antiproliferative and antitumor activities against gemcitabine resistant PANC-1 (PANC-GR) cells. Also, target validation experiment was employed to elucidate the molecular mechanism and verifying the target to overcoming gemcitabine resistance. Mechanistically, evodiamine derivatives have shown that inhibition of PKC β1 can modulate the proliferation of PANC-GR cells and exhibited tumor growth inhibitory activity in xenograft mouse model. Keywords: Pancreatic cancer cell, Gemcitabine resistance, Protein Kinase C β1 (PKC β1), Molecular mechanism Acknowledgements: This research was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (RS-2023-00273240). Citation Format: EunSeo Bae, Yijae Lim, Junhwa Hong, Woong Sub Byun, Simin Chun, Suckchang Hong, Sang Kook Lee. Strategy of targeting PKCβΙ protein to overcoming the acquired gemcitabine resistant pancreatic cancer 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 7202.
Abstract 6686: The mechanism of gut microbiome-mediated immune activation on the clinical efficacy of PD-1 blocking treatment in solid tumors
Authors: Nina Yi-Tzu Lin, Shota Fukuoka, Daisuke Motooka, Yuko Shigeno, Takuma Irie, Dieter M. Tourlousse, Kazutoshi Murotomi, Yuji Sekiguchi, Hideyuki Tamaki, Mariko Shindo, Takahiro Tsuji, Hiroaki Wake, Koichi Goto, Toshihiko Doi, Kohei Shitara, Keisuke Watanabe, Yuka Maeda, Shota Nakamura, Yoshimi Benno, Hiroyoshi Nishikawa, Shohei Koyama
Journal: Cancer Research (2024)

Abstract Gut microbiota is associated with antitumor efficacy of immune checkpoint blockade therapies, yet the mechanism is not largely understood. Here, we show that a novel bacterial strain of Ruminococcaceae isolated from the feces of patients who respond to PD-1 (programmed cell death 1) blockade efficiently primes/activates tumor-specific CD8+ T cells through effective stimulation/maturation of CD103+ dendritic cells (DCs) during migration from the gut to the tumor microenvironment (TME). The administration of this bacteria strain with PD-1 blockade significantly inhibited tumor growth, even when adding them to fecal transplantation of non-responder patients in animal models. Mechanistically, the bacterial strain promoted the IRF8-driven differentiation of CD103+ DCs by stimulating multiple Toll-like receptors and the accumulation of these DCs in tumors and tumor-draining lymph nodes. These CD103+ DCs prolonged engagement with cognate antigen-specific CD8+ T cells, which induced the activation of CD8+ T cells specific for a wide variety of tumor antigens and fostered their PD-1 expression through enhanced T-cell activation signals with NFATc1 nuclear translocation, thereby leading to abundant PD-1+CD8+ T cells, a key effector cell population in PD-1 blockade, with a broader T-cell receptor repertoire in the TME. Our findings with novel single bacterium isolated from feces of responder patients demonstrate the mode of action by gut microbiota to augment antitumor immunity. Citation Format: Nina Yi-Tzu Lin, Shota Fukuoka, Daisuke Motooka, Yuko Shigeno, Takuma Irie, Dieter M. Tourlousse, Kazutoshi Murotomi, Yuji Sekiguchi, Hideyuki Tamaki, Mariko Shindo, Takahiro Tsuji, Hiroaki Wake, Koichi Goto, Toshihiko Doi, Kohei Shitara, Keisuke Watanabe, Yuka Maeda, Shota Nakamura, Yoshimi Benno, Hiroyoshi Nishikawa, Shohei Koyama. The mechanism of gut microbiome-mediated immune activation on the clinical efficacy of PD-1 blocking treatment in solid 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 6686.