tbuckley/cabot-search huggingface dataset:
Abstract 5946: ZM-412, a potent and selective KIF18A inhibitor with robust efficacy as monotherapy in CIN-positive tumors and in combination with MMAE-conjugated ADC in CIN-negative tumors
Authors: Feng Zhou, Lei Zhou, Ruina Wang, Liting Xue, Xiaokang Qin, Zhengtao Li, Jian Yu, Renhong Tang
Journal: Cancer Research (2024)

Abstract Chromosomal instability (CIN), a hallmark of human cancer, is defined as the perpetual missegregation of whole chromosomes during mitosis. KIF18A has emerged as a potential therapeutic target of synthetic lethality to induce CIN tumor cell death because it is more required for the proliferation of CIN tumor cells than normal diploidy cells. Here, we identified a potent and selective KIF18A inhibitor ZM-412. In vitro, ZM-412 inhibited the kinesin motor enzymatic activity with an IC50 less than 30 nM, and arrested OVCAR3 cells in the G2/M phase with an EC50 around 2.0 nM. ZM-412 also selectively inhibited the proliferation of a panel of CIN-positive tumor cell lines with IC50 values less than 50 nM, whereas it didn’t affect the proliferation of CIN-negative cells such as PBMC and near-diploidy HCT116 as indicated by IC50 values over than 5 μM. A CIN-positive HCT116CIN model was established by cytochalasin D induction. Compared to parent HCT116 cells, it was sensitive to ZM-412 treatment, suggesting the high selectivity of ZM-412 to CIN tumors as monotherapy. Both KIF18A inhibitors and monomethyl auristatin E (MMAE) regulate microtubule dynamics, which provides a potential combination strategy. ZM-412 showed a significantly synergic effect with free MMAE or MMAE-conjugated ADC on the inhibition of proliferation in multiple kinds of cancer cell lines, including CIN-positive/negative tumor cell lines. In vivo, ZM-412 potently inhibited tumor growth in a dose-dependent manner in OVCAR3 and HT29 xenograft models. Moreover, ZM-412 showed a remarkable synergic effect on tumor growth inhibition with MMAE-conjugated LIV-1 ADC in OVCAR3 xenograft model. In conclusion, we discovered ZM-412 as a novel potent and selective KIF18A inhibitor, which has potential for the treatment of CIN cancers as monotherapy and for combination therapies for extended cancer types with MMAE-ADC. Citation Format: Feng Zhou, Lei Zhou, Ruina Wang, Liting Xue, Xiaokang Qin, Zhengtao Li, Jian Yu, Renhong Tang. ZM-412, a potent and selective KIF18A inhibitor with robust efficacy as monotherapy in CIN-positive tumors and in combination with MMAE-conjugated ADC in CIN-negative 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 5946.
Abstract 7259: Effectiveness and comparison of CAR-T cell therapies for synovial sarcoma; HER2-targeted CAR-T and NKG2D-based CAR-T
Authors: Tomohiro Miyazaki, Chihaya Imai, Naoki Oike, Yudai Murayama, Takashi Ariizumi, Minori Baba, Yasushi Kasahara, Hiroyuki Kawashima
Journal: Cancer Research (2024)

Abstract Introduction: In Japan since 2019, CAR-T cell therapy has been used to treat patients with relapsed or refractory B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma and has shown excellent clinical results. Clinical studies of CAR-T cell therapies targeting various antigens, such as HER2, have been conducted, but the therapeutic outcome in sarcoma is still limited. We have previously reported that HER2-targeted CAR-T cells show antitumor effects for synovial sarcoma in vitro. The purpose of this study is to compare HER2-targeted CAR-T cells and NKG2D-based CAR-T cells in antitumor effect and specific responses for synovial sarcoma in vitro. Materials and Methods: Surface expressions of HER2 and NKG2D ligands on three synovial sarcoma cell lines were detected by using recombinant human HER2 Fc chimeric protein and that of NKG2D, followed by staining with PE-conjugated anti-human IgG secondary antibody. We generated 4-1BB-type second generation CAR-T cells targeting NKG2D ligands and examined their antitumor effects and specific responses against synovial sarcoma cells. In addition, we compared the differences between HER2-targeted CAR-T cells and NKG2D-based CAR-T cells by co-culturing with synovial sarcoma cells using short-term assay (WST-8 assay), long-term assay (Real-time Cell Analysis) and CD107a assay. Results: HER2 and NKG2D ligands were found to be expressed by flow cytometry in three synovial sarcoma cell lines. In vitro, NKG2D-based CAR-T cells showed antitumor effects against synovial sarcoma cells, including degranulation and cytokine production. Furthermore, NKG2D-based CAR-T cells showed stronger antitumor effects than HER2-targeted CAR-T cells in both short- and long-term assays and expressed higher levels of CD107a. Conclusions: In this study, NKG2D-based CAR-T cells showed more antitumor effects than HER2-targeted CAR-T cells in vitro. Although the reason for this is not clear, we hypothesize that NKG2D ligands may be induced in synovial sarcoma cells by co-culture with CAR-T cells because HER2 is a cancer-specific antigen, whereas NKG2D ligands are ligands for activating receptors of natural killer cells. Further studies, including in vivo studies, will be conducted to verify the difference in anti-tumor effects between these CAR-T cells. Citation Format: Tomohiro Miyazaki, Chihaya Imai, Naoki Oike, Yudai Murayama, Takashi Ariizumi, Minori Baba, Yasushi Kasahara, Hiroyuki Kawashima. Effectiveness and comparison of CAR-T cell therapies for synovial sarcoma; HER2-targeted CAR-T and NKG2D-based CAR-T [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 7259.
Abstract 7102: The central dogma of hepatocellular carcinoma: Genomic, transcriptomic, and proteomic changes
Authors: Hoi Tang MA, Chun Yin YU, Lau Yan NG
Journal: Cancer Research (2024)

Abstract Cancer is a disease condition characterized by remarkable heterogeneity, wherein numerous molecular features display considerable disparities even with the same patient cohorts, leading to varied treatment outcomes. The primary factor contributing to the substantial differences observed across cancers stems from unique combinations of genetic mutations. Epigenetic alterations further contribute to differential gene expression and splicing, thereby enhancing transcriptomic diversity. The protein products originating from the cancer transcriptome constitute the specific intracellular and extracellular environment, consequently exerting supplementary effects on epigenetic, transcriptomic, and proteomic changes. The complex interplay and mutual influence between genetic aberrations, transcriptomes, and proteomes significantly contribute to shaping the extensive spectrum of molecular characteristics observed in cancer. With label-free mass spectrometry, RNA-sequencing, and low-pass whole genome sequencing, the quantification of the proteome, transcriptome, and genetic abbreviation of the cancer can be evaluated. With the mouse hydrodynamic tail vein injection (HDVI) models of hepatocellular carcinoma (HCC), different subtypes of HCC derived from different genetic abbreviations can be generated. With the proteome, transcriptome, and genetic abbreviation data of the better-defined HCC from HDVI models and HCC patients, the patient-derived HCC can be classified according to the origin of the genetic abbreviation used in the generation of the HDVI-derived HCC. Furthermore, the proteome of patient-derived plasma will be analyzed, and the signature change unique to HCC classified by different origins of genetic abbreviation will provide an abstract of the proteome, transcriptome, and genetic abbreviation of the HCC tissue. The transcriptomics and proteomics data of HDVI mice produced from five distinct sets of genetic abbreviations have been measured. The proteome and transcriptome of tissue, as well as the proteome of plasma, from a small cohort of HCC patients were studied and classified using this resource to illuminate the fundamental landscape of HCC. The final results will be presented and discussed at the meeting. Citation Format: Hoi Tang MA, Chun Yin YU, Lau Yan NG. The central dogma of hepatocellular carcinoma: Genomic, transcriptomic, and proteomic changes [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 7102.
Abstract 5451: FOXC2 influences EMT-induced stem cell properties through regulation of FABP4 in breast cancer
Authors: Breanna R. Demestichas, Vinita Shivakumar, Esmeralda Ramirez-Peña, Joseph Taube, Petra den Hollander, Sendurai A. Mani
Journal: Cancer Research (2024)

Abstract Cancer stem cells (CSCs) pose a significant clinical challenge due to their inherent resistance to therapies and prevalence in cancer recurrence. CSCs have the ability for self-renewal and to adapt to different microenvironments during dissemination and seeding into distal organs, and these properties are critical in metastasis. We and others have shown that epithelial to mesenchymal transition (EMT) drives the acquisition of stem cell properties, particularly via the forkhead box protein C2 (FOXC2) transcription factor. FOXC2 is a master regulator of EMT and is necessary for the induction and maintenance of CSC properties. Importantly, FOXC2 is not expressed in most adult tissues except adipocytes, in which it dictates several aspects of lipid metabolism. Additionally, metabolic changes during EMT can equip cancer cells with enhanced survival mechanisms during tumor progression and metastasis. We hypothesized that FOXC2 regulates metabolism in EMT-induced cells, facilitating stem cell properties and metastatic competence. To determine the downstream metabolic genes regulated by FOXC2 and that enhance stemness properties in cancer cells, we performed gene expression profiling and identified fatty acid binding protein 4 (FABP4), which is known to be involved in lipid metabolism, especially in adipocytes and macrophages. We demonstrate that inhibition of FOXC2 expression using shRNA in EMT-induced cells markedly reduces FABP4 expression. In agreement with this, we found that the overexpression of FOXC2 expression rescues the expression of FABP4. In addition, FOXC2 binds to the FABP4 promoter and regulates its expression suggesting that FABP4 is a direct target of FOXC2. We demonstrate that both lipid uptake and CSC formation is inhibited in a dose-dependent manner using a FABP4-specific small molecule inhibitor. Additional experiments are underway to assess the role of FABP4 in CSC formation in vivo and in contributions to metastasis, using our small molecule inhibitor in mouse models of metastatic breast cancer. Overall, our data indicate that FABP4 is a key regulator of stemness in breast cancer cells and targeting the FOXC2—FABP4 axis may provide therapeutic benefits for breast cancer. This work also provides insights into the metabolic shifts that occur during EMT and CSC formation, which warrants further investigation into these mechanisms. Citation Format: Breanna R. Demestichas, Vinita Shivakumar, Esmeralda Ramirez-Peña, Joseph Taube, Petra den Hollander, Sendurai A. Mani. FOXC2 influences EMT-induced stem cell properties through regulation of FABP4 in breast 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 5451.
Abstract 2555: Real-world data analysis of comprehensive genomic profiling using plasma samples from non-small cell lung cancer patients
Authors: Momoko Morishita, Koki Fujii, Michiko Ueki, Hiroaki Ikushima, Hideaki Isago, Kousuke Watanabe, Katsutoshi Oda, Hidenori Kage
Journal: Cancer Research (2024)

Abstract Introduction: Comprehensive genomic profiling (CGP) tests which use plasma samples can detect driver mutations and are recommended when tissue samples are unavailable. Multiple studies have shown that plasma CGP tests can result in genomically matched treatment for cancer patients, especially in gastrointestinal cancer. However, data for non-small cell lung cancer (NSCLC) remain limited. Methods: We searched the database of the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), which comprised 99.7% of the CGP data under insurance coverage in Japan. NSCLC patients analyzed with FoundationOne Liquid CDx (F1LCDx) between August 1 2021 to July 31 2023 were included, all of whom were previously treated. Result: 694 patients with NSCLC underwent liquid biopsy. Among them, 572 cases were adenocarcinoma, and 71 were squamous cell carcinoma. The median age was 68 years (range: 24-93), and 423 patients were male. Pathogenic or likely pathogenic EGFR mutations, ALK rearrangements, ROS1 rearrangements, MET exon 14 skipping mutations, BRAF V600E, RET fusions, ERBB2 mutations, and KRAS G12C were detected in 174 cases (25.1%), 18 cases (2.6%), 2 cases (0.3%), 9 cases (1.3%), 3 cases (0.4%), 7 cases (1.0%), 26 cases (3.7%) and 17 cases (2.4%), respectively. Among the 499 patients without known driver mutations, driver mutations were detected by F1LCDx in 60 patients (12.0%). The detection rate of each driver oncogene is shown in Table 1. Conversely, among the 174, 20, 9 and 3 patients with known EGFR, ALK, ROS1, or BRAF V600E alterations, F1LCDx showed false negative results in 48 (27.6%), 10(50.0%), 8 (88.9%), and 3 cases (100%) (EGFR/BRAF vs. ALK/ROS1, p = 0.001), respectively. Conclusion: In patients without known driver oncogenes, mutations associated with approved therapeutic implications were detected in 12.0%. The detection of gene rearrangements using liquid biopsy may be limited compared with genetic mutations. Genomic profiling detected by FoundationOne Liquid CDx Cases (%) EGFR, known EGFR, unknown ALK, known ALK, unknown ROS1, known ROS1, unknown BRAF V600E, known BRAF V600E, unknown Detected by F1LCDx 126 (72.4) 48 (9.2) 10 (50.0) 8 (1.2) 1 (11.1) 1 (0.15) 0 3 (0.43) Undetected by F1LCDx 48 (27.6) 472 (90.8) 10 (50.0) 666 (98.8) 8 (88.9) 684 (99.9) 3 (100) 688 (99.6) Total 174 520 20 674 9 685 3 691 Citation Format: Momoko Morishita, Koki Fujii, Michiko Ueki, Hiroaki Ikushima, Hideaki Isago, Kousuke Watanabe, Katsutoshi Oda, Hidenori Kage. Real-world data analysis of comprehensive genomic profiling using plasma samples from non-small cell lung cancer patients [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 2555.
Abstract 1408: Intrahepatic IgA complex induces polarization of cancer-associated fibroblasts to matrix phenotypes in the tumor microenvironment of HCC
Authors: Pil Soo Sung
Journal: Cancer Research (2024)

Abstract Background and Aims: Cancer-associated fibroblasts (CAFs) are activated fibroblasts that play key roles in the tumor microenvironment (TME). Immunoglobulin A (IgA) contributes to inflammation and anti-tumor immunity dismantling in the human liver. We investigated the effects of the IgA complex on CAFs in the TME of hepatocellular carcinoma (HCC). Approach and Results: CAF dynamics in HCC TME were analyzed via single-cell RNA sequencing of HCC samples. CAFs were isolated from 40 HCC samples. The isolated CAFs were treated with mock or serum-derived IgA dimers. Following treatment with the mock or serum IgA dimers in vitro, co-culture experiments were performed using CAF and CD8+ T cells. Single-cell analysis showed that sub-cluster proportions in the CAF-fibroblast activation protein-α (FAP) matrix were significantly increased in patients with high serum IgA levels. We were performed flow cytometry on fresh surgical tissues and observed a significant increase in the mean fluorescence intensity (MFI) of FAP in the CD68+ cells from patients with high serum IgA levels compared to those with low serum IgA levels (p&amp;lt;0.001). We validated that the transferrin receptor (CD71) is expressed in CAFs (p&amp;lt;0.01). IgA-treated CAFs exhibited higher programmed death-ligand 1 (PD-L1) expression levels than mock-treated CAFs (p&amp;lt;0.05). Co-culture with CAFs induced the attenuation of the cytotoxic function of activated CD8+ T cell, and these cells co-cultured with IgA-treated CAFs exhibited increased expression levels of programmed death-1 (PD-1) compared to those co-cultured with mock-treated CAFs (p&amp;lt;0.05). Conclusions: Intrahepatic IgA induces polarization of HCC CAFs into more malignant matrix phenotype and attenuates cytotoxic T cell function. Our study uncovers five dynamic CAF subpopulations within HCC tissues and highlights their potential roles in tumor progression and immune suppression. Citation Format: Pil Soo Sung. Intrahepatic IgA complex induces polarization of cancer-associated fibroblasts to matrix phenotypes in the tumor microenvironment of HCC [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 1408.
Abstract 2563: Understanding the new subgroup- Her 2 low breast cancer
Authors: Radhika Kulkarni, Muhammad Ali Shahid, Oscar Hinojosa Castro, Kunj Patel, Chun-Hui Lin, Courtney Rose, Vrushali Dabak
Journal: Cancer Research (2024)

Abstract Introduction: Outcomes have greatly improved for patients with HER2+ breast cancer. Recently, tumors with IHC 1+ or 2+/negative FISH have been classified as ‘HER2-low’. The development of novel HER2 agents has shown clinical benefit in this subset of patients. Information on the clinical characteristics of these patients which could be prognostic, and which could impact therapeutic options is limited. Methods: This was an IRB-approved study. Relevant patient demographics, disease characteristics, and treatment details of patients with metastatic breast cancer seen at our center from 2018 to 2021 were collected by chart review. All data analyses were performed using R version 4.3.1, and a p-value ≤ 0.05 was considered statistically significant. Results: A total of 102 patients with metastatic breast cancer were included. Patients were divided as HER2+, HER-, HER2 low ER+ and HER2 low ER -. 66.6% of patients had HER2 low disease. Patients with HER2 low ER- disease were more likely to have tumors that were of higher grade (grade 3, 71.4%, p=0.003), higher mean Ki67 (60%, p&amp;lt;0.001), and of ductal histology (100%, p=0.006). There was a statistically significant difference in PFS among the four groups (p=0.001). Median survival was longer in patients with HER2 low ER+ compared to the HER2- group. (1.42 vs 0.58, p&amp;lt;0.001, Table 1). Amongst HER2 low ER+ patients, there was a significant PFS difference in those treated with CDK4/6 inhibitors compared to chemotherapy (2.83 vs. 0.67, p=0.009). We found no difference in PFS between patients who were HER2 1+ ER+ and HER2 2+ ER+. In multivariate analysis, there was no significant association of race, grade, menopausal status, Ki67, histologic subtype, and metastatic sites with PFS. Table 1. PFS Summary Group Total number Progression/Death Median Survival HER2- 13 13 0.58 HER2 low ER- 14 11 0.88 HER2 low ER+ 54 32 2.42 HER2+ 20 12 1.08 Conclusion: In this small single-center retrospective study, patients with metastatic HER2 low ER- breast cancer had higher-grade tumors. HER2 low ER+ patients had a better PFS compared to HER2- patients. This seems to suggest that the HER2 low group may have some inherent biologic differences. Larger studies are needed. Citation Format: Radhika Kulkarni, Muhammad Ali Shahid, Oscar Hinojosa Castro, Kunj Patel, Chun-Hui Lin, Courtney Rose, Vrushali Dabak. Understanding the new subgroup- Her 2 low breast 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 2563.
Abstract 2274: Genomic and transcriptomic analyses of chemical hepatocarcinogenesis aggravated by loss of oncoproteins in hepatocytes
Authors: Xinyi Wang, Jiemeng Zhang, Yingluo Liu, Shuo Zhang, Yan Liang, Min Zong, Xiaoxue Lin, Michael Karin, Gensheng Feng
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death without effective treatment. Oncogenic drivers, including PTPN11/Shp2, Ikkβ kinase (IKK), c-Met and β-catenin, as well as tumor microenvironment as illustrated by a carcinogen or diethylnitrosamine (DEN)-treated models, have combined contribution to cancer progression that have distinct prevalence in human HCC progression. We previously found that disruption of Ras/Erk by Shp2 deletion combined with deletion of NF-κB unexpectedly dysregulated circadian clock genes which leads to further cancer progression. Except for this, limited reports investigated how various other oncogenic genes aberration would incorporate with DEN to induce HCC. Further, no reports investigated the dynamic evolution of transcriptomic aberration incorporating genetic changes and the differential functional pathways involved in DEN plus oncogene triggered-HCC progression. Thus, we here sought to investigate the context-dependent contribution of PTPN11/Shp2, IKK, c-Met and β-catenin to HCC using hepatocyte-specific deletion models (SKO, IKO, MKO, BKO) combined with DEN treatment. Exome sequencing and RNAseq were used to identify dynamic changes of the genomic and transcriptomic variations of HCC development under the influence of both genetic deletion and DEN-treatment. We found that upregulated epithelial-mesenchymal transition (EMT), cancer metastasis/migration and downregulated fatty-acid and cholesterol metabolism were highly involved across models. Macrophages together with genes including Spi1, Clec7a, and microRNA networks including miR-122 and miR-155 etc. were also deregulated. Specifically, upregulated IL2-STAT5 signaling in DEN-SKO liver tissues, upregulated myogenesis, KRAS signaling and EMT as well as apoptosis in DEN-MKO, downregulated xenobiotic metabolism and bile acid metabolism in DEN-IKO and -BKO were identified to be distinct to oncogenic deletion in relation with HCC development. Citation Format: Xinyi Wang, Jiemeng Zhang, Yingluo Liu, Shuo Zhang, Yan Liang, Min Zong, Xiaoxue Lin, Michael Karin, Gensheng Feng. Genomic and transcriptomic analyses of chemical hepatocarcinogenesis aggravated by loss of oncoproteins in hepatocytes [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 2274.