tbuckley/cabot-search huggingface dataset:
Abstract 3051: JunAP, a peptide antagonist against the activator protein 1 transcription factor complex, demonstrates cancer cell cytotoxicity and reduced invasion in vitro and tumor regression in vivo in TNBC models
Authors: Karen Mendelson, Zachary F. Mattes, Siok Leong, Ricardo Ramirez, Mark Koester, Claudio Scuoppo, Julia Diehl, Erin Gallagher, Jerel Gonzales, Franco Abbate, Lila Ghamsari, Gene Merutka, Barry J. Kappel, Abi Vainstein-Haras, Jim A. Rotolo
Journal: Cancer Research (2024)

Abstract The activator protein 1 (AP-1) transcription factor is a dimeric complex consisting of proteins from the JUN, FOS, MAF, and ATF families. AP-1 complexes have been identified as novel therapeutic targets in cancer due to their role in tumor growth, invasion, metastasis, angiogenesis and chemoresistance. Dimerization of components of the AP-1 complex via leucine zipper domain interactions is required for DNA binding and subsequent transcriptional activity. We designed a peptide (Jun antagonizing peptide, JunAP) targeting the basic leucine zipper motif of AP-1 to antagonize AP-1 complex formation and prevent associated activity. Fluorescence polarization and DNA ELISA assays demonstrate target binding and selectivity of JunAP towards AP-1 family members, co-immunoprecipitation experiments reveal that JunAP blocks protein-protein interactions between cJun and its key binding partners, and reporter assays confirm inhibition of AP-1 transcriptional activity in vitro. Pathway analysis of RNA sequencing data confirmed by qPCR analysis shows that JunAP disrupts key pathways required for cell survival and migration. Corresponding functional in vitro assays reveal that JunAP exhibits an inhibitory effect on invasion in Boyden chamber assays and demonstrates potent cytotoxicity in Jun-dependent cells. Further, in a BT549 triple negative breast cancer subcutaneous xenograft model, administration of JunAP results in tumor regression, demonstrating the anti-cancer potential of targeting the AP-1 complex. In summary, these data support JunAP as a potent peptide antagonist of the AP-1 transcription factor family that warrants further development as a potential therapeutic option for AP-1 driven tumors. Citation Format: Karen Mendelson, Zachary F. Mattes, Siok Leong, Ricardo Ramirez, Mark Koester, Claudio Scuoppo, Julia Diehl, Erin Gallagher, Jerel Gonzales, Franco Abbate, Lila Ghamsari, Gene Merutka, Barry J. Kappel, Abi Vainstein-Haras, Jim A. Rotolo. JunAP, a peptide antagonist against the activator protein 1 transcription factor complex, demonstrates cancer cell cytotoxicity and reduced invasion in vitro and tumor regression in vivo in TNBC models [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 3051.
Abstract 5712: Functional dissection of CDK7 in transcription using a highly selective CDK7 inhibitor Q901
Authors: Hyerim Jung, Dahun Um, Yoonji Lee, Donghoon Yu, Dayoung Lee, Jiye Ahn, Jeongjun Kim, Seung-Joo Lee, Jaeseung Kim, Kiyean Nam, Tae-Kyung Kim
Journal: Cancer Research (2024)

Abstract CDK7 is a well-known regulator of both the cell cycle and transcription and plays a crucial role in cell cycle progression by catalyzing T-loop phosphorylation of other CDKs. CDK7 is also an integral subunit of the general transcription factor, TFIIH and regulates transcription through phosphorylation of RNA Polymerase II (Pol II) at CTD Ser5 and CDK9. We used Q901, a highly selective CDK7 inhibitor to further investigate the molecular function of CDK7 in the transcriptional process. Q901 is currently being evaluated in a phase 1 clinical study for selected advanced solid tumors. Compared to previously reported CDK7 inhibitors, Q901 has increased specificity and efficacy, but the impact on transcription have not been studied in detail. In our study, we combined RNA Pol II (pan, Ser5P, Ser2P) ChIP-seq and PRO-seq techniques in the MCF7 breast cancer cell line. The findings demonstrated that the Q901 effectively altered transcription and the RNA Pol II profile in a subset of genes, leading to a significant reduction in Ser5 phosphorylation levels in RNA Pol II. The downregulated genes were associated with critical pathways including downstream of oncogenic genes (MYC and E2F), DNA damage repair, cell cycle checkpoint, and gene expression. To verify whether these genes were the direct targets of CDK7, we performed CDK7 ChIP-seq analysis. CDK7 binding exclusively to the genes that were downregulated by Q901, without any detectable binding to upregulated genes. Despite the universal role of general transcription machinery in transcription, the data demonstrated that the highly selective inhibition of CDK7 in transcription of various oncogenic pathways underlies the potent in vitro and in vivo anti-cancer efficacy of this specific CDK7 inhibitor. Citation Format: Hyerim Jung, Dahun Um, Yoonji Lee, Donghoon Yu, Dayoung Lee, Jiye Ahn, Jeongjun Kim, Seung-Joo Lee, Jaeseung Kim, Kiyean Nam, Tae-Kyung Kim. Functional dissection of CDK7 in transcription using a highly selective CDK7 inhibitor Q901 [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 5712.
Abstract 2746: MAGE-A3 co-expression with IDH1-R132H and IL-1β in colon cancer
Authors: Andy/Xi Han, Rachel Gonzalez, Jina Yom, Zhaoying Guo, Bailey Gilmore, Eden Zewdu, Tianli Qu, Hailey/YiChen Guo, Qi Ren, Xiaomin Hu, Ranran Zhang, Zhaohui Wu, Xuan Liu, Wei Fu
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) remains a significant cause of cancer death worldwide with an estimated 52,000 deaths in 2023. Over the past few decades, the incidence rate of CRC in individuals younger than 50 has been steadily increasing. Currently, diagnostic biomarkers play an important role in the detection and treatment of CRC. MAGE-A3 has been shown to be expressed in many tumor types, including colon cancer by RNA expression. Due to their high sequence homology, members of the MAGEA family have been difficult to evaluate and screen for their protein expression. However, in a previous study, highly specific antibodies were identified using CytoSections for MAGE-A3 immunohistochemistry. IL-1β is a cytokine that induces inflammatory responses and when localized to the nucleus in colon cancer cells it can promote stemness. IL-1β expression has been shown to be increased in wildtype IDH1 positive glioblastoma. However, the relationship between IL-1β and IDH1 has not been studied in colon cancer. In this study, the difference in the expression of MAGE-A3, IL-1β, and wildtype IDH1 compared to mutant IDH1-R132H in colon cancer tissues was evaluated. The results show that IL-1β, wildtype IDH1, and MAGE-A3 were co-expressed in 27 of the 38 colon cancer tumors. However, IDH1-R132H expression was only seen in 20% of the tumors. This study suggests that MAGE-A3, IL-1β, and IDH1 are candidate biomarkers for immunotherapy due to their high expression in colon cancer tissues. Citation Format: Andy/Xi Han, Rachel Gonzalez, Jina Yom, Zhaoying Guo, Bailey Gilmore, Eden Zewdu, Tianli Qu, Hailey/YiChen Guo, Qi Ren, Xiaomin Hu, Ranran Zhang, Zhaohui Wu, Xuan Liu, Wei Fu. MAGE-A3 co-expression with IDH1-R132H and IL-1β in colon 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 2746.
Abstract 6968: Extracellular vesicles as carriers of signaling factors in cancer
Authors: Antonia Schubert, Nadine Winkler, Ajaree Mongkolsittisilp, Matthias Schulz, Oksana Voloshanenko, Meike Schaffrinski, Dominique Kranz, Karin Nienhaus, Dirk Jäger, Lorenz Trümper, Judith Büntzel, Claudia Binder, Gerd Ulrich Nienhaus, Michael Boutros
Journal: Cancer Research (2024)

Abstract Extracellular vesicles (EVs) are small, membrane-bound structures released by cells. They contain various biomolecules and have emerged as mediators of cellular signaling. EVs of various origins can be isolated from body fluids and hold potential as novel biomarkers. However, their clinical implementation as biomarkers is hampered by complex isolation procedures, limited expertise in routine labs, and a lack of mechanistic understanding of signal transfer, particularly in vivo. To better understand how EVs carry oncogenic signaling factors, we performed mechanistic investigations into the role of EVs in WNT signaling as a representative cancer-associated signaling pathway, as well as ex vivo validation experiments analyzing patient-derived EVs. Hydrophobic WNT ligands can use EVs to travel the extracellular space. However, little is known about the quantities of WNT secretion onto different EV fractions and potentially other vehicles. To explore WNT secretory routes and potential functional differences, we generated fluorescently tagged marker constructs of the non-canonical ligand WNT5a, which has context-dependent tumor-suppressing or -promoting functions in cancer. In additional in vitro experiments, we tested how the WNT signaling activation state and cancer-specific WNT mutations, such as CRISPR/Cas9-induced APC truncations, quantitatively and qualitatively affect EV shedding in colorectal cancer cell lines. Further functional testing of EV-bound vs. non-EV WNT ligands is ongoing. For proof-of-concept analyses and to test EVs as biomarkers, we set up the liquid biopsy study EValuate. The project aims for cross-entity analysis of EV profiles and correlation of results to cancer presence, stage, and survival. For quality control and before pipeline implementation, we tested various EV isolation methods and compared different sample pre-processing steps. By combining multidisciplinary expertise in biophysics, molecular biology, and basic and clinical cancer research, we aim to gain a better mechanistic understanding of EV-mediated signal transfer and facilitate the integration of EVs as diagnostic and prognostic biomarkers into clinical studies. Citation Format: Antonia Schubert, Nadine Winkler, Ajaree Mongkolsittisilp, Matthias Schulz, Oksana Voloshanenko, Meike Schaffrinski, Dominique Kranz, Karin Nienhaus, Dirk Jäger, Lorenz Trümper, Judith Büntzel, Claudia Binder, Gerd Ulrich Nienhaus, Michael Boutros. Extracellular vesicles as carriers of signaling factors in 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 6968.
Abstract 2356: NAV-006: A next-generation rituximab targeting CD20 for the treatment of B-cell lymphomas immunosuppressed by MUC16/CA125
Authors: Luigi Grasso, J. Bradford Kline, Nicholas C. Nicolaides
Journal: Cancer Research (2024)

Abstract Rituximab is a CD20-targeting antibody that is the standard-of-care for patients with Non-Hodgkin Lymphoma (NHL) cases. Rituximab’s mechanism of action includes complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), herein referred to as Humoral Immuno-Oncology (HIO) mechanisms. Recent clinical evidence suggest that high serum levels of the MUC16 (CA125) protein inversely correlate with the effectiveness of rituximab clinical activity in 40-50% of follicular lymphoma (FL) as well as diffuse large B-cell lymphoma patients with newly diagnosed or relapsed/refractory (R/R) disease. In this study we demonstrated that CA125 binds to and suppresses the activity of rituximab, tafasitamab as well as the bispecific mosunetuzumab and glofitamab antibodies, which are approved for treating cases with indolent disease. These therapies have an overall response rate around 50-60%, suggesting the presence of a mechanism that allows lymphoma cells to escape these agents’ immune-mediated killing effects. CA125 may facilitate this immunosuppressive mechanism, and in fact, upon binding rituximab, CA125 reduces its affinity for the Fc receptor, CD16a, thus suppressing ADCC. Using a proprietary technology called Block-Removed Immunoglobulin Technology (BRITE) that employs randomized amino acid substitution and HIO effector function screening, we have identified a rituximab variant named NAV-006. NAV-006 is refractory to the immunosuppressive effects mediated by CA125 via its reduced CA125 interaction and increased HIO activity as compared to parent rituximab as well as the other antibodies used to treat R/R FL. In an in vivo model of human B-cell lymphoma, NAV-006 showed superior efficacy compared to parent rituximab. These data warrant further investigation of NAV-006 as a next generation anti-CD20 antibody that could improve upon the efficacy of antibody-mediated therapies used to treat NHL patients with high levels of CA125. Citation Format: Luigi Grasso, J. Bradford Kline, Nicholas C. Nicolaides. NAV-006: A next-generation rituximab targeting CD20 for the treatment of B-cell lymphomas immunosuppressed by MUC16/CA125 [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 2356.
Abstract 2658: The circadian clock modulates cancer immune checkpoint therapy through immune cell trafficking
Authors: Jake N. Lichterman, Tarun Srinivasan, Wenling Li, Parastoo Sabaeifard, Laura A. Coughlin, Nicole Poulides, Lora V. Hooper, Andrew Y. Koh
Journal: Cancer Research (2024)

Abstract Immune checkpoint inhibitor therapy (ICT) can provide durable remissions for cancer patients with previously incurable malignancies. However, ICT is ineffective for many cancer types, and even those who initially respond may develop ICT resistance and succumb to their cancer. Tumor cell extrinsic factors, termed host factors, have recently emerged as key mediators and biomarkers of ICT response. One intriguing host factor that may influence ICT response is the circadian clock, an evolutionarily conserved transcriptional-translational feedback loop that allows mammalian organisms to adapt to environmental exposures (e.g. light). However, whether “the clock” modulates the ICT anti-tumor immune response is unknown. Utilizing preclinical mouse models of cancer immunotherapy, we found that ICT efficacy is time-of-day dependent. ICT was most efficacious if ICT was administered at two hours after first light exposure (Zeitgeber time 2, ZT2) and least efficacious at ZT18. Utilizing flow cytometry, bulk cytokine analysis, and single cell RNA sequencing, we characterized the anti-tumor immune response after administering ICT at ZT2 and ZT18. There was an increase in effector granzyme B- and interferon-γ producing CD8+ T-cells in the tumor at ZT2 versus ZT18. This was accompanied by an increase in CD11c+ dendritic cells (DCs) and intratumoral chemokines (e.g. CXCL10) that promote DC/T-cell migration into the tumor microenvironment, and leads to enhanced DC-T-cell priming and anti-tumor immunity. Interestingly, these time-of-day dependent differences in tumor immune cell infiltration were present prior to the administration of ICT. To interrogate the role of the clock in mediating these time-of-day dependent differences, we characterized the response to ICT in mice that lack the core clock gene, BMAL1. Loss of BMAL1 in DCs (BMAL1fl/fl crossed with CD11c-cre) attenuated ICT efficacy, abrogated time-of-day dependent differences in ICT efficacy and dampened anti-tumor immunity. These findings highlight a role for a novel host factor, the circadian clock, in mediating the efficacy of cancer immune checkpoint therapy. Citation Format: Jake N. Lichterman, Tarun Srinivasan, Wenling Li, Parastoo Sabaeifard, Laura A. Coughlin, Nicole Poulides, Lora V. Hooper, Andrew Y. Koh. The circadian clock modulates cancer immune checkpoint therapy through immune cell trafficking [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 2658.
Abstract 5340: NK-humanized mouse models for the <i>in vivo</i> evaluation of NK cell-based therapies in solid tumors
Authors: Pauline Rettman, Samira Benhamouche-Trouillet, Michel Pelat, Katarzyna Franciszkiewicz, Georges Azar, Lydia Blot, Loreley Calvet, Sukhvinder Sidhu, Céline Nicolazzi
Journal: Cancer Research (2024)

Abstract Novel immunotherapeutic strategies targeting Natural Killer (NK) cells using monoclonal or multi-specific antibodies and immune modulator molecules are under development and suitable mouse models are needed to evaluate these therapeutics. We developed and characterized robust in vivo models that allow the engraftment and long-term maintenance of fully functional human NK (huNK) cells in immunodeficient transgenic mice for human cytokines (IL15). In efficacy studies, we confirmed that huNK cells are recruitable by NK cell-based therapies including therapeutic antibodies or multi-specific biologics and able to control tumor growth in these models.To establish a more relevant model for better clinical translatability for Fc-competent therapeutics evaluation, we optimized the model by validating a mouse strain with a functional knock-out of murine Fcγ receptors (FcgR-KO) to minimize the confounding impact of mouse immune cells. We characterized huNK cells kinetics and profile by flow cytometry compared to NOG-huIL15 mice. In efficacy studies with the FcgR-KO strain, therapeutic antibodies are inactive in non-NK-humanized mice, whereas in NK-humanized mice huNK cells can be recruited by the therapeutic antibody to control tumor growth by ADCC, in B cell lymphoma or multiple myeloma bearing mice.We also report the development of NK-humanized models for the evaluation of NK-based therapies in solid tumors. We characterized huNK intratumoral infiltration in several subcutaneous tumor xenograft models and evaluated the impact of tumor environment on the expression of functional NK markers (NKp46, NKG2D, Tim3, CD69) by flow cytometry and IHC studies.In summary, we have developed and optimized robust murine models sustaining fully functional huNK cells that can be proficiently recruited in vivo by various NK-based therapeutics. These models can also be used to evaluate the efficacy of combination therapies. Citation Format: Pauline Rettman, Samira Benhamouche-Trouillet, Michel Pelat, Katarzyna Franciszkiewicz, Georges Azar, Lydia Blot, Loreley Calvet, Sukhvinder Sidhu, Céline Nicolazzi. NK-humanized mouse models for the in vivo evaluation of NK cell-based therapies 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 5340.
Abstract 3061: A positive feedback loop between GLS1 and c-Myc drives tumor aggressiveness
Authors: Jianqiang Yang, Fanghui Chen, Fan Yang, Yong Teng
Journal: Cancer Research (2024)

Abstract Both GLS1 and c-Myc are upregulated in head and neck squamous cell carcinoma (HNSCC) primary tumors and further increased in metastatic tumors. However, the regulation between these two molecules remains largely unknown. GLS1 is a critical enzyme that regulates glutamate, which plays an important role in cancer metabolism that supports cancer growth and survival. Our bioinformatic analysis of the TCGA HNSCC cohort revealed a strong correlation between c-Myc and GLS1 expression. We describe the importance of c-Myc in regulating GLS1 and vice versa. c-Myc protein directly binds to the promoter of the GLS1 gene and upregulates its expression at the transcriptional level. Interestingly, blocking GLS1 signaling in HNSCC cells by lentiviral shRNA knockdown or CB-839 treatment downregulates USP1, one of the best characterized human DUBs, which in turn reduces c-Myc protein stability via the ubiquitin-proteasome pathway. The GLS1-c-Myc axis thus represents a novel positive feedback loop that is critical for driving the aggressiveness of HNSCC. As the treatment of HNSCC remains a major challenge, these novel findings provide the molecular basis for combining GLS1-specific inhibitors with c-Myc-targeted therapy for the treatment of HNSCC patients. Citation Format: Jianqiang Yang, Fanghui Chen, Fan Yang, Yong Teng. A positive feedback loop between GLS1 and c-Myc drives tumor aggressiveness [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 3061.
Abstract 1343: BSI-111, a highly selective anti-CD16a monoclonal antibody with potent agonist activity for building a NK cell engager platform
Authors: Jinyu Liu, Wenwen Dai, Hongyan Li, Xiaodong F. Liu, Jun Li, Shukai Xia, Qun Lyu, Hugh M. Davis, Mingjiu Chen, Zeyu Peng
Journal: Cancer Research (2024)

Abstract Background: Natural killer cells (NK) are innate lymphocytes endowed with the ability to recognize and kill cancer cells. CD16a, a well-characterized activating receptor predominantly expressed on NK cells, is a low-affinity receptor for the IgG Fc domain and is crucial for stimulating NK cell-mediated tumor cell killing. Unlike CD16a, CD16b is mainly expressed on granulocytes as a GPI-anchored receptor and is not involved in the lysis of tumor cells although CD16a and CD16b share 97% sequence identity in their extracellular domains. Due to the high homology of extracellular domains of CD16a and CD16b, it is extremely challenging to develop CD16a-specific agonistic antibodies without binding CD16b+ granulocytes, the most abundant subset in leukocytes. Here we report the development of an anti-CD16a-specific monoclonal antibody with potent NK cell activation. Experimental procedures: Humanized mice were immunized with recombinant CD16a-ECD-Fc. The Biosion proprietary H3 (High-throughput, High-content and High-efficiency) antibody screening platform was used to identify an anti-CD16a monoclonal antibody lead candidate - BSI-111. The target binding specificity, binding activity, and affinity of BSI-111 were evaluated by protein-based ELISA, cell-based FACS and Biacore-based SPR. A cell-based agonist reporter assay and a primary NK cell activation assay were used to evaluate the bioactivity of BSI-111. Summary: BSI-111 is a fully human monoclonal antibody with the following critical properties: (1) specifically binds to CD16a without recognizing CD16b; (2) binds the two allelic variants of CD16A - 158F and 158V with similar high affinities; (3) shows cross-reactivity to cynomolgus CD16a; (4) can significantly activate NFAT signaling in a cell-based reporter assay; (5) exhibits strong activity on activating primary NK cells; and (6) has potentially longer half-life and silenced Fc-effector function through Fc-engineering. Conclusion: BSI-111 demonstrates great biophysical properties and functional characteristics, supporting the development of anti-CD16a-based NK cell engagers for potential benefit of cancer patients. Citation Format: Jinyu Liu, Wenwen Dai, Hongyan Li, Xiaodong F. Liu, Jun Li, Shukai Xia, Qun Lyu, Hugh M. Davis, Mingjiu Chen, Zeyu Peng. BSI-111, a highly selective anti-CD16a monoclonal antibody with potent agonist activity for building a NK cell engager 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 1343.