tbuckley/cabot-search huggingface dataset:
Abstract 5148: Plakophilin 3 and ovarian cancer progression: Functional transition from early expression to advanced-state regulation through RB and STAT3 pathways
Authors: Ha-Yeon Shin, JueYoung Kim, Jae-Hoon Kim
Journal: Cancer Research (2025)

Abstract Background: Ovarian cancer (OC) is a heterogeneous disease with a high mortality rate and poor prognosis, primarily due to late-stage diagnosis. The identification of reliable biomarkers is crucial for improving patient outcomes. Plakophilin 3 (PKP3) is often overexpressed in cancers, yet its role in OC remains poorly understood. Methods: We performed immunohistochemistry with tissue microarray, including normal (n=39), benign (n=66), borderline (n=44), and ovarian cancer (n=187), and analyzed clinical and survival rates according to the expression of PKP3. Either lacking or overexpressing PKP3 in immortalized normal cell and OC cell lines, we measured cell proliferation, cell cycle, and migration. Molecule change associated them checked western blot and qRT-PCR. Additionally, cellular localization of PKP3 in cancer cells was confirmed via cell fraction and immunofluorescence. Results: The expression levels of PKP3 in OC are higher than in normal and benign tissues; notably, PKP3 shows the highest expression in stage I compared to other stages. Analysis of overall and disease-free survival revealed that patients with high PKP3 expression had a better prognosis than those with low PKP3 expression. Overexpression of PKP3 in immortalized normal cell lines led to increased cell growth. The depletion of PKP3 in OC cells triggered G1 cell cycle arrest. This was achieved through the attenuation of retinoblastoma (RB) protein phosphorylation and suppression of E2F1 target gene expression, ultimately resulting in reduced cell growth. Although PKP3 depletion decreased OC cell growth, it paradoxically increased cell migration. This increase in migration was mediated by the activation of STAT3. Regulation of RB and STAT3 activation by PKP3 was confirmed to occur in the nucleus. We found that alteration of PKP3 expression in normal and OC ultimately regulates the progression of OC. Conclusion: PKP3 promotes the initiation of OC by driving cell growth, and in advanced stages, its reduced expression is associated with increased epithelial-mesenchymal transition (EMT), leading to a worse prognosis. This study suggests that PKP3 could serve as a biomarker for early diagnosis and that targeting the PKP3-STAT3 axis may offer new therapeutic opportunities for OC. Citation Format: Ha-Yeon Shin, JueYoung Kim, Jae-Hoon Kim. Plakophilin 3 and ovarian cancer progression: Functional transition from early expression to advanced-state regulation through RB and STAT3 pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5148.
Abstract 7199: Synergistic anticancer effects of milciclib and mirdametinib: mechanistic insights into cell cycle arrest, DNA damage, and senescence
Authors: Xinyu Pei, Juifang Fan, Anh Nguyen Nguyen, Hannah Neiger, Imran A. Khan, Vladimir Bezrookove, Yu Zhou, Maureen Veilleux, Lily S. Wang, Valerie A. Gerriets, John K. Cusick, Pierre Y. Desprez, Li Zheng, Mohammed Kashani-Sabet, Binghui Shen, Yihui Shi
Journal: Cancer Research (2025)

Abstract Milciclib, a cyclin-dependent kinase (CDK) inhibitor, has recently been identified as a modulator of pre-mRNA splicing, broadening its therapeutic potential. However, resistance to CDK inhibitors frequently arises due to activation of compensatory pathways, such as the MEK-ERK signaling cascade, which drives unchecked cell cycle progression and circumvents critical checkpoints. RNA sequencing of Milciclib-treated cells revealed significant upregulation of the MEK pathway, highlighting a potential resistance mechanism and supporting the strategy of targeting MEK in combination therapy. To address this challenge, we investigated the combination of Milciclib with the MEK inhibitor Mirdametinib (PD-0325901) across various cancer types, including colorectal cancer. The combination synergistically inhibited cancer cell proliferation by inducing cell cycle arrest at G0/G1 and G2/M phases. It also impaired homologous recombination repair, as evidenced by reduced RAD51 levels, and enhanced DNA damage (γH2AX). Furthermore, Mirdametinib alone and in combination with Milciclib promoted cellular senescence, characterized by the upregulation of p16 and p21. In vivo, the combination treatment significantly inhibited tumor growth in animal models. These findings highlight the complementary mechanisms of action of Milciclib and Mirdametinib. The synergy observed in this combination therapy provides a strong rationale for further clinical investigation. Citation Format: Xinyu Pei, Juifang Fan, Anh Nguyen Nguyen, Hannah Neiger, Imran A. Khan, Vladimir Bezrookove, Yu Zhou, Maureen Veilleux, Lily S. Wang, Valerie A. Gerriets, John K. Cusick, Pierre Y. Desprez, Li Zheng, Mohammed Kashani-Sabet, Binghui Shen, Yihui Shi. Synergistic anticancer effects of milciclib and mirdametinib: mechanistic insights into cell cycle arrest, DNA damage, and senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7199.
Abstract 6089: The bispecific antibody KA-3458, targeting CD38 and CD28, specifically enhances T cell activation within the tumor microenvironment
Authors: Guojin Wu, Jiabei Liang, Zhengcheng Guo, Hao Peng, Feng Hao, Jinying Ning
Journal: Cancer Research (2025)

Abstract KA-3458 is a bispecific antibody (BsAb) designed to target CD38 and human CD28, aiming to enhance T cell activation within the tumor microenvironment, particularly in blood cancers like multiple myeloma and lymphoma, where CD38 is highly expressed. While bispecific antibodies targeting tumor antigens and activating T cell receptor signaling have shown clinical promise, the addition of CD28 co-stimulatory signals may further boost T cell responses against tumors. KA-3458, engineered in an IgG4 format with an identical light chain, was created using our common light chain bispecific antibody discovery platform and knob-into-hole technology. The antibody’s two Fabs show high affinity for CD38 and relatively lower affinity for CD28. In in vitro combination assays, KA-3458 significantly enhances T cell activation and cytotoxic activity of CD3 T cell engagers targeting CD20 or GPRC5D, which are critical for the treatment of lymphoma or multiple myeloma, respectively. Cytokine release assays performed with human PBMCs co-cultured with lymphoma cells revealed that KA-3458 enhances the release of INF-γ but not IL-6, in the presence of a CD20 T cell engager, suggesting a favorable safety profile. In PBMC-humanized immunodeficient mouse models, KA-3458 further improves the cytotoxicity of CD3 T cell engagers against CD20 or GPRC5D, targeting tumors in lymphoma or multiple myeloma models, respectively, which strongly express CD38. Additionally, KA-3458 has a normal half-life in Balb/c mice and demonstrates excellent developability. Toxicity studies are currently underway. In conclusion, KA-3458, developed using our common light chain bispecific antibody discovery platform, shows great potential as a preclinical candidate for the treatment of relapsed/refractory B-cell lymphoma and multiple myeloma. Citation Format: Guojin Wu, Jiabei Liang, Zhengcheng Guo, Hao Peng, Feng Hao, Jinying Ning. The bispecific antibody KA-3458, targeting CD38 and CD28, specifically enhances T cell activation within the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6089.
Abstract 7051: CCL21 therapy in conjunction with low-dose metronomic cyclophosphamide generates superior responses against neuroblastoma in vivo
Authors: Benjamin Gephart, Gabrielle Brumfield, Donald W. Coulter, Joyce Solheim
Journal: Cancer Research (2025)

Abstract Neuroblastoma is a pediatric malignancy that arises from aberrant neural crest progenitor cell division and proliferation. Relapsed and refractory disease often has a poor prognosis, with the long-term survival rate less than 30%. Neuroblastoma is canonically considered to be an immunologically cold and non-immunogenic tumor type, with dense populations of immune suppressive cell populations that have been shown to impair anti-tumor immunity. Despite the significant clinical response in other tumor types, immune checkpoint inhibitors have only shown limited clinical efficacy in neuroblastoma. Superior treatment modalities are needed to increase overall survival with less severe toxicity in the treatment of neuroblastoma. CCL21 is a chemokine that mediates the migration of immune cell populations such as T cells, NK cells, and dendritic cells, which are key immune cell populations for robust anti-tumor immunity. Prior preclinical studies have highlighted the effectiveness of CCL21 therapy as a potential treatment modality for multiple solid tumor types; however, CCL21’s effectiveness against neuroblastoma is poorly understood. We sought to investigate the effectiveness of intratumoral delivery of CCL21 therapy against neuroblastoma in vivo. We desired to also characterize the immunomodulatory properties of the alkylating agent cyclophosphamide against neuroblastoma both in vitro and in vivo. Cyclophosphamide is part of the standard-of-care treatment protocol for neuroblastoma and has been shown to possess unique immunomodulatory properties at low doses. Herein, we demonstrate that CCL21 therapy in conjunction with metronomic low-dose cyclophosphamide chemotherapy generates superior controlling of neuroblastoma tumor growth in an immunocompetent, syngeneic Neuro2a mouse model. In our in vitro studies, we show that low-dose cyclophosphamide up-regulates cell surface calreticulin expression, as well as cell surface PD-L1 expression on neuroblastoma tumor cells, suggesting that it has potential to facilitate sensitization to anti-PD-L1 checkpoint blockade. In short, this research shows the therapeutic potential of CCL21 and metronomic low-dose cyclophosphamide chemotherapy in the treatment of non-immunogenic tumor types such as neuroblastoma. Furthermore, this research supports the technical feasibility of a novel in situ tumor immunotherapy strategy for neuroblastoma in a preclinical setting. Citation Format: Benjamin Gephart, Gabrielle Brumfield, Donald W. Coulter, Joyce Solheim. CCL21 therapy in conjunction with low-dose metronomic cyclophosphamide generates superior responses against neuroblastoma in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7051.
Abstract 7198: Preclinical efficacy of the combination of MEK inhibitor plus KRAS G12D inhibitor for non-small cell lung cancer with <i>KRAS G12D</i>
Authors: Yu Tanaka, Mirai Tsukuda, Gaku Yamamoto, Eri Sugiyama, Hiroki Izumi, Tetsuya Sakai, Shigeki Umemura, Yoshitaka Zenke, Shingo Matsumoto, Kiyotaka Yoh, Koichi Goto, Hibiki Udagawa
Journal: Cancer Research (2025)

Abstract KRAS G12D is observed in 3 - 8% of non-small cell lung cancer (NSCLC). Currently, no targeted therapies are approved for solid tumors including NSCLC with KRAS G12D. MRTX1133 is a selective KRAS G12D inhibitor in advanced development. A previous preclinical data showed that MRTX1133 was effective in pancreatic carcinoma, but might not in NSCLC. Thus, we evaluated the efficacy of MRTX1133 monotherapy and investigated potential therapeutic strategies for NSCLC with KRAS G12D using in vitro and in vivo models. Cell viability assays demonstrated that MRTX1133 was less effective in KRAS G12D-mutated NSCLC cell lines. MRTX1133 suppressed phosphorylation of ERK in KRAS G12D-mutated NSCLC cell lines at 2 - 4 hours, but rebound of phosphorylation of ERK was observed at 24 - 48 hours. To identify potential combination drugs that can enhance the efficacy of MRTX1133, we evaluated phosphorylation of receptor tyrosine kinases in KRAS G12D-mutated NSCLC cell lines treated with MRTX1133 monotherapy and performed a drug combination screening for KRAS G12D-mutated NSCLC cell lines. Although no phosphorylation of receptor tyrosine kinases that could be combination drug candidates were observed, several MEK inhibitors, such as trametinib, selumetinib and binmetinib, enhanced the efficacy of MRTX1133 in cell viability assays. MEK inhibitors suppressed rebound of phosphorylation of ERK by MRTX1133 monotherapy at 24 - 48 hours. The combination of trametinib with MRTX1133 suppressed tumor growth compared to MRTX1133 monotherapy with tolerable toxicity in KRAS G12D-mutated NSCLC in vivo models. In conclusion, our findings indicate that the preclinical efficacy of MRTX1133 monotherapy was limited for NSCLC with KRAS G12D, and therapeutic potential of MEK inhibitors in combination with MRTX1133. Citation Format: Yu Tanaka, Mirai Tsukuda, Gaku Yamamoto, Eri Sugiyama, Hiroki Izumi, Tetsuya Sakai, Shigeki Umemura, Yoshitaka Zenke, Shingo Matsumoto, Kiyotaka Yoh, Koichi Goto, Hibiki Udagawa. Preclinical efficacy of the combination of MEK inhibitor plus KRAS G12D inhibitor for non-small cell lung cancer with KRAS G12D [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7198.
Abstract 6460: Spatiotemporal multi-omics uncover tumor ecosystem dynamics driving metastatic colonization
Authors: Liang Wu, Yu Zhong, Shang Liu, chunqing wang, Zefan zhang, Yunfan Sun, Jian zhou, Jia Fan, Xun xu
Journal: Cancer Research (2025)

The mechanisms underlying the interaction between disseminated tumor cells (DTCs) and their tissue microenvironment during metastasis colonization are poorly understood. We integrated multimodal single-cell and spatial profiling from liver cancer mouse models and human metastases to track the spatiotemporal dynamics of DTCs and their microenvironments across nine sequential time points from single-cell seeding until overt lung metastasis. We identified a residual population of quiescent Phgdhhigh DTCs that survive initial innate immune clearance and become transiently enriched in micrometastases. These cells shape an immune-scarce microenvironment through PHGDH-dependent, H3K27me3-mediated epigenetic silencing of chemokine transcription, promoting metastatic expansion. Cx3cr1high interstitial macrophages were also found to be transiently enriched before DTCs expansion, creating an immune-privileged niche for metastatic outgrowth by recruiting immunosuppressive cells. Inactivating the Phgdh-H3K27me3 axis in DTCs or depleting interstitial macrophages restored immune surveillance and inhibited metastatic colonization. These findings provide new therapeutic concepts for developing micrometastasis-targeting regimens. Citation Format: Liang Wu, Yu Zhong, Shang Liu, chunqing wang, Zefan zhang, Yunfan Sun, Jian zhou, Jia Fan, Xun xu. Spatiotemporal multi-omics uncover tumor ecosystem dynamics driving metastatic colonization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6460.
Abstract 6543: Progesterone signaling alters the metabolic profile and immune cell landscape of mammary gland tumors
Authors: Eilidh I. Chowanec, Christy R. Hagan, Jason Gertz
Journal: Cancer Research (2025)

Abstract Estrogen and progesterone signaling together drive hormone-receptor positive breast cancer growth and progression. However, there have been limited studies on the independent role that progesterone and its receptor, the progesterone receptor (PR), play in the development of breast cancer. Using the SSM2 tumor cell line, that expresses both the estrogen receptor (ER) and PR, we treated cells with either progesterone or vehicle (EtOH) and performed RNA-seq. The results of these experiments showed that progesterone treatment changes the metabolism of SSM2 tumor cells in vitro, altering the amount of free cholesterol and fatty acids in conditioned media. Previous studies in the Hagan lab have shown that progesterone signaling promotes mammary tumor growth and changes the immune landscape of the mammary gland towards immunosuppression. Therefore, we performed a tumor study using orthotopic injection of SSM2 tumor cells. Mice were treated with progesterone or placebo at the time of SSM2 tumor cell implantation. The results of this study showed that progesterone increases SSM2 tumor growth. Additionally, to investigate immune cell changes, we performed scRNA-seq on the progesterone and placebo-treated tumors. ScRNA-seq showed that progesterone-treated tumors harbored less CD3+ T cells than placebo-treated tumors. Additionally, progesterone-treated tumors had a greater number of TREM2+ macrophages than the placebo-treated tumors. The findings of our scRNA-seq data corroborated our in vitro findings that progesterone treatment of SSM2 tumor cells changes their metabolic profile. Our findings demonstrate that progesterone signaling promotes an immune suppressed microenvironment in the mammary gland through an increase in TREM2+ macrophages and a decrease in CD3+ T cells. This evidence provides rationale to investigate the use of anti-progestins as a mechanism to overcome the immune-cold tumor microenvironment seen in progesterone receptor positive breast tumors. Citation Format: Eilidh I. Chowanec, Christy R. Hagan, Jason Gertz. Progesterone signaling alters the metabolic profile and immune cell landscape of mammary gland tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6543.
Abstract 6141: FGFR1 promotes endocrine resistance and regulates DNA sensing via STING modulation in hormone receptor-positive breast cancer
Authors: Sushil Dhakal, Torbjørn Amundsen Lien, Phuong Vu, Helene Midtun Flatekvål, Jens Henrik Norum, Therese Sørlie
Journal: Cancer Research (2025)

Abstract Alterations in the receptor tyrosine kinase Fibroblast Growth Factor Receptor 1 (FGFR1), such as gene amplification and overexpression, are frequently observed in hormone receptor-positive breast cancers, driving aberrant signaling pathways that promote tumor growth, metastasis, drug resistance, and immune evasion. This study investigates the dual role of FGFR1 in mediating endocrine resistance and modulating innate immune sensing via the cGAS-STING pathway and Type 1 interferon (IFN) responses. Our findings reveal a direct link between FGFR1 activity and endocrine resistance in estrogen receptor-positive T47D breast cancer cells. Strikingly, FGFR1 expression negatively correlates with Type 1 IFN responses in these cells, while endocrine-resistant cells exhibit upregulated STING expression at both mRNA and protein levels. Pharmacological inhibition of FGFR1 using erdafitinib or shRNA-mediated silencing enhances the expression of interferon-stimulated genes (ISGs) by activating the STING-TBK1-IRF3 signaling axis. Mechanistically, we identified that constitutive FGFR1 kinase activity activates AKT, which suppresses STING-TBK1-mediated Type 1 IFN responses as a negative feedback mechanism. In vivo, the combination of FGFR1 inhibition endocrine therapy led to tumor regression in a luminal patient-derived xenograft (PDX) model, driven by an enhanced tumor-intrinsic Type 1 IFN response. These results suggest that FGFR1 acts as an innate immune checkpoint, enabling tumor cells to suppress STING mediated Type 1 IFN response and evade antitumor immunity in hormone receptor-positive breast cancer. Targeting FGFR1 may, therefore, represent a promising strategy to overcome endocrine resistance and restore immune surveillance in this context. Citation Format: Sushil Dhakal, Torbjørn Amundsen Lien, Phuong Vu, Helene Midtun Flatekvål, Jens Henrik Norum, Therese Sørlie. FGFR1 promotes endocrine resistance and regulates DNA sensing via STING modulation in hormone receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6141.
Abstract 6466: Discovery Proteome and Whole Transcriptome Atlas analysis of skin cancer reveals biomarkers associated with immunotherapy response and resistance
Authors: Arutha Kulasinghe, Christine Kang, Hiromi Sato, Brian Filanoski, Lori Hamanishi, Ashley Heck, Margaret Hoang, Alyssa Rosenbloom, Michael Rhodes, Joseph M. Beechem
Journal: Cancer Research (2025)

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and represents a major global health burden. Approximately 50% of cSCC patients develop primary resistance and 20% will develop secondary resistance to immune checkpoint inhibitors (ICI). There are limited biomarkers that reflect the tumor dynamics predictive of response to ICI therapy and we need to develop a better understanding of the cSCC tumor microenvironment (TME). Enabling simultaneous analyses of proteins and RNAs at ultra-high plex in spatial context, the GeoMx Digital Spatial Profiler (DSP) offers an advanced same slide multiomics workflow and is uniquely positioned to help unravel cellular dynamics throughout the cSCC TME. In this study, we spatially profiled over 1000 proteins (GeoMx Human Discovery Proteome Atlas (DPA)) and over 18,000 transcripts (GeoMx Whole Transcriptome Atlas) using the DSP on formalin fixed paraffin embedded sections of pre-treatment cutaneous skin cancers prior to immunotherapy. Pathology-informed, tumour and stromal regions were sampled across whole tissues to generate histologically relevant assessments of the skin tissues. Covering areas such as immuno-oncology, oncology, immunology, epigenetics, metabolism, cell death, and signaling pathway regulation, the DPA panel supported the discovery of biomarkers and potential therapeutic targets. Our study identified unique tumour and stromal signatures and biomarkers associated with both resistance and sensitivity to immunotherapy at both protein and RNA resolutions. Moreover, coverage across the protein hallmarks of cancer provided deeper insights into the tumour microenvironment dictating clinical responses to therapy. Our study provides an integrated pipeline for discovery based spatial proteomic and transcriptomic assessments of skin cancers. Citation Format: Arutha Kulasinghe, Christine Kang, Hiromi Sato, Brian Filanoski, Lori Hamanishi, Ashley Heck, Margaret Hoang, Alyssa Rosenbloom, Michael Rhodes, Joseph M. Beechem. Discovery Proteome and Whole Transcriptome Atlas analysis of skin cancer reveals biomarkers associated with immunotherapy response and resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6466.