tbuckley/cabot-search huggingface dataset:
Abstract 1183: Non-canonical RNA binding of the MYBL2 transcription factor promotes melanoma
Authors: Kaizhen Wang, Xiaonan Xu, Shiun Chang, Olga Vera, Nhan Phan, Xiaoqing Yu, Florian A. Karreth
Journal: Cancer Research (2025)

Abstract Melanoma originates from melanocytes, and malignant transformation of melanocytes is affected by various factors, including non-mutational gene alterations. MYBL2 is a transcription factor primarily known for its role in regulating cell cycle progression, and in this study, we showed that MYBL2 copy number gains occur in one fifth of melanoma patients. We demonstrated that aberrant MYBL2 upregulation promotes melanoma growth in vitro and in vivo while its silencing has the opposite effects. Interestingly, a MYBL2 transactivation-deficient mutant retains oncogenic function, indicating that MYBL2 promotes melanoma growth independent of its transcription factor function. Notably, we found that MYBL2 is a non-canonical RNA binding protein, and its RNA binding is crucial for its melanoma-promoting function. MYBL2 binds RNA through an arginine rich motif and a C-terminal RNA binding domain, crosslinking-immunoprecipitation followed by high-throughput sequencing revealed that MYBL2 primarily binds introns of protein-coding genes in the nucleus. Moreover, MYBL2 does not affect the fate and function of its direct mRNA targets. Instead, binding to RNA enhances the association of MYBL2 with chromatin, thereby indirectly rewiring a transcriptional program that correlates with poor patient survival. Surprisingly, we observed that MYBL2 binds RNA exclusively in melanoma cells, but not in melanocytes. This phenomenon is primarily due to the mRNA expression landscape found in melanoma cells, and modifications of MYBL2 protein may also be involved to a lesser extent. In summary, our work identified a novel oncogenic function of MYBL2 through its RNA binding activity, extending our current understanding of MYBL2 and highlighting a critical mechanism in melanoma progression. Citation Format: Kaizhen Wang, Xiaonan Xu, Shiun Chang, Olga Vera, Nhan Phan, Xiaoqing Yu, Florian A. Karreth. Non-canonical RNA binding of the MYBL2 transcription factor promotes melanoma [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 1183.
Abstract 1182: Modulating splicing of NELFE as a therapeutic strategy for hepatocellular carcinoma
Authors: Laura M. Reynolds, Ryan Lamm, Kai Zhang, Anna Barry, Corinne Wessner, Ji-Bin Liu, Alvaro Lucci, Brittany N. Ruiz, Meghan D. Grim, John Eisenbrey, Hien Dang
Journal: Cancer Research (2025)

Abstract Hepatocellular carcinoma (HCC) is already one of the deadliest cancers with the death rate only expected to increase in the United States over the next few decades. This is, in part, due to its various risk factors that result in a heterogenous disease arising from the accumulation of genetic and epigenetic alterations. Negative Elongation Factor E (NELFE) is altered in more than 30% of HCCs and elevated gene expression is associated with worse patient outcomes. We discovered a rare (&amp;lt;1% general population) germline intronic heterozygous single nucleotide polymorphism (SNP) (G&amp;lt;A) in ∼3.8% of our HCC cohort which is associated with better patient outcomes. Patients with the SNP had decreased NELFE mRNA expression in their tumors compared to wildtype (WT) patients. Moreover, SNP patients had longer recurrence free and overall survival times. Using a minigene, we found the SNP decreases the binding of an essential splicing protein, U2AF65, which promoted exon 10 skipping. Thus, we hypothesize alternative splicing (AS) of NELFE can be used as a therapeutic strategy for HCC. To investigate the effects of exon 10 loss, we employed a pharmacological approach (antisense oligonucleotides (ASOs)) and a genetic based approach (CRISPR/Cas9) to target exon 10 splice junctions. Loss of exon 10 through ASO induced AS and CRISPR-mediated exon deletion produced a shorter isoform we called d.ex10 and decreased full-length NELFE protein expression. Furthermore, cells treated with ASOs had significantly decreased cell proliferation, migration, invasion, and colony formation in vitro and inhibited tumor growth in vivo. To reduce potential off-target and toxicity effects of ASO in vivo, we will utilize FDA-approved ultrasound contrast agents (microbubbles) for targeted delivery of ASO to tumors. In conclusion, NELFE ASOs could be a potential therapeutic strategy for HCC patients. Citation Format: Laura M. Reynolds, Ryan Lamm, Kai Zhang, Anna Barry, Corinne Wessner, Ji-Bin Liu, Alvaro Lucci, Brittany N. Ruiz, Meghan D. Grim, John Eisenbrey, Hien Dang. Modulating splicing of NELFE as a therapeutic strategy for hepatocellular carcinoma [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 1182.
Abstract 436: NRF2 activity impairs the efficacy of sotorasib in human KRAS-mutant lung adenocarcinoma
Authors: T Hess, Hansa Joshi, Yaas Azmoudeh, Gord Zhu, Francis Spitz, David Shersher, Samera Hamad
Journal: Cancer Research (2025)

Abstract Lung cancer continues to be the leading cause of cancer-related mortality in the United States, with lung adenocarcinoma (LUAD) representing the most common histological subtype. Clinical evidence has demonstrated that tumor plasticity—, the transformation between lung cancer subtypes—, plays a crucial role in the development of resistance to chemotherapy and targeted therapies. Hyperactivation of NRF2, a transcription factor that normally protects cells from oxidative damage, is implicated in the resistance to various types of therapies including chemotherapies and targeted therapies. This study aimed to identify if NRF2 induces the resistance to carboplatin, and/or to sotorasib, a targeted therapy of KRAS-mutant LUAD, through histological transformation. We used KRAS-mutant human lung adenocarcinoma cell lines, high NRF2WT-A549, and H358 with NRF2E79Q activating mutation. Our results show that treatment of high-NRF2 LUAD cell lines with sotorasib induces the transformation to neuroendocrine tumors (NE) and augments the NRF2 levels in vitro. Further, this transformation increased the growth and invasion of the transformed tumor cells. Interestingly, the low-NRF2 version of H358 (without NRF2E79Q activating mutation) did not have these changes. Further, LUAD cell lines had good responses to carboplatin with and without NRF2 activation. This NRF2-treatment interaction study shows that carboplatin might be a good option in NRF2-high LUAD with KRAS mutation and that targeting NRF2 in NRF2high LUAD tumors could enhance the efficacy of sotorasib and prevent the transformation after treatment. Current studies in our lab are testing these changes in vivo using immunodeficient mice. Citation Format: T Hess, Hansa Joshi, Yaas Azmoudeh, Gord Zhu, Francis Spitz, David Shersher, Samera Hamad. NRF2 activity impairs the efficacy of sotorasib in human KRAS-mutant lung adenocarcinoma [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 436.
Abstract 951: A novel oncolytic adenovirus platform with multi-gene immunomodulation for ovarian cancer treatment
Authors: Er Yue, Edward Wang
Journal: Cancer Research (2025)

Abstract Ovarian cancer (OC) remains a challenging malignancy with limited treatment options and a poor prognosis, emphasizing the urgent need for innovative therapeutic strategies. We have established a conditionally replicating oncolytic adenovirus (CRAd) platform designed to selectively target CA125 transactivation for OC treatment. To enhance therapeutic efficacy, we engineered the CRAd to include two gene-expression cassettes in the E3 region and each cassette can express two genes linked by a P2A peptide, enabling the incorporation of four exogenous genes in one virus. We rationally chose the following cytotoxic and immunoregulatory genes to integrate into one virus to enhance oncolytic and immunoregulatory capacity and amplify the anti-cancer immune response, full-length tumor necrosis factor-related apoptosis-inducing ligand (fl-TRAIL), CD137L, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon alpha-2b (IFN-α2b). We successfully generate the virus by transfecting the recombined Ad/Muc16 genome into HEK293 packaging cells. Ovarian cancer cells expressing CA125 were infected with Ad/Muc16, and expression of all four genes were confirmed via ELISA or flow cytometry. The anti-cancer efficacy of Ad/Muc16 was evaluated in immune-competent syngeneic mouse models of ovarian cancer (ID8/C57BL/6 and STOSE/FVB mice). Mouse ovarian cancer cells (ID8 and STOSE) infected with Ad/Muc16 were served as a whole-cell cancer vaccine in a subcutaneous inoculation model to establish an immune response. The vaccinated mice were re-challenged with parental ovarian cancer cells. Ad/Muc16 treatment elicited a robust anti-cancer immune response, significantly suppressing the growth of re-challenged parental cells and prolonging survival compared to control groups. This CRAd platform integrate with multiple genes demonstrates a novel strategy for specific targeting OC by combining oncolytic virotherapy with immune modulation. Citation Format: Er Yue, Edward Wang. A novel oncolytic adenovirus platform with multi-gene immunomodulation for ovarian cancer treatment [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 951.
Abstract 936: HPV-related cancer model development and its application in the efficacy evaluation of a saRNA cancer vaccine
Authors: Zhongbao Song, GuangXu Ding, Anran Xia, Lihuan Bai, Wanqing Ma, Qiuhong Li, Xu Chen, Zhixiang Zhang, Qingyang Gu
Journal: Cancer Research (2025)

Abstract Cancer remains one of the most serious diseases threatening human health, influenced by many factors, such as genetic, physical, chemical and biological factors. Among various cancers, a special subtype is associated with viral infections. Globally, about 10% of all cancers are caused by viral infections including those from HPV, HBV, EBV and KSHV. After infection, these viruses manipulate the proliferation, metabolism, immunity and other life processes of the host cells through various mechanisms, resulting in malignant cell lesions. Therefore, targeting these viruses offers a novel therapeutic approach for virus-related cancers. In this study, codon optimization and site-direct mutagenesis were performed on HPV18 E6 and E7 genes, which were then cloned into a lentivirus vector to establish an HPV18 E6/E7-overexpressing cell line (EMT6-HPV18). EMT6-HPV18 cells stably expressed HPV18 oncogenes E6 and E7 in vitro and in vivo, and induced tumor formation in mice. To further investigate the potential of this model for evaluating HPV18-related anti-tumor drugs, we designed a self-replicating RNA (saRNA) expressing HPV18 E6 and E7, linked to FLT3L and CCL11 with the 3' and 5' terminal, respectively. Immunogenicity of the saRNA was validated after three rounds of immunizations by ELISpot and ICS flow cytometry, showing a marked increase in E6/E7-specific IFN-γ+ T cell response. Subsequently, the therapeutic effect was evaluated in the EMT6-HPV18 subcutaneous tumor model, where saRNA treatment remarkably inhibited tumor progression, improved early-stage survival rates, and induced long-term anti-tumor immunity. Immune profiling revealed significant infiltration of immune cells into the tumors post-saRNA treatment, namely CD4+ T cells, CD8+ T cells and DCs with significant increase in E6/E7 specific IFN+ T cell and memory T cell subsets. In conclusion, we have successfully established an HPV18 E6/E7-expressing tumor model, demonstrating that the saRNA therapeutic vaccine effectively inhibits tumor progression in HPV18-related malignancies. Citation Format: Zhongbao Song, GuangXu Ding, Anran Xia, Lihuan Bai, Wanqing Ma, Qiuhong Li, Xu Chen, Zhixiang Zhang, Qingyang Gu. HPV-related cancer model development and its application in the efficacy evaluation of a saRNA cancer vaccine [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 936
Abstract 920: Determining the role of Siglecs in macrophage mediated immune evasion in prostate cancer
Authors: Nathan S. Lam, Ru M. Wen, James D. Brooks
Journal: Cancer Research (2025)

Abstract Siglecs (sialic acid-binding immunoglobulin-like lectins) are a family of cell surface proteins that are mainly expressed in immune cells. Recent studies show that Siglecs play important roles in immune evasion for tumors. We previously reported that Siglec-7 and Siglec-9 contribute to immune evasion by interacting with their ligands in prostate cancer, and blocking these interactions inhibits prostate cancer tumor progression. Further, Siglec-7 and Siglec-9 are highly expressed in macrophages in metastatic human prostate tumors. However, how macrophages mediate immune evasion via Siglec-dependent pathways remains unknown. Here, we have found that Siglec-7 and Siglec-9 are expressed in monocyte-differentiated macrophages derived from peripheral blood mononuclear (PBMC) cells. We will further profile Siglec expression in macrophages derived from PBMC and tumor tissues from patients with prostate cancer. The Siglecs on macrophages will be modulated, and their function will be evaluated through in vitro and in vivo models. Our study will provide insight into understanding macrophage-mediated immune evasion through Siglec-dependent mechanisms. Citation Format: Nathan S. Lam, Ru M. Wen, James D. Brooks. Determining the role of Siglecs in macrophage mediated immune evasion in prostate 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 920.
Abstract 91: Mechanistic insights on the regulation of IL-1β expression by the androgen receptor in prostate cancer cells
Authors: Yetunde Oyende, Jaden Drumm, Anthony DiNatale, Alessandro Fatatis
Journal: Cancer Research (2025)

Abstract Prostate cancer (PCa) in its early stages is driven by the activation of androgen receptor (AR) signaling. Local treatment modalities such as surgery and radiation cure most patients with locally confined or low-grade disease. However, over time, ∼20% of patients recur with metastatic tumors and are treated with androgen deprivation therapy (ADT) and AR inhibitors (ARIs) but eventually develop incurable metastatic castration-resistant prostate cancer (mCRPC). A significant fraction of metastatic tumors in PCa harbor cancer cells that lack AR expression (ARNeg). We have previously reported that ARNeg cancer cells express IL-1β, which promotes bone colonization of PCa and other cancers. We have shown that this results from constitutively transcriptional repression by the AR, which binds to a half-ARE on the IL-1β promoter. Thus, we reveal that exposure to ADT and/or ARIs also results in the de-repression of IL-1β transcription in PCa cells that express AR. Here, we extend these studies to other AR variants and show that similarly to AR full-length, AR-V7, a constitutively active AR-variant, also represses the transcription of the IL-1β gene. These findings have high clinical relevance since the current targeting of AR – and possibly of AR-V7, which is detected in ∼70% of mCRPC patients, would unleash the pro-metastatic effects of IL-1β. We also present evidence that histone deacetylases directly interact with the AR and act as co-repressors of IL-1β transcription. Furthermore, we found that IL-1β production in PCa cells is independent of inflammasome and caspase 1-8 recruitment. Finally, we show that IL-1β downregulates AR expression and alters EMT markers in PCa cells. Taken together, these findings help delineate a likely scenario of functional interactions occurring in metastatic tumors harboring PCa cells with mixed AR status, either ab initio or promoted by AR targeting. We propose that combining ADT/ARIs with inhibitors IL-1β signaling will address both the presence of ARNeg PCa cells and unintended consequences of therapy-induced AR inhibition in the metastatic niche. Citation Format: Yetunde Oyende, Jaden Drumm, Anthony DiNatale, Alessandro Fatatis. Mechanistic insights on the regulation of IL-1β expression by the androgen receptor in prostate cancer cells [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 91.
Abstract 911: Cancer stem cells establish intrinsic immune resistance through suppressing IFN-mediated antitumor immunity
Authors: Xuejie Huang, Weijie Guo, Yuxuan Phoenix Miao
Journal: Cancer Research (2025)

Abstract Although the cancer immunotherapy has generated promising outcomes in the clinics, a substantial proportion of cancer patients either show resistance to immunotherapy or experience relapse following an initial response. This issue is particularly urgent for patients with squamous cell carcinomas (SCCs), highlighting the critical need to understand the mechanisms behind immune evasion and immunotherapy resistance in these cancers. Recently, our lab identified a subset of tumor-initiating stem cells (tSCs) in skin and head/neck SCCs that respond to transforming growth factor β (TGF-β) and play a key role in driving tumor relapse post-immunotherapy. Notably, these tSCs are resistant to T-cell attacks despite retaining functional antigen presentation, resulting in only transient responses to immune checkpoint blockade therapy across SCC types. Here, my current study has uncovered a central role for Sox2 as a master regulator that drives immune resistance in TGF-β-responsive tSCs. Through RNA-seq and qPCR analyses, we observed that Sox2 amplification in tSCs significantly blunted their interferon-γ (IFN-γ) responsive potentials. Mechanistically, we found that Sox2 neither blocks IFN-γ signaling transduction nor directly binds to the enhancers or promoters of most IFN-γ-induced genes. Instead, we discovered that the reduced IFN-γ response in Sox2-overexpressing cells is likely due to the altered Stat1-mediated transcriptional repression. This study uncovered a stem cell specific transcription regulation that provides new insights in developing new strategies to abolish tSC-specific immune resistance. Citation Format: Xuejie Huang, Weijie Guo, Yuxuan Phoenix Miao. Cancer stem cells establish intrinsic immune resistance through suppressing IFN-mediated antitumor immunity [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 911.
Abstract 583: Preclinical development of [68Ga]Ga/[225Ac]Ac-FL-031 theranostic pair for the treatment of SSTR2-positive cancers
Authors: Junyu Yang, Taishan Hu, Lanjiao Zhao, Yihu Xie, Juan Zhang, Fa Liu
Journal: Cancer Research (2025)

Abstract Somatostatin receptor 2 (SSTR2) is frequently overexpressed in solid tumors including neuroendocrine tumors (NETs) and small cell lung cancer (SCLC), making it a promising target for radionuclide drug conjugates (RDC) based cancer imaging and therapy. Gallium-68 and Lutetium-177 labeled somatostatin analogs [68Ga]Ga/[177Lu]Lu-DOTATATE, a theranostic pair, have been approved by FDA for detecting and treating gastroenteropancreatic (GEP)-NETs. Currently, [225Ac]Ac-DOTATATE is under clinical development for the treatment of SSTR2-positive cancers. To further optimize the theranostic profile of SSTR2-targeting RDC, we have applied our proprietary UniRDCTM platform technologies to discover FL-031, a novel and potentially next generation SSTR2-targeting RDC vector. We then evaluated the feasibility of PET/CT imaging with [68Ga]Ga-FL-031, as well as the in vivo biodistribution and efficacy profiles of [225Ac]Ac-FL-031 in SSTR2+ xenograft mouse models. The radiochemical purity (RCP) of radiolabeled FL-031 was determined by radio high-performance liquid chromatography (radio-HPLC). FL-031 was successfully labeled with 68Ga and 225Ac, achieving an RCP of over 98% and specific activities of 18.5 MBq/nmol and 185 kBq/nmol, respectively. Subsequently, PET/CT imaging and in vivo biodistribution as well as efficacy was conducted in SSTR2-expressing SCLC and NET tumor-xenograft models. After administration of 3.7 MBq [68Ga]Ga -FL-031 in mice implanted with SCLC-21H SCLC xenografts, PET/CT images demonstrated intense tumor uptake which was significantly higher than in normal organs at 1- and 3-hour post-dosing. In the in vivo biodistribution study, [225Ac]Ac-FL-031 showed high and durable tumor uptake in mice implanted with AR42J NET xenografts with fast clearance in normal organs. Importantly, in SSTR2+ xenograft models, [225Ac]Ac-FL-031 exhibited significant anti-tumor activity at dose levels of 37 kBq or lower without notable changes in body weight and hematology parameters. In summary, [68Ga]Ga-FL-031 PEC/CT proved suitable in detecting SSTR2-positive tumors in preclinical models. [225Ac]Ac-FL-031 demonstrated a promising in vivo biodistribution profile and anti-tumor activity in SSTR2-expressing xenograft models. In conclusion, our data suggest that [68Ga]Ga/[225Ac]Ac-FL-031 is a promising theranostic pair for further development as a diagnostic imaging and RDC therapy for SSTR2-positive cancers. Citation Format: Junyu Yang, Taishan Hu, Lanjiao Zhao, Yihu Xie, Juan Zhang, Fa Liu. Preclinical development of [68Ga]Ga/[225Ac]Ac-FL-031 theranostic pair for the treatment of SSTR2-positive cancers [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 583.