tbuckley/cabot-search huggingface dataset:
Abstract 3484: Lipid nanoparticle-mediated <i>in vitro</i> transfection of microbubble-activated T cells
Authors: Seeta Nyayapathy, Paige Gronevelt, Julie M. Rumble
Journal: Cancer Research (2025)

Abstract Immunotherapy of cancer has revolutionized approaches to controlling and curing cancer, with adoptive transfer of chimeric antigen receptor T cells (CAR-T cells) representing a potentially curative treatment for previously unresponsive tumors. CAR-T cell therapy consists of ex vivo expansion of autologous T cells, transfection with the chimeric antigen receptor (CAR) and transfer into the patient. The CAR allows those T cells to identify and kill any cells expressing the antigen of interest, typically a surface protein expressed abundantly and primarily by the tumor. While these methods are extremely effective in a subset of patients, there is opportunity for improvement that may broaden the efficacy of this type of therapy. First, the application of selection, activation and expansion microbubbles has been shown to result in a less “exhausted” phenotype of the T cells at the end of the expansion phase, resulting in better overall T cell responses. In addition, alternative methods of transfection such as lipid nanoparticles (LNPs) may improve both transfection efficiency and viability. LNP lipid components can be tuned to optimally encapsulate different cargo types and transfect different cell types. Therefore, we formulated a variety of different LNPs to encapsulate either mRNA or pDNA encoding a reporter gene and assessed the relative transfection efficiency in microbubble-activated T cells. Additionally, we evaluated the final activation/exhaustion profile of the transfected cells to determine how uptake of different LNPs may affect the killing effectiveness. These results may ultimately suggest process improvements that have the potential to expand the number of CAR-T recipients who have improved responses to therapy. Citation Format: Seeta Nyayapathy, Paige Gronevelt, Julie M. Rumble. Lipid nanoparticle-mediated in vitro transfection of microbubble-activated T 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 3484.
Abstract 3471: CD47 blockade-based local immunotherapy for endometrial cancer
Authors: Kerem Yucebas, Sooah Ko, Omair Khan, Irving Weissman, Shiying Jin
Journal: Cancer Research (2025)

Abstract Endometrial cancer (EC) incidence and mortality have been persistently increasing, indicating the limitations of current therapeutic measures. We have developed an immunotherapy for EC targeting the immune checkpoint molecule CD47. CD47 is a transmembrane protein that serves as a ligand for receptor signal regulatory protein-α (SIRPα) expressed on macrophages. When CD47 on tumor cells and SIRPα on macrophages interact, phagocytosis of malignant cells is inhibited. We found that macrophage phagocytosis of human EC cells is enhanced by an anti-CD47 monoclonal antibody (mAb). Our preclinical studies revealed the anti-CD47 mAb effectively reduces tumor burden without displaying overt signs of toxicity when administered through transvaginal local treatment in PR-cre+/-;Ptenflox/flox female mice with endometrial carcinoma. Thus, our findings provide rationale for the clinical application of anti-CD47 local immunotherapy to benefit women at risk for endometrial cancer development. Citation Format: Kerem Yucebas, Sooah Ko, Omair Khan, Irving Weissman, Shiying Jin. CD47 blockade-based local immunotherapy for endometrial 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 3471.
Abstract 2808: LUCAT1 facilitates areca nut-induced cell invasion and therapeutic resistance in head and neck cancer through STAT1 transcriptional modulation
Authors: Hung-Han Huang, Ann-Joy Cheng
Journal: Cancer Research (2025)

Abstract Areca nut is a significant carcinogen associated with head and neck cancer (HNC) in Southeast Asia, but the mechanisms, particularly those involving long non-coding RNAs (lncRNAs), remain unclear. We previously identified the lncRNA LUCAT1 as induced by arecoline, a key areca nut component, and this study explores its crucial role in HNC progression. Silencing LUCAT1 reduced several arecoline-induced malignant features. These include cell invasion through epithelial-mesenchymal transition (EMT) modulation and chemo-radiotherapy resistance via reactive oxygen species (ROS) scavenging and autophagy regulation. RNA sequencing (RNA-seq) of LUCAT1-silenced cells revealed 2, 326 downstream effectors enriched in oncogenic pathways, including EGFR, VEGF, HIF-1, and extracellular matrix-receptor interactions. This underscored LUCAT1’s pivotal role in cell motility and survival. LUCAT1 predominantly localizes in the nucleus, suggesting transcriptional regulation. Bioinformatic analysis of its promoter revealed 491 transcription factors binding to a DNase hypersensitivity site (DHS). Integrative proteomic analysis of areca nut-treated HNC cells narrowed this to three key transcription factors (IRF6, CUX1, and STAT1). Among these, STAT1 was confirmed as the primary factor induced by arecoline to activate LUCAT1 transcription. Silencing STAT1 or inhibiting its phosphorylation using fludarabine suppressed LUCAT1 expression, reduced ROS-scavenging, and reversed arecoline-induced malignancy. Thus, this study demonstrates that areca nut upregulates LUCAT1 via STAT1 activation, contributing to cell invasion and therapeutic resistance in HNC. Additionally, fludarabine shows potential as a therapeutic agent to counteract areca nut-induced malignancy, offering a promising avenue to improve survival outcomes for HNC patients with areca nut-chewing. Citation Format: Hung-Han Huang, Ann-Joy Cheng. LUCAT1 facilitates areca nut-induced cell invasion and therapeutic resistance in head and neck cancer through STAT1 transcriptional modulation [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 2808.
Abstract 4679: FTO inhibition enhances the therapeutic index of radiation therapy in head and neck cancer
Authors: Lu Ji, Leighton Pu, Hongbin Cao, Stavros Melemenidis, Subarna Sinha, Li Guan, Eyiwunmi E. Laseinde, Sara Richter, Rie Eyben, Kerriann Casey, Christina Kong, Edward Graves, Quynh Le, Erinn Rankin
Journal: Cancer Research (2025)

Despite the use of intensive combined modality therapy such as chemoradiation or surgery and radiation, the overall survival rate for patients with HPV-negative head and neck squamous cell carcinoma (HNSCC) remains poor. This underscores the unmet clinical need for the development of more effective drug-radiotherapy combinations to enhance the therapeutic index of radiation therapy (RT). The RNA demethylase enzyme FTO has emerged as a promising target for cancer therapy. However, its role as a radiosensitizer in HNSCC remains unknown. Here, we investigated the potential of targeting FTO to augment the effectiveness of RT in HPV-negative HNSCC. We found that genetic and pharmacologic inhibition of FTO enhanced the efficacy of RT in both human and mouse HNSCC tumor xenografts. Importantly, FTO inhibition did not increase radiation-induced oral mucositis. Mechanistically, FTO inhibition radiosensitizes HPV-negative HNSCC cells through amplifying DNA damage while reducing RAD51 foci formation, providing a molecular rationale for exploiting FTO inhibitors as radiation sensitizers in HNSCC. Collectively, our results suggest that therapeutic targeting of FTO may be an effective strategy to enhance the therapeutic index of RT for the treatment of HNSCC. Citation Format: Lu Ji, Leighton Pu, Hongbin Cao, Stavros Melemenidis, Subarna Sinha, Li Guan, Eyiwunmi E. Laseinde, Sara Richter, Rie Eyben, Kerriann Casey, Christina Kong, Edward Graves, Quynh Le, Erinn Rankin. FTO inhibition enhances the therapeutic index of radiation therapy in head and neck 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 4679.
Abstract 6031: CD4+CD103+ tissue-resident memory T cells correlate with unfavorable prognosis in patients with head and neck cancer
Authors: Hideyuki Takahashi, Shota Ida, Hiroe Tada, Kazuaki Chikamatsu
Journal: Cancer Research (2025)

Abstract T cell memory is an important mechanism for long-term protection against diverse pathogens such as cancers. Tissue-resident memory T cell (TRM) is a subset of memory T cells that stably resides in tissues and controls local immune homeostasis. In the present study, we investigated the immunological profile and clinical significance of TRM in patients with head and neck squamous cell carcinoma (HNSCC). We analyzed RNA-sequencing data and clinical data obtained from The Cancer Genome Atlas (TCGA) database. In total, 520 cases, including 97 human papillomavirus (HPV)-positive HNSCCs and 423 HPV-negative HNSCCs, were analyzed. TRM-enriched tumors were identified based on the expression of both CD4/CD8A and ITGAE (CD103). TRM-enriched tumors tended to correlate with HPV-positive status and early T factor. Gene Set Enrichment Analysis revealed the enrichment of pathways relating to cytotoxic immune response in TRM-enriched tumors. Moreover, the expressions of immunostimulatory and immune checkpoint-related genes were elevated in TRM-enriched tumors. Notably, the enrichment of CD4+TRMs in tumors was an independent prognostic factor for shorter progression-free survivals (PFS). We also analyzed peripheral blood mononuclear cells obtained from 77 patients with HNSCC. The increased CD8+CD103+TRMs correlated with HPV-positive status and primary lesion of oropharynx. The proportion of CD4+CD103+TRMs negatively correlated with that of CD4+ naïve T cells, while that of CD8+CD103+TRMs negatively correlated with that of effector T cells. The proportion of CD4+CD103+TRMs positively correlated with Ki-67 expression in CD4+ T cells. Moreover, the elevated CD4+CD103+TRMs was an independent prognostic factor for shorter PFS. In conclusion, we highlighted the clinical and immunological significance of CD103+TRMs in both tumor tissues and peripheral blood of patients with HNSCC. Further characterization of TRMs could lead to the development of novel biomarkers for patients with HNSCC. Citation Format: Hideyuki Takahashi, Shota Ida, Hiroe Tada, Kazuaki Chikamatsu. CD4+CD103+ tissue-resident memory T cells correlate with unfavorable prognosis in patients with head and neck 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 6031.
Abstract 4703: EGFR is a promising therapeutic target in NF1 mutant melanoma
Authors: Milad Ibrahim, Irineu Illa-Bochaca, George Jour, Eleazar Vega-Saenz de Miera, Kelly Ruggles, Jeffrey Weber, Markus Schober1, Iman Osman
Journal: Cancer Research (2025)

Abstract Background: Molecularly targeted therapies and immunotherapy improved treatment outcomes for melanoma patients. However, patients with driver mutations in the Neurofibromin 1 (NF1) tumor suppressor gene, which represent 20-30% of melanomas, have not benefitted from these treatment advances, underscoring an unmet clinical need. Methods: We compared 13 NF1 mutant (NF1Mut) and 19 NF1 wild-type (NF1WT) patient-derived short-term cultures (STCs) integrating multi-omic analysis of DNA mutations (Whole Exome Sequencing), RNA expression, and gene regulation (RNA-Seq, ATAC-Seq, H3K4Me3 and H3K27Ac). Independent melanoma patients’ specimens (n= 40) were used for immunohistochemical validation studies. We then used STCs for functional studies defining the role of NF1 loss in melanoma and testing potential therapeutic targets in-vitro and in PDX models. Results: Comparing NF1Mut to NF1WT uncovered gene regulatory elements (ATAC P = 0.024, H3K27Ac P = 0.011) controlling a significantly increased transcription of EGFR in NF1Mut (P = 0.005). The significant upregulation of EGFR expression was confirmed by western blotting (P = 0.003) and IHC in an independent melanoma patient cohort (P = 0.0007). Functional studies revealed that EGF rapidly activates EGFR, AKT and ERK in NF1Mut but not NF1WT melanoma cells (P &amp;lt; 0.0001). Moreover, NF1 knockdown in NF1WT in-vitro resulted in an increased melanoma cell proliferation (P &amp;lt; 0.0001) as well as, EGFR, AKT and ERK activation. Genetic or immunological EGFR inhibition blunted cell proliferation, cell survival, and tumor growth in NF1Mut but not NF1WT melanoma STCs (P &amp;lt; 0.0001) and PDX models (P &amp;lt; 0.0001) independent of BRAF or NRAS mutation status. Conclusion: Our study uncovers a stereotypical and transcriptionally controlled activation of the EGFR-AKT signaling axis in NF1Mut melanoma, with EGFR inhibition limiting tumor growth in NF1Mut but not NF1WT melanomas. Data suggest a possible role of targeting EGFR as therapeutic target in melanoma patients with NF1Mut tumors. Citation Format: Milad Ibrahim, Irineu Illa-Bochaca, George Jour, Eleazar Vega-Saenz de Miera, Kelly Ruggles, Jeffrey Weber, Markus Schober1, Iman Osman. EGFR is a promising therapeutic target in NF1 mutant 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 4703.
Abstract 3421: XON7, a new emerging multitarget immunotherapy against metastatic soft tissue sarcomas
Authors: Carine Ciron, Gwenaelle Evanno, Pierre-Joseph Royer, Odile Duvaux, Firas Bassissi
Journal: Cancer Research (2025)

Abstract Context: Soft tissue sarcomas (STS) are rare and heterogeneous malignancies originating from mesenchymal tissues, comprising over 50 subtypes. While surgery and radiotherapy are effective for localized disease, advanced and metastatic STS have poor outcomes due to limited efficacy of standard treatments like doxorubicin and frequent therapeutic resistance. Advances in molecular profiling have enabled targeted therapies, such as PARP inhibitors, but their effectiveness remains limited by the diversity of STS and resistance mechanisms. In this study, we evaluate the safety and efficacy of XON7, a first-in-class glyco-humanized polyclonal antibody (GH-pAb), as a novel therapeutic approach to address these challenges. Methods: XON7’s antitumor efficacy was tested in a panel of primary patient-derived sarcoma tumors and established sarcoma cell lines using CellTiter-Glo assay. Mechanisms of action assessed included complement-dependent cytotoxicity (CDC), apoptosis, antibody-dependent cell cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Apoptotic pathways were explored via caspase 8/9 activation, reactive oxygen species (ROS) production, and mitochondrial membrane potential. In vitro 3D cultures, XON7's impact on tumor growth, spheroid formation, and metastasis was evaluated. In vivo XON7 efficacy was evaluated in patient-derived xenograft (PDX) models of STS, with tri-weekly treatments initiated at tumor volumes of 150-200 mm3. Results: XON7 acts via plural MOA (CDC, apoptosis and ADCP), it demonstrated a potent anti-tumor activity in a panel of soft tissue sarcoma cells, with cytotoxicity ranging from 60% to 100% at a concentration of 300 µg/ml. Apoptotic induction involved both intrinsic and extrinsic pathways as evidenced by caspase 8/9 activation, ROS generation and loss of mitochondrial membrane potential. In 3D culture, repeated exposure to XON7 at a concentration of 300µg/ml significantly reduced the surface and viability of spheroids (liposarcoma SW872 cell line). XON7 also demonstrated its ability to reduce tumorogenicity and metastasis in a transwell invasion assay. In a PDX mice model of dedifferentiated liposarcoma, XON7 inhibited tumor growth by 50% over 48 days. Conclusion: XON7 characterized by its plurality of action and potent antitumor efficacy, currently under clinical evaluation, XON7 emerges as a promising immunotherapy for soft tissue sarcomas. Citation Format: Carine Ciron, Gwenaelle Evanno, Pierre-Joseph Royer, Odile Duvaux, Firas Bassissi. XON7, a new emerging multitarget immunotherapy against metastatic soft tissue sarcomas [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 3421.
Abstract 743: A prognostic model based on plasma proteomics for predicting immuno-chemotherapy outcomes in advanced non-small cell lung cancer
Authors: Zhihuang Hu, Jialei Wang, Changbin Zhu, Xin Zhang, Shenglin Huang, Si Sun, Zhenhua Wu, Yao Zhang, Ying Lin, Jin Wang, Tao Hu, Zhan Huang, Hui Yu, Xinmin Zhao, Huijie Wang, Xianghua Wu
Journal: Cancer Research (2025)

Abstract Background: Predicting benefit from immune checkpoint inhibitors in advanced non-small cell lung cancer (aNSCLC) remains challenging. We developed a plasma proteomic model to evaluate immuno-chemotherapy (IC) outcomes. Methods: Blood samples were collected prior to 1st-line IC for analysis of plasma proteins and peripheral blood mononuclear cells (PBMC) from 194 aNSCLC patients without EGFR/ALK mutations. The Olink Immuno-Oncology Panel was used to detect the soluble proteins in plasma, and transcriptome sequencing was conducted on PBMC. Results: We optimized a prior prognostic model by incorporating a validation cohort and employing the Survival SVM method. This improved model, trained on plasma levels of eight proteins (CD27, TWEAK, CD8A, GZMH, IL6, PGF, TIE2, and TNFRSF12A), independently predicted overall survival (OS). Kaplan-Meier analysis validated significant differences in PFS and OS (p &amp;lt; 0.001, respectively). Repeated 10-fold cross-validation in the discovery cohort demonstrated model robustness, with stable predictive power for 12-month OS and PFS (AUCs: 0.86 and 0.68, respectively), which was further supported in the validation cohort (AUCs: 0.78 and 0.63, respectively). The model's independent prognostic value was further substantiated through Cox regression analyses (Table). Our model exceeded the performance of conventional PD-L1 TPS cutoff values of 1% or 50% in stratifying patient risk. Low-risk patients exhibited enriched memory B cells (p &amp;lt; 0.05), while high-risk patients showed an upregulation of angiogenesis-related proteins (p &amp;lt; 0.05), consistently observed across both cohorts. Validation of the eight proteins is ongoing using ELISA assays to further confirm their clinical utility. Conclusion: We established and validated an optimized plasma protein-based prognostic model that identifies distinct immune phenotypes and provides critical insights into aNSCLC progression. Citation Format: Zhihuang Hu, Jialei Wang, Changbin Zhu, Xin Zhang, Shenglin Huang, Si Sun, Zhenhua Wu, Yao Zhang, Ying Lin, Jin Wang, Tao Hu, Zhan Huang, Hui Yu, Xinmin Zhao, Huijie Wang, Xianghua Wu. A prognostic model based on plasma proteomics for predicting immuno-chemotherapy outcomes in advanced non-small cell lung 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 743.
Abstract 4326: KRB-456: A novel KRAS G12D switch-I/II allosteric pocket binder that thwarts pancreatic cancer patient-derived tumors
Authors: Aslamuzzaman Kazi, Alok Ranjan, Vasanth M. Kumar, Bogos Agianian, Martin Garcia Chavez, Vignesh Vudatha, Rui Wang, Rajani Kanth Vangipurapu, Liwei Chen, Perry Kennedy, Karthikeyan Subramanian, Quirke Jonathan Charles Kenneth, Francisca Beato, Patrick W. Underwood, Jason B. Fleming, Paul Hergenrother, Jose Trevino, Evripidis Gavathiotis, Said M. Sebti
Journal: Cancer Research (2025)

Currently, there are no clinically approved drugs that directly thwart mutant KRAS G12D, a major driver of human cancer. Here, we report on the discovery of a small molecule, KRB-456, that binds KRAS G12D and inhibits the growth of pancreatic cancer patient-derived tumors. Protein nuclear magnetic resonance studies revealed that KRB-456 binds the GDP-bound and GCP-bound conformation of KRAS G12D by forming interactions with a dynamic allosteric binding pocket within the switch-I/II region. Isothermal titration calorimetry demonstrated that KRB-456 binds potently to KRAS G12D with 1.5-, 2-, and 6-fold higher affinity than to KRAS G12V, KRAS wild-type, and KRAS G12C, respectively. KRB-456 potently inhibits the binding of KRAS G12D to the RAS-binding domain (RBD) of RAF1 as demonstrated by GST-RBD pulldown and AlphaScreen assays. Treatment of KRAS G12D-harboring human pancreatic cancer cells with KRB-456 suppresses the cellular levels of KRAS bound to GTP and inhibits the binding of KRAS to RAF1. Importantly, KRB-456 inhibits P-MEK, P-AKT, and P-S6 levels in vivo and inhibits the growth of subcutaneous and orthotopic xenografts derived from patients with pancreatic cancer whose tumors harbor KRAS G12D and KRAS G12V and who relapsed after chemotherapy and radiotherapy. These results warrant further development of KRB-456 for pancreatic cancer. Citation Format: Aslamuzzaman Kazi, Alok Ranjan, Vasanth M. Kumar, Bogos Agianian, Martin Garcia Chavez, Vignesh Vudatha, Rui Wang, Rajani Kanth Vangipurapu, Liwei Chen, Perry Kennedy, Karthikeyan Subramanian, Quirke Jonathan Charles Kenneth, Francisca Beato, Patrick W. Underwood, Jason B. Fleming, Paul Hergenrother, Jose Trevino, Evripidis Gavathiotis, Said M. Sebti. KRB-456: A novel KRAS G12D switch-I/II allosteric pocket binder that thwarts pancreatic cancer patient-derived 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 4326.