tbuckley/cabot-search huggingface dataset:
Abstract 7527: Investigating biomarkers for immune-related adverse events following immune checkpoint inhibitor therapy in recurrent lung cancer patients
Authors: Yujin Kudo, Jun Matsubayashi, Satoshi Takahashi, Masaru Hagiwara, Masatoshi Kakihana, Toshitaka Nagao, Tatsuo Ohira, Norihiko Ikeda
Journal: Cancer Research (2024)

Abstract Background: The application of immune checkpoint inhibitors (ICIs) as adjuvant therapy post-lung cancer surgery is expected to confer significant benefits. However, the risk factors for severe immune-related adverse events (irAEs) remain incompletely understood, and managing irAEs may require long-term steroid use. The identification of biomarkers for irAEs in patients with surgically resected lung cancer is an urgent need. Methods: We analyzed 43 lung cancer patients who received ICI treatment for recurrence postoperatively. Macrodissection of lung cancer lesions was performed on FFPE specimens from resected lungs, from which total RNA was extracted. We conducted gene expression analysis of 770 immune-related genes using the PanCancer Immune Profiling Panel (NanoString Technologies, Inc., Seattle, WA, USA). The relationship between gene expression changes and irAEs or the efficacy of ICI treatment was examined. For validation, immunostaining of proteins strongly associated with irAEs was performed to determine their expression status in tissue specimens. Results: Among the 43 patients (30 males, 13 females, median age 68), 28 had adenocarcinoma, and 15 had squamous cell carcinoma. PD-L1 positivity was observed in 36 patients. The treatment regimens included pembrolizumab monotherapy for 18 patients and combination immunotherapy for 25 patients, with 25 patients responding to treatment and 7 developing irAEs. There was a marked difference in gene expression between adenocarcinoma and squamous cell carcinoma, with a notably higher number of tumor-infiltrating lymphocytes (TILs) in adenocarcinoma. An increase in TILs was observed in cases with irAEs across both cancer types. Additionally, an increased CD8/Treg ratio and CD8/exhausted T cell ratio were noted in adenocarcinomas with irAEs. A strong correlation between IRF5 gene expression and the occurrence of irAEs in adenocarcinoma was also confirmed by immunohistochemistry. Conclusion: We have identified tumor immune microenvironments correlated with the onset of irAEs following ICI treatment in patients with postoperative recurrence of lung cancer. This discovery could contribute to perioperative treatment strategies and improve our understanding of tumor immune mechanisms. Citation Format: Yujin Kudo, Jun Matsubayashi, Satoshi Takahashi, Masaru Hagiwara, Masatoshi Kakihana, Toshitaka Nagao, Tatsuo Ohira, Norihiko Ikeda. Investigating biomarkers for immune-related adverse events following immune checkpoint inhibitor therapy in recurrent lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7527.
Abstract 5743: Liposome platform enables X-ray induced photodynamic therapy treatment against human triple negative breast cancer cells
Authors: Biyao Yang, Rui Sang, Yi Li, Ewa Goldys, Wei Deng
Journal: Cancer Research (2024)

Abstract In this study, we employed X-ray induced photodynamic therapy (X-PDT) for the treatment on triple negative breast cancer (TNBC) cells. To do this, we rationally developed a liposome delivery system co-loaded with protoporphyrin IX (PPIX) and perfluorooctyl bromide (PFOB). Low-dose X-ray at 2Gy was employed to activate PPIX for reactive oxygen species (ROS) generation, and the co-loading of PFOB provided additional oxygen to augment ROS production. The highly toxic ROS triggered TNBC cell death. In vitro X-PDT effects including intracellular ROS generation, cytotoxicity, cell viability and apoptosis/necrosis assay in TNBC cells were studied. Our results indicate that the nanocarriers effectively induced X-PDT effect with very low dose radiation, which makes it possible to damage cancer cells. Our strategy may offer a paradigm-shifting treatment alternative for TNBC patients who need neoadjuvant radiotherapy but wish to avoid long term detrimental effect on functional outcome by undergoing X-PDT using only a fraction of the conventional radiotherapy. Citation Format: Biyao Yang, Rui Sang, Yi Li, Ewa Goldys, Wei Deng. Liposome platform enables X-ray induced photodynamic therapy treatment against human triple negative breast cancer cells [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 5743.
Abstract 5420: NLRX1 involves in prostate cancer cell growth, survival and migration
Authors: Wan-Wan Lin, Varsha Rathore
Journal: Cancer Research (2024)

Abstract Prostate cancer (PCa) is one of the most common male cancer and is the second leading cause of death in men. The basic working components about its cause and progression are not surely known in the research as well as the practitioner community. The current curing therapies such as surgery, radiation therapy, cryotherapy, and hormone therapy are not very encouraging. Subsequently, there is a need to investigate new potential targets for focused treatment. NLRX1 (NOD9 or NLR family member X1) is one member among the NLRs and is a non-inflammasome forming NLR sub-group localized in mitochondria. Previous studies showed that NLRX1 is involved as a tumor suppressor in colorectal cancer and hepatocellular carcinoma. However, NLRX1 serves as tumor promoter in breast cancer and head and neck cancer sarcoma. The present study focuses on the role of NLRX1 in prostate cancer cells under stress conditions including serum-free and hydrogen peroxide (H2O2) to understand cell regulation and functions of NLRX1. We used human prostate cancer PC3 and LNCaP cell lines as the models and the following methods, including Annexin V/PI staining for cell viability, BrdU incorporation for cell proliferation, mitoSOX staining for mitochondrial ROS, wound healing assay for cell migration and Boyden chamber for cell invasion. First, we assessed the TCGA database via UCSC Xena and found that prostate cancer tumors have high NLRX1 expression than normal tissues. Next, we knock down the NLRX1 through lentivirus transduction. We found that silencing NLRX1 expression can decrease cell proliferation in PC3 cells. Furthermore, silencing NLRX1 can significantly decrease cell viability under H2O2 in PC3 cells and serum-free condition in both cancer cell lines. In addition, we found that H2O2-induced cell death is reversed by necroptosis inhibitor Nec-1. Moreover, NLRX1 silencing reduces cell migration in both PC3 and LNCaP cells and can inhibit cell invasion in both cell lines at 24 h. These results suggest that NLRX1 is a positive regulator of cell growth, migration and invasion in prostate cancer cells, and NLRX1 provides a cell-protective role in response to H2O2 and serum-free stress. Thus, this study will provide a potential target for the development of a therapeutic strategy for prostate cancer. Citation Format: Wan-Wan Lin, Varsha Rathore. NLRX1 involves in prostate cancer cell growth, survival and migration [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 5420.
An emerging terpolymeric nanoparticle pore former as an internal recrystallization inhibitor of celecoxib in controlled release amorphous solid dispersion beads: Experimental studies and molecular dynamics analysis
Authors: Jamie Anne Lugtu-Pe, Xuning Zhang, Sako Mirzaie, Hao Han R. Chang, Nour AL-Mousawi, Kuan Chen, Yongqiang Li, Anil Kane, Daniel Bar-Shalom, Xiao Yu Wu
Journal: Acta Pharmaceutica Sinica B (2024)

Solid oral controlled release formulations feature numerous clinical advantages for drug candidates with adequate solubility and dissolution rate. However, most new chemical entities exhibit poor water solubility, and hence are exempt from such benefits. Although combining drug amorphization with controlled release formulation is promising to elevate drug solubility, like other supersaturating systems, the problem of drug recrystallization has yet to be resolved, particularly within the dosage form. Here, we explored the potential of an emerging, non-leachable terpolymer nanoparticle (TPN) pore former as an internal recrystallization inhibitor within controlled release amorphous solid dispersion (CRASD) beads comprising a poorly soluble drug (celecoxib) reservoir and insoluble polymer (ethylcellulose) membrane. Compared to conventional pore former, polyvinylpyrrolidone (PVP), TPN-containing membranes exhibited superior structural integrity, less crystal formation at the CRASD bead surface, and greater extent of celecoxib release. All-atom molecular dynamics analyses revealed that in the presence of TPN, intra-molecular bonding, crystal formation tendency, diffusion coefficient, and molecular flexibility of celecoxib were reduced, while intermolecular H-bonding was increased as compared to PVP. This work suggests that selection of a pore former that promotes prolonged molecular separation within a nanoporous controlled release membrane structure may serve as an effective strategy to enhance amorphicity preservation inside CRASD.
Abstract 7514: Tumor intrinsic CDC42BPB confers resistance to anti-PD-1 immune checkpoint blockade in breast cancer
Authors: Ravindra Pramod Deshpande, Kerui Wu, Shih-Ying Wu, Abhishek Tyagi, John Hunting, Jimmy Ruiz, Wencheng Li, Kounosuke Watabe
Journal: Cancer Research (2024)

Abstract Immune checkpoint blockade has been used to treat breast cancer, but the clinical responses remain relatively poor, especially for the triple-negative subtype. The weak responsiveness is attributed to tumor intrinsic as well as tumor extrinsic factors, suggesting a need for novel approaches. We have used the CRISPR Cas9 kinome knockout library consisting of 763 kinase genes to identify tumor intrinsic kinase conferring resistance to anti-PD-1 immune checkpoint blockade and identified the CDC42BPB kinase as a potential target to overcome the resistance to anti-PD-1 immunotherapy. We found that CDC42BPB is highly expressed in breast cancer patients who are non-responsive to immunotherapy. Importantly, a small molecule pharmacological inhibitor, BDP5290, which targets CDC42BPB synergized with anti-PD-1 and enhanced tumor cell killing by promoting T-cell proliferation in both in vitro and in vivo assays. Moreover, anti-PD-1 resistant breast cancer cells showed higher expression of CDC42BPB, and its inhibition rendered the resistant cells more susceptible to T cell killing in the presence of anti-PD-1. We also found that CDC42BPB phosphorylated AURKA which in turn upregulated PD-L1 through cMYC. Our results have revealed a robust link between tumor intrinsic kinase and immunotherapy resistance and provided a rationale for a novel combination therapy of CDC42BPB inhibition and anti-PD-1 immunotherapy for breast cancer. Citation Format: Ravindra Pramod Deshpande, Kerui Wu, Shih-Ying Wu, Abhishek Tyagi, John Hunting, Jimmy Ruiz, Wencheng Li, Kounosuke Watabe. Tumor intrinsic CDC42BPB confers resistance to anti-PD-1 immune checkpoint blockade in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7514.
Abstract 2484: Association of artificial intelligence (AI)-based HER2 scoring with clinical outcomes to first-line trastuzumab plus chemotherapy in HER2-positive metastatic gastric cancer (mGC)
Authors: Minsu Kang, Yoojoo Lim, Hyeon Jeong Oh, Ji Ae Lee, Jin Won Kim, Ji-Won Kim, Sanghoon Song, Heon Song, Keun-Wook Lee
Journal: Cancer Research (2024)

Abstract Background: Although trastuzumab plus chemotherapy is the treatment of choice for HER2-positive mGC, not all patients respond to the therapy. To date, there is no reliable and efficient biomarker that can predict the response to trastuzumab-based treatment. Methods: Clinical data and pathology slides from HER2-positive mGC patients treated with first-line trastuzumab and capecitabine/5-fluorouracil plus cisplatin were retrospectively collected. HER2 positivity was confirmed using standard methods with immunohistochemistry (IHC) and/or in situ hybridization. An AI-based model was applied to a single HER2 IHC-stained whole slide image (WSI) of each patient to identify and quantify the tumor cells with HER2 IHC staining intensity categories of 0, 1+, 2+, or 3+ on the slide. The proportion of tumor cells with 3+ staining intensity among total tumor cells (h3 percentage) in each slide was calculated and analyzed in relation to clinical outcomes. Results: A total of 160 cases were included in this analysis. Overall, the median progression-free survival (PFS) was 9.2 mo, and the overall survival (OS) was 18.9 mo. By standard IHC HER2 grading, 107 (66.9%) 3+ and 53 (33.1%) 2+ cases were included. The median AI-estimated h3 percentage in these patients was 14.8% (range 0 - 99.5%). The patients with their best tumor response of complete (CR) or partial response (PR) (44.4%) exhibited significantly higher h3 percentages (mean h3 percentage 46.6% in CR/PR vs. 29.4% in stable or progressive disease, p = 0.018). The h3 percentage exhibited strong associations as a continuous variable with longer PFS (hazard ratio [HR] 0.94 [95% confidence interval (CI) 0.90 - 0.99] for 10% change of h3 percentages, p = 0.015) or OS (HR 0.93 [95% CI 0.89 - 0.98] for 10% change of h3 percentages, p = 0.004). Notably, patients having a proportion of 3+ tumor cells at ≥ 90% (27/160, 16.9%) showed particularly longer PFS (median PFS 21.4 mo in ≥ 90% vs. 8.5mo in &amp;lt; 90%, p = 0.006) and OS (median OS 40.3 mo in ≥ 90% vs. 16.6 mo in &amp;lt; 90%, p = 0.004). Conclusion: AI-based models interpreting WSI can provide additive predictive information to HER2-positive mGC patients treated with trastuzumab plus chemotherapy. Citation Format: Minsu Kang, Yoojoo Lim, Hyeon Jeong Oh, Ji Ae Lee, Jin Won Kim, Ji-Won Kim, Sanghoon Song, Heon Song, Keun-Wook Lee. Association of artificial intelligence (AI)-based HER2 scoring with clinical outcomes to first-line trastuzumab plus chemotherapy in HER2-positive metastatic gastric cancer (mGC) [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 2484.
Abstract 2872: GLUT3 promotes metabolic plasticity that drives radiation resistance in glioblastoma
Authors: Lobna Abdulrahman, Justine Bailleul, Hanna Hoang, Aaron Tang, Erina Vlashi
Journal: Cancer Research (2024)

Abstract Glioblastomas (GBM) are the most common and malignant brain tumors in adults. While radiation therapy (RT) offers a significant advantage for GBM patients, improving long-term survival remains elusive largely due to the remarkable resistant nature of these tumors. We have shown that metabolic plasticity, especially rewiring of glucose metabolism, promotes radiation survival in GBM. In this study, we investigate the role of glucose transporter 3 (GLUT3) translocation to the cell surface in radiation resistance of GBM. The effect of radiation on GLUT3 total protein levels was determined in patient-derived gliomaspheres via westerns blots, while cellular localization of GLUT3 was determined via immunofluorescence, flow cytometry and cell fractionation assays. The role of the AMPK and αvβ3 integrin in the radiation-induced GLUT3 translocation to the cell membrane was probed via small molecule inhibitors and activators. To determine the role of GLUT3 in radiation survival, GLUT3 levels were knocked down via siRNA and shRNA, followed by functional in vitro and in vivo assays. We provide evidence that irradiated gliomaspheres translocate GLUT3 to the plasma membrane, in a radiation-induced oxidative stress-dependent manner, effectively increasing their glucose uptake and promoting radiation survival. Our data also suggest that GLUT3 translocation to the cell surface contributes to RT resistance. AMPK and αvβ3 integrin are linked to radiation-induced translocation of GLUT3 to the cell membrane, suggesting that targeting these pathways is a potential approach to sensitize GBM tumors to radiation therapy. Citation Format: Lobna Abdulrahman, Justine Bailleul, Hanna Hoang, Aaron Tang, Erina Vlashi. GLUT3 promotes metabolic plasticity that drives radiation resistance in glioblastoma [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 2872.
Abstract 5747: Microwave responsive thermosensitive lipid nanoparticles for spatiotemporal delivery of chemotherapeutics
Authors: Cesar B. Aparicio-Lopez
Journal: Cancer Research (2024)

Abstract Pancreatic cancer is a highly lethal malignancy with an urge for the exploration of novel treatments. One promising approach is microwaved-induced hyperthermia, which has shown great antitumor and synergistic effects when combined with other therapies. The application of microwaves produces heat by dielectric hysteresis which depends on the dielectric properties of molecules. Ionic liquids (ILs) are compounds composed of ions with &amp;lt;100 °C melting point and have strong dielectric properties. In short, we propose the creation of microwave-sensitive nanoparticles using IL, enabling precise hyperthermia induction with low-powered microwaves in localized areas. To achieve this, we stabilize a core composed of 1-butyl-methylimidazolium bromide or 1-butyl-3-methylimidazolium hexafluorophosphate using Span 80, Tween 20, and Triton-X as surfactants, along with phosphatidylcholine lipids as “cosurfactants”. Employing a double emulsion procedure for fabrication, nanoparticles are characterized using dynamic light scattering, Fourier-transform infrared spectroscopy, and transmission electron microscopy. Furthermore, we assess microwave sensitivity by comparing thermal changes between liposomes loaded with 120 mM and 250 mM NaCl solutions. Subsequently, we evaluate biocompatibility and heat effects by incubating IL nanoparticles with BXPC3 and KPC cells, monitoring cell viability through MTT assays. We aim to confine the ILs within the nanoparticle core rather than incorporating them into the membrane. We anticipate increased microwave sensitivity, translating to reduced off-target effects and enhanced precision in hyperthermia treatment. This research holds promise for improving the therapeutic outcomes of pancreatic cancer treatment. Citation Format: Cesar B. Aparicio-Lopez. Microwave responsive thermosensitive lipid nanoparticles for spatiotemporal delivery of chemotherapeutics [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 5747.
Abstract 54: Engineering chimeric antigen receptor (CAR) T cells using autoantigen binding domains for treatment of B cell malignancies with increased specificity
Authors: Abiagil Cheever, Hunter Lindsay, MacKenzie Hansen, Chloe Kang, K. Scott Weber, Kim O'Neill
Journal: Cancer Research (2024)

Abstract Introduction: Chronic inflammation often leads to cancer, and many autoimmune diseases lead to a significantly increased risk of developing cancer. Though many autoimmune diseases, like Graves’ Disease (GD), don’t have treatments that address this risk. Chimeric antigen receptor (CAR) T cells are an effective treatment for hematological cancers by eliminating all B cells, but a more targeted form of CAR T cells could eliminate specific B cell populations in B cell malignancies, including GD. Methods: To allow our CAR T cells to target specific B cell populations that cause GD, we engineered chimeric autoantigen receptors (CAAR) with epitopes of thyroid stimulating hormone receptor (TSHR) as the binding domain. This acts as bait for the anti-TSHR B cells. Jurkat T cells were lentivirally transduced with these CAAR plasmids. Anti-TSHR B cell lines were engineered by transducing Nalm6 cells with lentivirus for anti-TSHR B cell receptors. Cytotoxicity assays were performed on primary human TSHR CAAR T cells incubated with the anti-TSHR B cell lines. Cytokine production, proliferation, and cytotoxicity assays were performed on these coincubated cells to determine the efficacy of our TSHR CAAR T cells. Results: Two of the three Jurkat TSHR CAAR T cells showed significant binding to anti-TSHR antibodies (TRAbs). They also showed significant activation, measured by CD69 expression, when incubated with plate bound TRAbs, but not soluble TRAbs. The B cell lines were validated by binding to TSHR. The primary TSHR CAAR T cells showed significantly increased proliferation and production of TNF, IFN-y, and IL-2, when compared with controls. The TSHR CAAR T cells also had significant cytotoxic action against the anti-TSHR B cell lines, but not Nalm6 B cells. The cytotoxic function was comparable to our CD19 CAR T cell with the same activation domains, though it demonstrated specificity to only anti-TSHR B cells. Conclusion: TSHR CAAR T cells are a potentially curative treatment for GD that will stop chronic inflammation and could reduce GD patient’s risk of developing thyroid cancer. This is also an important development in CAR T cell therapies that allows for specific targeting of certain B cell populations. Citation Format: Abiagil Cheever, Hunter Lindsay, MacKenzie Hansen, Chloe Kang, K. Scott Weber, Kim O'Neill. Engineering chimeric antigen receptor (CAR) T cells using autoantigen binding domains for treatment of B cell malignancies with increased specificity [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 54.