tbuckley/cabot-search huggingface dataset:
Abstract 4252: Evaluation of NXI-101 in non-small cell lung cancer (NSCLC) using patient-derived organotypic tumor spheroids (PDOTS): Targeting a novel tumorigenic pathway
Authors: Julia Vail, Hyung Gun Maeng, Je Woong Jang, Kyungjin Boo, Je-In Youn, Alyssa Martin, Aaron Goldman, Kyoung Wan Yoon, Michael A. Perricone
Journal: Cancer Research (2024)

Abstract ONCOKINE-1 (OK-1), a soluble protein that is released by tumor cells, is implicated in the resistance of immunotherapy. Here we evaluated the efficacy of NXI-101, a monoclonal antibody that binds and neutralizes OK-1, in a model of patient-derived organotypic tumor spheroids (PDOTS) derived from non-small cell lung carcinoma (NSCLC) patients. NSCLC PDOTS were treated with NXI-101 and the effects of the drug were evaluated on day 3 post-treatment. Cytotoxicity was measured by Hoechst/Propidium Iodide staining and quantified by measuring the area-weighted percentage of cell death. Significant cytotoxicity was observed in 2 out of 10 patient tumors (20%) as a monotherapy and 4 out of 10 (40%) when used in combination with atezolizumab. The therapeutic response for both treatments was positively correlated (p&amp;lt;0.05) with the level of OK-1 expression, determined by immunohistochemistry using tissue sections taken on the day of tumor specimen collection. NXI-101 alone and in combination with atezolizumab had immunomodulatory effects that were associated with cytotoxic response. For example, transcriptomic analysis, Nanostring IO 360 Panel, indicated that the drug treatments resulted in the inhibition of TGF-β pathways and stimulated a number of immune pathways in 3 of the 4 responsive PDOTS. These pathways include interferon-α, JAK-STAT, and dendritic cell activation markers. We also observed evidence of activation of these same pathways in 2 of the 6 non-responsive PDOTS. These data support the prospects of NXI-101 as a first-in-class therapeutic for the treatment of NSCLC when used alone or in combination with an immune checkpoint inhibitor. Moreover, the findings highlight the PDOTS platform's substantial value in capturing patient-specific tumor response variability and providing robust support for the mechanistic evaluation of cancer therapeutics. Citation Format: Julia Vail, Hyung Gun Maeng, Je Woong Jang, Kyungjin Boo, Je-In Youn, Alyssa Martin, Aaron Goldman, Kyoung Wan Yoon, Michael A. Perricone. Evaluation of NXI-101 in non-small cell lung cancer (NSCLC) using patient-derived organotypic tumor spheroids (PDOTS): Targeting a novel tumorigenic pathway [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 4252.
Abstract 3174: Crosstalk between protein translation and DNA replication during stress response and cancer therapy
Authors: Fangfang Wang
Journal: Cancer Research (2024)

Abstract Tumor microenvironment, which includes both various types of cells (tumor cells, stromal cells, immune cells, etc.) and an interstitial fluid system, plays a key role in tumorigenesis, therapy response, and disease outcome. While the cell component has been heavily studied in cancer treatment, the interstitial fluid system has not. A key feature of the fluid system is constant oscillation of osmolytes such as salt, glucose, and proteins due to unstable blood supply and tumor metabolism, resulting in cycles of osmotic stress and recovery. Yet, how this osmotic stress - recovery cycle mediates tumorigenesis and cancer therapy remains poorly understood. Our unpublished results reveal sequential activation of molecular events during osmotic stress and recovery. In the stress stage, protein translation, transcription, and DNA replication are inhibited. Following recovery, protein translation resumes, gene transcription is greatly upregulated, but DNA replication is not immediately recovered. It turns out that a DNA replication checkpoint is activated during recovery; as a result, DNA replication is halted. Defects in activating protein translation inhibition during stress fail to activate the replication checkpoint during recovery, indicating a causative link from protein translation inhibition to DNA replication checkpoint activation. Many genes involved in this crosstalk are altered in a wide range of human tumors. Ovarian cancer cells that are resistant to standard of care (for instance, cisplatin) demonstrate defects in this crosstalk; however, they were also more sensitive to a combination of osmotic stress followed by the presence of replication checkpoint inhibitors during recovery than parental cancer cells. These findings highlight a unique role of the interstitial fluid system in tumor development and therapy response. They also suggest a new anticancer strategy by combining osmotic stress with checkpoint inhibitors. Key words: Tumor microenvironment; osmotic stress; protein translation control; DNA replication checkpoint; cancer therapy Citation Format: Fangfang Wang. Crosstalk between protein translation and DNA replication during stress response and cancer therapy [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 3174.
Abstract 256: A novel transcriptional complex of OLIG2-STAT5 mediates glioma stem cell self renewal and invasion
Authors: Aunay Miller, Costanza Lo Cascio, Mylan Blomquist, James B. McNamara, Keely Orndorff, Matthew Dufault, Christopher Sereduk, Joseph Loftus, Shwetal Mehta, Nhan L. Tran
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults, despite current treatment options. One of the major contributing factors to this dismal outcome is a subset of cells called glioma stem cells (GSCs) that are highly tumorigenic, invasive, and resistant to conventional treatments. Thus, studies that focus on the properties of GSC biology are needed to develop novel therapies to improve overall survival. Here we report a novel role of STAT5 in GSC stemness and survival. In GBM tumors, STAT5 has been shown to be active in the infiltrative, residual population of cells remaining post-surgery. Knockdown of STAT5 results in the decrease in GSC stemness and therapeutic resistance. Interestingly, we find that expression of OLIG2, a key cell fate factor important for the tumorigenic potential of GSCs, affects STAT5 activation with a positive correlation between OLIG2 and STAT5 mRNA expression in GBM tumors. Furthermore, we find that in GSCs expressing EGFRvIII, STAT5 interacts with OLIG2 and pharmacological inhibition of STAT5 activation or knockdown of STAT5 expression results in decrease of OLIG2-mediated GSC invasion. Together, these data suggest a novel transcriptional complex, STAT5-OLIG2, in the potential role for GSC survival, maintenance, and invasion. Citation Format: Aunay Miller, Costanza Lo Cascio, Mylan Blomquist, James B. McNamara, Keely Orndorff, Matthew Dufault, Christopher Sereduk, Joseph Loftus, Shwetal Mehta, Nhan L. Tran. A novel transcriptional complex of OLIG2-STAT5 mediates glioma stem cell self renewal and invasion [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 256.
Abstract 2906: Inducing and disabling COX-2 S-nitrosylation to investigate its role in breast cancer progression
Authors: Reuben J. Hoffmann, AeSoon Bensen, Elise de Wilde, James E. Korkola, Pepper Schedin
Journal: Cancer Research (2024)

Abstract Background: We aim to assess the effect of S-nitrosylation of COX-2 on tumor attributes in models of early breast cancer. COX-2 is involved in tumor progression in many solid cancers. It is a known oncogene in murine breast cancer models, and targetable by NSAIDs. In women, its clinical correlation to breast cancer progression as well as its efficacy as a therapeutic target have yielded mixed results. These incongruities may be due, in part, to a post-translational modification, as COX-2 undergoes S-nitrosylation on Cys-526. Commercially-available antibodies selectively bind to either the S-nitrosylated (SNO-COX-2) or non-nitrosylated (nCOX-2) forms, and immunohistochemical staining of human tissue reveals that the two forms of COX-2 localize to different cellular sites in normal breast tissue and have opposite associations with breast cancer progression (PMID 33298921). Hypothesis: S-Nitrosylated and non-nitrosylated COX-2 have distinct roles in cancer progression. Approach: MCF10DCIS.com is a human breast cancer cell line chosen due to its ability to form DCIS-like (“stage 0”) lesions in culture and xenografting, which can progress to invasion when induced by signals from the tumor microenvironment (TME). Approach 1: Detect extracellular matrix (ECM) and ligand factors that upregulate SNO-COX-2, independently or in ECM/ligand pairs. We utilized a 2D microenvironment microarray (MEMA) and tested 357 TME conditions. Approach 2: Validate TME conditions in 3D culture. Approach 3: Develop a mutant MCF10DCIS.com line in which COX-2 cannot be S-nitrosylated by inducing a single disabling missense mutation at Cys-526 via CRISPR. Results: The MEMA revealed several conditions in which SNO-COX-2 was upregulated, including fibular collagens and SSP1. In 3D culture, increased SNO-COX-2 was associated with the presence of markers for EMT and an invasive growth phenotype, whereas nCOX-2 was not. Following CRISPR transformation, 59 individual MCF10DCIS.com clones were isolated and the target site of each sequenced. We identified 10 heterozygotic clones with the desired mutation, including a classical heterozygote that also retained the WT allele. Ongoing: Current studies include a second round of CRISPR to produce a homozygous mutant cell line as well as validation of the mutant protein. The resulting cell lines will model the loss of COX-2 S-nitrosylation in breast cancer cells while retaining otherwise-functional COX-2. Citation Format: Reuben J. Hoffmann, AeSoon Bensen, Elise de Wilde, James E. Korkola, Pepper Schedin. Inducing and disabling COX-2 S-nitrosylation to investigate its role in breast cancer progression [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 2906.
Abstract 4864: Epidemiological characteristics and treatment strategies of gastric cancer with neuroendocrine differentiation (NED)
Authors: Zhen Huang, Jinlai Wei, Yifan Shen, Jun Zhang
Journal: Cancer Research (2024)

Abstract Background: Gastric cancer with neuroendocrine differentiation (NED) occurs in 10% to 40% of cases, a significant proportion that is under-researched. The lack of clinical guidelines for this subgroup necessitates the development of effective treatment protocols. Methods: This study enrolled 149 gastric cancer patients, analyzing retained surgical wax blocks via immunohistochemistry for syn, CgA, and CD56 expressions. Patients were categorized into NED-positive and NED-negative groups for analysis, employing continuous variable analysis, categorical variable analysis, clustering, principal component analysis (PCA), feature importance analysis, heatmap analysis, and survival prognosis. Moreover, the clinical efficacy and safety of first-line (surufatinib + SOX + anti PD-1 antibody, n=3) and second-line (surufatinib + anti PD-1 antibody, n=3) treatments were observed in six advanced gastric cancer with NED patients, exploring the epidemiological characteristics, feasibility, and importance of clinical treatments for NED. Results: The study revealed a 10.1% incidence of NED positivity in gastric cancer patients. NED-positive patients exhibited a rapid decline in early survival probability, with a median relapse-free survival of 32.4 months compared to 41.5 months in NED-negative patients, indicating a poorer prognosis for NED-positive patients. In-depth analysis suggested significant correlations between NED status and factors such as gender, tumor location, pathological type, and AJCC staging, with the most significant associations observed in males, stage IIIA, and gastric angle location. In the six advanced gastric cancer with NED cases, effective tumor reduction was observed in both first-line (100% tumor shrinkage rate, ORR 66.7%, DCR 100%) and second-line treatments (66.7% tumor shrinkage rate, ORR 33.3%, DCR 100%), showing sustained partial responses (PR) exceeding 10 months in two patients and 7 months in one patient, respectively. The major grade 3 or higher TEAEs being neutropenia and thrombocytopenia in the first-line, and hypertension and proteinuria in the second-line therapy. Conclusion: This study provides pivotal epidemiological and clinical treatment evidence for gastric cancer with NED, underscoring the necessity of personalized treatment strategies for this subgroup. Future research should focus on refining treatment protocols to enhance the quality of life and overall prognosis for these patients. Citation Format: Zhen Huang, Jinlai Wei, Yifan Shen, Jun Zhang. Epidemiological characteristics and treatment strategies of gastric cancer with neuroendocrine differentiation (NED) [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 4864.
Abstract 7563: Efficacy of JPI-547, novel dual PARP inhibitor, in endometrial cancer cell line
Authors: Shin-Wha Lee, So-Hyun Nam, Su-Bin Park
Journal: Cancer Research (2024)

Abstract Objectives: PARP inhibitor is effective in treating DNA repair deficiency endometrial cancer. Endometrial cancer (EC) is one of the most common gynecological cancers in developed countries and its incidence is increasing, and the prognosis of patients with early stage and low-risk EC is very good, but the prognosis of progressive and recurrent EC is poor. Novel PARP inhibitor JPI-547 is a PARP and tankyrase dual inhibitor, and in cancer cells, tankyrase inhibitor plays an important role in DNA repair, telomere maintenance, and cell survival. This experiment was conducted to determine whether the reactivity of the PTEN mutant EEC was increased by using the Novel PARP inhibitor. Method: Human endometrioid endometrial cancer cell lines, Hec-1A, Hec-1B and Ishikawa were obtained. Cell viability assay for the drugs Olaparib and JPI-547 were assessed. Colonies consisting of at least 50 cells were counted. The number of dead cells was counted in five different areas of the hemocytometer, and the experiment was performed three times. The percentage of dead cells was analyzed compared to the untreated group. We confirmed the efficacy by siRNA transfection and immunofluorescence. Result: When treated with Olaparib, there was no change in cell viability in the rest of the cells except for Ishikawa cells, which are PTEN mutations. It decreased by 35.4% in Ishikawa cells, whereas when treated with JPI-547, all cell lines Hec-1A, Hec-1B, and Ishikawa cell viability decreased by 28%, 34.3%, and 48.7%, respectively. PTEN knock-down reduced cell visibility by 28% when treated with olaparib, whereas when treated with JPI-547, Hec-1A (siCont) and Hec-1A (siPTEN) decreased by 26% and 42%, respectively, in all cells regardless of whether PTEN knock-down is present. When treated with Olaparib, dead cells were identified only in PTEN knock-down cells, increasing by 22%. When treated with JPI-547, dead cells increased by 25.5% and 33% in all cells of Hec-1A (siCont) and Hec-1A (siPTEN), respectively. It was confirmed that JPI-547 can reduce cell viability regardless of the formation of Rad51 according to PTEN. Conclusion: JPI-547, a novel PARP inhibitor, showed good efficacy in PTEN mutation and PTEN-wild-type EEC cell lines than in conventional PARP inhibitor. The effect of reducing survival of ECC cell line with JPI-547 was confirmed with or without PTEN mutation. Further evaluation and in vivo experiments are needed to prove the efficacy of JPI-547 in EC. Citation Format: Shin-Wha Lee, So-Hyun Nam, Su-Bin Park. Efficacy of JPI-547, novel dual PARP inhibitor, in endometrial cancer cell line [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 7563.
Abstract 640: <i>In vivo</i> rescue of p53 tumor suppressor function with ADGN-531 across Pan-p53 alterations
Authors: Gilles Divita, Audrey Grunenberger, Elodie Czuba, Veronique Josserand, Melanie Guidetti, Neil Desai
Journal: Cancer Research (2024)

Abstract p53 tumor suppressor mutations result in loss of function of p53 in approximately 50% of all human cancers.TP53 missense, nonsense mutations and p53 deletion are present in about 50%, 12% and 5% of all p53 driven cancers, respectively. To date there is no effective treatment for rescuing p53 function in cancers using a pan-p53 approach. The use of ADGN-531 is a new potent strategy combining mRNA with a tumor selective peptide nanocarrier to rescue of p53 tumor suppressor function. ADGN-531 contains proprietary p53-mRNA complexed with proprietary short amphipathic peptides in the form of nanoparticles. ADGN-531 was evaluated on 20 different cancer cell lines harboring various p53 mutations. In-vivo efficacy of IV-administered ADGN-531 nanoparticles was evaluated on colorectal SW403 (p53 nonsense/KRASG12V), osteosarcoma SaOs2 (p53 null) and NSCLC NCI-H358 (p53 null/KRASG12C) mouse xenografts at a dose of 0.25-1.0 mg/kg weekly. ADGN-531/sotorasib synergy was evaluated in vitro on NCI-H358 (p53 null/KRASG12C) and Mia-PACA (p53R48W/KRASG12C) cells and in vivo on NCI-H358 mouse xenograft. ADGN-531 markedly inhibits the growth of a large panel of cancer cells harboring p53-missense or nonsense mutations or p53-deletion, by rescuing p53 transcriptional activity and subsequent expression of its target proteins. ADGN-531 induces cell cycle arrest in G1 due to p21 upregulation and apoptosis following BAX and PUMA activation. IV-administration of ADGN-531 resulted in dose responsive tumor growth inhibition in SaOs2, SW403 and H358 xenografts independent of KRAS status. We demonstrated a strong synergy in a NSCLC H358 xenograft (tumor regression 80%) when restoring P53 function with ADGN-531 (0.5mg/kg, weekly) along with inhibition of KRASG12C mutant using sotorasib (10mg/kg, daily). ADGN-531 potentiated the effect of sotorasib on sotorasib resistant cells harboring high level of KRASG12C in permanent active state. ADGN-531 treatments are well tolerated, no sign of clinical toxicity was detected after single or repeated administrations. ADGN-531 is effective in rescuing p53 function both in vitro and in vivo across a wide range of p53 alterations. Our study provides a proof-of-concept that restoration of tumor suppressor function by ADGN-531 could be used as a single agent therapy in P53 altered tumors independent of other driver mutations e.g., KRAS, or with other therapies for potent combinatorial cancer treatment. Citation Format: Gilles Divita, Audrey Grunenberger, Elodie Czuba, Veronique Josserand, Melanie Guidetti, Neil Desai. In vivo rescue of p53 tumor suppressor function with ADGN-531 across Pan-p53 alterations [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 640.
Abstract 2840: Development, characterization, and validation of a systemic human mantle cell lymphoma model utilizing luciferase expressing Jeko-1 tumor cells
Authors: David Harris, Andrew Wong, Elizabeth Rainbolt, Nicole Westrick, Justin Avery, Joseph Kolb, Aswani Vunnava, Zachary Ward, Chassidy Hall, Bincy John
Journal: Cancer Research (2024)

Abstract Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma that is clinically and biologically heterogenous. MCL murine models are scarce and reliable in vivo models are necessary for pre-clinical testing and identification of improved novel therapeutics. To address this need, we established and characterized a human MCL in vivo model by systemic implantation of the luciferase-expressing Jeko-1 cell line (Jeko-1-luc) into immunodeficient NCG mice. Tumor growth kinetics was evaluated by testing multiple cell inoculums, and disease progression was monitored by in vivo serial bioimaging, three-dimensional optical imaging (3D), and ex-vivo endpoint analyses. Jeko-1-luc tumor growth profile revealed moderate latency with a median survival of 40 days post implant. Subsequently, we utilized 3D optical imaging and ex-vivo imaging that confirmed the localization of tumor growth predominantly in lungs, spleen, and skeletal regions. Additionally, we determined the surface expression of selected B-cell lineage markers including CD19, CD20, and CD22. Next, we evaluated the efficacy and effect on survival in response to various standard of care agents including Vincristine, Rituximab, Palbociclib, Temsirolimus, and Cyclophosphamide. The quantification of tumor burden by in vivo and ex-vivo bioluminescent imaging demonstrated that the highest therapeutic activity and overall survival was achieved by Palbociclib and Vincristine. Flow cytometric analyses further demonstrated that tumor cells obtained from blood and selected tissues including spleen and bone marrow showed reduced tumor burden in treatment groups relative to the control group. Taken together, these results illustrate the translational value of the Jeko-1-luc model and provides a platform for evaluating novel treatment modalities for mantle cell lymphoma. Citation Format: David Harris, Andrew Wong, Elizabeth Rainbolt, Nicole Westrick, Justin Avery, Joseph Kolb, Aswani Vunnava, Zachary Ward, Chassidy Hall, Bincy John. Development, characterization, and validation of a systemic human mantle cell lymphoma model utilizing luciferase expressing Jeko-1 tumor 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 2840.