bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3504: ARS2 and paraspeckle interactions: A nexus for lncRNA mediated drug resistance and cancer progression in hepatocellular carcinoma
Authors: Thillainadesan Gobi , Leong Hon Sing , Alawamry Omar
Published: March 2024

Paraspeckles, elaborate sub-nuclear assemblies composed of the lncRNA NEAT1-2 and a cohort of RNA-binding proteins, have a noted association with cancer progression and drug resistance. The specific mechanisms, however, have remained obscure. Our investigation into Hepatocellular Carcinoma (HCC) reveals a critical interaction: the sequestration of ARS2—an RNA-binding protein vital for the suppression of mRNA transcripts and the maturation of miRNAs—within paraspeckles. This sequestration leads to increased levels of NEAT1-2, derails miRNA processing, and diminishes the gene-silencing function of ARS2, thereby enhancing the expression of oncogenic genes. This discovery positions the ARS2-paraspeckle axis as a pivotal factor in cancer biology and a promising target for future treatments.

Citation Format: Gobi Thillainadesan, Hon Sing Leong, Omar Alawamry. ARS2 and paraspeckle interactions: A nexus for lncRNA mediated drug resistance and cancer progression in hepatocellular carcinoma [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 3504.
Abstract 3512: Joint probabilistic modeling of multimodal metabolic data with UnitedMet
Authors: Xie Amy X. , Bradshaw Casey , Tosh Christopher , Tansey Wesley , Reznik Ed
Published: March 2024

Metabolites play a crucial role in the functioning of biological systems. Measurements of metabolite abundances by metabolomics and metabolic pathway activity by isotope-tracing are powerful approaches to study metabolic phenotypes. However, large-scale measurements of metabolite levels and pathway activity remain extremely scarce due to the technical challenges. Motivated by the strength of RNA-metabolite covariation, we present UnitedMet, a Bayesian probabilistic method for end-to-end joint modeling of RNA-sequencing and metabolic datasets that is capable of dimensionality reduction, data integration and metabolic modality prediction. UnitedMet demonstrates high accuracy predicting metabolite levels and isotopologue distributions from gene expression data in human tumor samples. To evaluate UnitedMet’s efficacy in clinical applications, we inferred metabolomic profiles and isotope labeling patterns from the RNA sequencing data of clear cell renal cell carcinoma (ccRCC) patients enrolled in TCGA and clinical trials. Correlation analysis between genetic mutations and predicted metabolic phenotypes revealed that BAP1 mutations were associated with increased contribution of glucose to TCA cycle in ccRCC. Increased TCA cycle activity was found to be associated with disease progression and poorer clinical outcome. UnitedMet, therefore, provides a solution that could be broadly applicable to enhance multimodal metabolomic datasets and facilitates comprehensive study of interplays between metabolic profiles, molecular alterations and human phenotypes.

Citation Format: Amy X. Xie, Casey Bradshaw, Christopher Tosh, Wesley Tansey, Ed Reznik. Joint probabilistic modeling of multimodal metabolic data with UnitedMet [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 3512.
Abstract 3600: Reversal of iNKT cell dysfunction in cholangiocarcinoma
Authors: Htwe Khin Su Su , Soontrapa Kitipong , Jirawatnotai Siwanon , Prasopporn Sunisa , More-Krong Pimkanya , Sampattavanich Somponnat , Wongkajornsilp Adisak
Published: March 2024

Invariant natural killer T (iNKT) cells are CD1d-restricted unconventional T cells possessing innate and adaptive immunity with high anti-tumor activities. Yet, the effectiveness of iNKT cell therapy in clinical trials is limited due to iNKT cell dysfunction after exposure to the tumor microenvironment. Aggressive cholangiocarcinoma (CCA) cell lines were used to study iNKT cell reactivity. These CCA cell lines lacked CD1d molecules and responded poorly to iNKT cells. The iNKT cells became dysfunctional after the exposure to CCA by 48 h. In this study, we overcame iNKT cell dysfunction by searching for a small molecule to prevent or reverse the gene sets regulating iNKT cell dysfunction, thus prolonging anti-tumor activity. It was found that P53 and estrogen early response pathway gene sets were enriched in dysfunctional iNKT cells which were reversed by vorinostat, an HDAC inhibitor. Anti-CCA activity of iNKT cells was regained with a subtherapeutic dose of vorinostat as protection. Interestingly, vorinostat could not totally recover the anti-tumor effect of iNKT cells that have already developed into the dysfunctional stage. Significant tumor size reduction was seen in the humanized mouse model after iNKT cell adoptive therapy was given in combination with vorinostat compared to monotherapy with either iNKT cell or vorinostat alone. This study demonstrated that inhibiting the gene sets regulating iNKT cell dysfunction by vorinostat could prevent iNKT cell dysfunction, and prolong its anti-tumor activities. This combination could be a novel treatment option for CD1d-negative CCA patients resistant to standard chemotherapy.

Citation Format: Khin Su Su Htwe, Kitipong Soontrapa, Siwanon Jirawatnotai, Sunisa Prasopporn, Pimkanya More-Krong, Somponnat Sampattavanich, Adisak Wongkajornsilp. Reversal of iNKT cell dysfunction in cholangiocarcinoma [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 3600.
Abstract 3630: Measuring EGFr on extracellular vesicles in human plasma samples
Authors: Olsen Dorte Aa. , Hansen Torben F. , Brandslund Ivan , Madsen Jonna S.
Published: March 2024

Introduction: Extracellular vesicles (EVs), secreted extracellularly by almost all types of cells, play a pivotal role in intercellular communication and have emerged as valuable indicators in disease progression. Their potential for cancer diagnostics and monitoring is particularly noteworthy. Epidermal growth factor receptor (EGFr) is a major driver of several cancers and serve as an important target or co-target in cancer treatment. The purpose of this study was to develop an assay for measuring EGFr on EVs directly in plasma samples. Additionally three assays were developed to measure the total concentration of plasma EVs.

Methods: Recognizing the expected low concentrations of EGFr on EVs, the immunoassays were developed using Single molecule array (Simoa) technology, which has shown up to a 1000-fold improvement in sensitivity as compared to conventional immunoassay approaches. Commercial available calibrator material and antibodies against surface markers (EGFr, CD9, CD63 and CD81) were used to develop four assays: CD81-EGFr, CD81-CD9, CD81-CD63, and CD9-CD63. Plasma samples from healthy individuals (n=13) and small cohorts of various cancer patients (n=30, lung, colorectal, ovarian) were used for development, validation and testing.

Results: Each assay was tested for dilution linearity, limit of detection, analytical variation and pre-analytical stability of EVs. EGFr on EVs was lower in cancer patients (median: 489 × 106 EVegfr/mL) compared with healthy individuals (median: 663 × 106 EVegfr/mL). Conversely, total EV concentrations were markedly higher in plasma from cancer patients compared with healthy individuals (CD81-CD9: 9157 vs 4088, CD81-CD63: 3634 vs 1582, CD9-CD63: 9538 vs 1210, median values x106 EV/mL). Positive correlations were observed among the total EV assays (r=0.6, p<0.0001).

Conclusion: The developed assays allow measurement of EGFr on EVs and total EVs in human plasma samples. Notable, total EV concentrations were highly increased in cancer as compared with healthy individuals. The assays are now ready for a comprehensive validation using large cohorts of cancer samples.

Citation Format: Dorte Aa. Olsen, Torben F. Hansen, Ivan Brandslund, Jonna S. Madsen. Measuring EGFr on extracellular vesicles in human plasma samples [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 3630.
Abstract 3634: Copy number alterations in chromosome 19 genes associate with reduced immune infiltrate and adverse outcomes in lung cancer
Authors: Henick Brian S. , Georgis Yohanna , Herzberg Benjamin O. , Concepcion-Crisol Carla P. , Taylor Alison M.
Published: March 2024

Deleterious mutations in STK11/LKB1, KEAP1, and SMARCA4 have been shown to be associated with adverse response to immunotherapy in several lung cancer cohorts. However, the biological and clinical implications of deletions of these genes, which all reside on chromosome 19p (chr19p), has not been extensively described. We sought to first characterize the association between immune infiltration and these copy number changes in chr19p. To do this, we analyzed mutation, copy number, and gene expression data from non-small cell lung cancer cohorts in the Cancer Genome Atlas (TCGA). Chr19p is frequently deleted across cancers in the TCGA dataset, with higher rates in lung adenocarcinoma. In both lung adenocarcinoma and squamous cell carcinoma, nearly half of TCGA tumors have deletion of chr19p including STK11, KEAP1, and SMARCA4, and these tumors are enriched for STK11 mutation. Immune infiltrate (estimated by methylation patterns) was not significantly associated with STK11 mutation but was significantly reduced in tumors with chr19 deletion when controlling for tumor type and overall copy number load. In addition, low-level deletion of any of these genes correlated with decreased expression of immune signaling pathways.

Based on these findings, we next wanted to characterize the association between chr19p copy number and immunotherapy response. We previously reported that low-level deletion of STK11 correlated with an immunosuppressive, treatment-refractory phenotype in samples collected from non-small cell lung cancer (NSCLC) patients with resectable disease in a phase II study of neoadjuvant atezolizumab + chemotherapy. To confirm these findings in a larger cohort, we examined the AACR GENIE NSCLC biopharma collective (BPC) dataset. A subset of this cohort included patients treated with immunotherapy (atezolizumab, nivolumab, and/or pembrolizumab) and with copy number data available or GISTIC analysis of individual genes (n = 204). Here, deletion of any of these three genes correlated with worse overall survival, and this was statistically significant for STK11 deletion. Overall, our data suggests that a broader set of patients, defined by copy number changes in these genes, may experience this adverse immunobiology. Further study to elucidate the mechanistic implications of this association is warranted.

Citation Format: Brian S. Henick, Yohanna Georgis, Benjamin O. Herzberg, Carla P. Concepcion-Crisol, Alison M. Taylor. Copy number alterations in chromosome 19 genes associate with reduced immune infiltrate and adverse outcomes in lung 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 3634.
Abstract 3646: A spatially resolved single cell proteomic atlas of small bowel adenocarcinoma
Authors: Dereli Zeynep , Bozorgui Behnaz , Wang Huamin , Weinstein John , Overman Michael , Korkut Anil
Published: March 2024

Small bowel adenocarcinoma (SBA) is a rare malignancy associated with poor prognosis. The cellular and proteomic heterogeneity within the tumor immune microenvironment (TIME) of SBA is a likely driver of prognosis, disease progression and response to therapy. There is, however, a major gap in our knowledge of tumor and immune interactions in SBA. Cyclic Immunofluorescence (CycIF), an antibody-based, highly multiplexed imaging technology for spatially resolved single cell level proteomic profiling, is well suited to map the proteomic heterogeneity and organization of TIME in SBA. Here, using CycIF, we have generated a spatially resolved single-cell proteomic atlas of TIME for 136 tumor and normal samples from clinically and genomically annotated SBA patients (N=37). The SBA TIME Atlas covers information on expression levels, spatial position, and cell morphology for > 40 proteomic markers of tumor-intrinsic processes and states, diverse immune cell types, immune checkpoints, and tumor vascularization. In total, we collected proteomics data from > 600,000 cells. Using a hierarchical decision tree of cell type markers, we have generated the cell identity annotations for > 350,000 cells, with positional information. A comprehensive computational analysis of the SBA atlas revealed various spatial and heterogeneity features that may impact the TIME organization in fine detail. Using those features, we have compared the proteomic heterogeneity in tumor vs. normal cell populations, identifying spatial and single-cell correlates of key clinical variables (e.g., patient survival, age, sex, disease stage, metastatic status). We have also performed differential analyses of spatial features involving protein markers and cell types with respect to genomic alteration states and have mapped the spatial enrichment of likely actionable immune check proteins to immune and tumor cells. Such mapping may guide future therapeutic decisions. Overall, we expect that the SBA TIME Atlas will provide a useful resource and inform future translational studies, as well as basic research for better mechanistic understanding and treatment of this disease.

Citation Format: Zeynep Dereli, Behnaz Bozorgui, Huamin Wang, John Weinstein, Michael Overman, Anil Korkut. A spatially resolved single cell proteomic atlas of small bowel adenocarcinoma [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 3646.
Abstract 3685: Improved detection of minimal residual disease in colorectal cancer patients using adaptive noise cancellation algorithm
Authors: Bao Hua , Tang Wanxiangfu , Li Ningyou , Wu Min , Zhang Jinfeng , Zhu Baihan , Wu Xue , Shao Yang
Published: March 2024

Objective: Existing methods for detecting circulating-tumor DNA (ctDNA) through fixed panels exhibit constrained sensitivity, while customized panels are time-consuming and rely on prerequisite tumor mutation profiles. Here, we aimed to introduce an adaptive noise cancellation approach for efficient Minimal Residuals Disease (MRD) detection in colorectal cancer patients employing a fixed panel under both tumor-informed and tumor-naïve situations.

Methods: 108 plasma samples were collected from 52 colorectal cancer patients (11 relapse, 41 non-relapse) at various post-surgical timepoints. Comprehensive mutational profiling of plasma samples was conducted using a fixed MRD panel (SHIELDINGTM ULTRA) that encompasses hotspots in 2365 cancer-related genes. Background errors were removed by an adaptive noise cancellation algorithm relying on DNA fragment profiling, normal pool, and white blood cell background and intra-run plasma sampling. Variants were called both with (tumor-informed) and without (tumor-naïve) the present of tumor tissue.

Results: Our longitudinal analysis of 108 plasma samples yielded 90.9% sensitivity, 97.6% specificity and 97.6% negative predictive value in the tumor-informed scenario. The ctDNA positive patients exhibited significantly higher risk than those with negative ctDNA status (Hazard Ratio = 87.2, p = 3.5 × 10^(-5)). For landmark analysis, 33 plasma samples (≤7 days post-operation) were assessed, yielding a remarkable performance of 66.7% sensitivity and 100% specificity. Our approach showed robustness under tumor-naïve scenario, illustrating 90.9% sensitivity, 92.7% specificity and 97.4% NPV for the longitudinal analysis. This corresponded to an increased risk of 49 times in the ctDNA positive patients (HR = 49.0, p = 2.2 × 10^(-4)). Notably, the results of tumor-naïve samples closely aligned with those of tumor-informed samples, showing a concordance of 92.6% and substantial agreement (Cohen’s Kappa = 0.691).

Conclusion: Our method stands as an ultra-sensitive tool for identifying colorectal patients at high risk of recurrence. By employing an adaptive noise cancellation algorithm, our fixed panel approach demonstrates superiority over existing fixed panels in accuracy and proves to be a cost-effective alternative to personalized panels. Significantly, it extends potential clinical utilization towards tumor-naïve patients, which is not feasible for personalized panels.

Citation Format: Hua Bao, Wanxiangfu Tang, Ningyou Li, Min Wu, Jinfeng Zhang, Baihan Zhu, Xue Wu, Yang Shao. Improved detection of minimal residual disease in colorectal cancer patients using adaptive noise cancellation algorithm [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 3685.
Abstract 3745: Metabolomic profiling of lipid and metabolite in cirrhosis patients with and without hepatocellular carcinoma
Authors: Powell Hannah , Ruiz Elisa , Grimm Sandra L. , Najjar Omar , Olivares Luis , Scheurer Michael , Serag Hashem B. El , Coarfa Cristain , Kaochar Salma
Published: March 2024

Early detection of hepatocellular carcinoma (HCC) is crucial for improving patient outcomes, as curative treatments are most effective at the early stages of the disease. The lack of robust biomarkers, particularly a non-invasive diagnostic tool, precludes significant improvement of clinical outcomes for HCC patients. Serum metabolites are one of the best non-invasive means for determining patient prognosis. Established biomarkers for HCC including alpha-fetoprotein (AFP), have shown suboptimal performance in early disease stages. This study aimed to develop a combined metabolite and lipid panel to differentiate early-stage HCC from cirrhosis. Unbiased metabolomic and lipidomic analyses of serum samples were performed for 28 and 30 patients with early HCC and cirrhosis, respectively. We developed an unbiased high-resolution liquid chromatography mass spectrometry (LC-MS) based metabolic profiling platform and evaluated differences in the serum global metabolome and lipidome. This method enabled the detection of over 1200 metabolites and up to 800 lipid molecules in this select cohort. We identified 124 metabolites and 246 lipids that were upregulated and 208 metabolites and 73 lipids that were downregulated in HCC compared to cirrhosis. Using multiomic integrative analysis, we identified the overlap between differentially expressed metabolites and lipid and previously published transcriptomic signatures and illustrate that the overlapping signature associates with clinical disease progression. Lastly, we leveraged machine learning models to identify a minimal panel of lipids and metabolites that accurately distinguish between cirrhosis patients with HCC and without HCC. The best performing classifier was derived using Support Vector Machines, achieving a median AUC of 0.98 over 100 cross-validation iterations, and we showed that we need as little as 12 metabolite and lipids for effective discrimination between cirrhosis and early HCC.

Citation Format: Hannah Powell, Elisa Ruiz, Sandra L. Grimm, Omar Najjar, Luis Olivares, Michael Scheurer, Hashem B. El Serag, Cristain Coarfa, Salma Kaochar. Metabolomic profiling of lipid and metabolite in cirrhosis patients with and without hepatocellular carcinoma [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 3745.
Abstract 3755: Impact of antigen retrieval and other parameters on detection of FGFR2b in various solid tumors on a BenchMark ULTRA automated staining platform: Development of a new IHC assay for FGFR2b
Authors: Watson Autumn Sky , Le Catherine , Wertheimer Anne M. , Escobedo Spencer , So Lisa , Siddegowda Bhavani Bagevalu , Palting John D. , Marion Susan , Stratton Steven P. , Aggeler Birte
Published: March 2024

Background: Fibroblast growth factor receptor 2b (FGFR2b) is part of the FGFR transmembrane tyrosine kinase receptor family. This protein has gained more attention in recent years as a tumor progression biomarker in numerous solid tumors. The detection of FGFR2b by immunohistochemistry (IHC) has been used recently in immunotherapy clinical trials with multiple tumor types. During IHC assay development on formalin-fixed paraffin embedded tissue, a thorough study of antigen retrieval through cell conditioning or enzyme incubation, primary antibody incubation, and detection parameters is critical to evaluate staining performance.

Design: A study of an investigational anti-FGFR2b (FPR2-D) assay developed on a BenchMark ULTRA automated staining platform explored the effect of antigen retrieval and detection parameters on staining performance. VENTANA System Software was used to modify steps in the IHC staining protocol resulting in 42 permutations. Ten different solid tumors were stained with these modifications to the assay and subsequently evaluated for FGFR2b expression.

Result:s The results demonstrate that the staining clarity, intensity, and dynamic range within tissue cases of FGFR2b staining can vary widely between different solid tumor types. While most permutations of the initial assay parameters had minimal impact on the staining performance and readability by a pathologist, the order of the enzyme treatment and the cell conditioning steps (in addition to increased incubation time of primary antibody) had a significant impact when comparing across different solid tumors. Detection of FGFR2b seemed to have a greater susceptibility by tumor type to the antigen retrieval process than has traditionally been observed in other biomarkers.

Conclusion: The overall results of this investigation show the importance of an extensive parameter screening approach when evaluating new antibody targets and indication combinations in IHC to ensure optimal staining performance. This is critical to downstream testing and the potential use of new assays in the context of in vitro diagnostics.

Citation Format: Autumn Sky Watson, Catherine Le, Anne M. Wertheimer, Spencer Escobedo, Lisa So, Bhavani Bagevalu Siddegowda, John D. Palting, Susan Marion, Steven P. Stratton, Birte Aggeler. Impact of antigen retrieval and other parameters on detection of FGFR2b in various solid tumors on a BenchMark ULTRA automated staining platform: Development of a new IHC assay for FGFR2b [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 3755.
Abstract 3768: Optimization of digital pathology through laser capture microdissection with a 405 nm laser
Authors: Philipson Thomas , Howard Marissa , Johnson Kevin , Still Amanda , Yunusov Furkat , Petricoin Emanuel , Espina Virginia , Gonzalez Noel , Carpino Alan , Liotta Lance
Published: March 2024

Tumor cellular heterogeneity is a complex problem in cancer molecular diagnostics and personalized therapy. The tumor is a product of the different types and interactions of host and immune cells. Investigators have created a variety of methods to procure separate subpopulations of the tumor microenvironment for individual analysis. One of the most successful methods of this is laser capture microdissection (LCM). This method captures specific subpopulations of cells under direct microscopic visualization. This LCM technology has successfully been used for over 20 years, revealing a variety of insights into cancer pathogenesis and mechanisms of therapeutic response employed in numerous clinical trials. Nevertheless, there are two drawbacks to the current systems. For UV cutting (365 nm), the tissue is significantly damaged by the UV light energy. Infrared (808 nm) laser systems do not damage the tissue however, this method has low power and poor resolution. Our first hypothesis to be tested is that a new class of near UV 405 nm laser will have small capture areas approaching single cells while simultaneously preventing cellular damage. The second weakness of LCM is the requirement for an open-faced tissue section without a coverslip. Moreover, when visualizing the tissue of interest, the identification of regions of interest is obscured due to the refractive index mismatch between the laser microdissection cap and the tissue surface. We hypothesize that using a volatile organic compound with a refractive index similar to glass would elucidate the tissue region of interest to allow proper visualization. We successfully developed and tested a near 405 nm wavelength LCM system that utilizes a “liquid” coverslip to visualize the sample of interest with higher clarity, resolution, and contrast for immunohistochemistry, immuno-fluorescence, blood smear slides, and conventional hematoxylin-eosin tissue staining. Overall, these critical improvements LCM technology now allow for single-cell tissue capture, system automation, tissue visualization, and opens the door for artificial intelligence-assisted spatial profiling.

Citation Format: Thomas Philipson, Marissa Howard, Kevin Johnson, Amanda Still, Furkat Yunusov, Emanuel Petricoin, Virginia Espina, Noel Gonzalez, Alan Carpino, Lance Liotta. Optimization of digital pathology through laser capture microdissection with a 405 nm laser [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 3768.
Abstract 3782: IASLC grading system predict distant metastases for resected lung adenocarcinoma
Authors: Wang Yuezhu , Smith Margaret R. , Liu Yin , Green Mary E. , Hassan Omer A. , Balmaceda Alexandra M. , Sexton Tammy , Li Wencheng , Xing Fei
Published: March 2024

The International Association for the Study of Lung Cancer (IASLC) proposed a new histological grading system for invasive lung adenocarcinoma (LUAD). However, whether this new grading system is able to predict distant metastases in LUAD patients has not been evaluated. This study investigated the feasibility of using this grading system to predict the occurrence of brain and bone metastases in patients with resectable LUAD which identifies patients who have a high probability of developing distant metastases after surgery. We collected clinical information and pathological reports of 179 early stage LUAD patients who underwent resection during 2008 to 2015 from Wake Forest Comprehensive Cancer Center. All patients were followed up for 5 years and both bone and brain metastasis-free survival were calculated. Tumor grading of all samples was evaluated by both IASLC grading and predominant pattern-based grading systems. The ability of predicting distant metastases using IASLC grading and tumor stage were examined by receiver operating characteristic curves (ROC). 28 out of 179 patients developed distant metastases in five years with a median overall survival of 60 months for metastasis-free patients and 38.9 for patients with distant metastasis. Compared to predominant pattern-based grading system, IASLC grading system showed a stronger correlation with distant metastasis incidence. Complex gland pattern is enriched in patients who developed bone and brain metastases compared to metastasis-free patients. IASLC grading system also showed a superior prediction power of distant metastasis compared to tumor stage with area under curve (AUC) of 0.69 for brain metastasis and 0.71 for bone metastasis. IASLC grading system is capable of predicting the incidence of distant metastasis among early-stage invasive LUAD patients.

Citation Format: Yuezhu Wang, Margaret R. Smith, Yin Liu, Mary E. Green, Omer A. Hassan, Alexandra M. Balmaceda, Tammy Sexton, Wencheng Li, Fei Xing. IASLC grading system predict distant metastases for resected lung adenocarcinoma [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 3782.
Abstract 3826: Predictive and prognostic factors in NUT carcinoma: A systematic review and individual patient data meta-analysis
Authors: Abdulwali Sameeha K. , El-Sibai Abduljalil M. , Ali Saad S. , Alaklabi Abdulaziz M. , Abdalla Hytham M. , Sabbah Ahmad N. , Shafqat Areez , Fawzy Nader A. , Sabbah Belal N. , Badran Ahmed , Arabi Tarek Z.
Published: March 2024

Background: NUT carcinoma (NC) is a rare cancer affecting midline structures and involving the lung, bones, and lymph nodes. Data on NC are limited mostly to case reports and case series.

Methods: PubMed, Web of Science, and Scopus were systematically searched for original articles describing confirmed NC patients. A quantitative individual patient data meta-analysis (IPD-MA) analyzing overall survival and risk factors for progression was performed for all NC patients with a clear age at diagnosis. Relevant patient characteristics and clinical parameters were compared in a multivariate Cox regression model.

Findings: Out of 4,701 studies screened, 175 studies met the inclusion criteria for the systematic review. 117 (66.9%) were case reports. 284 patients were included in the IPD-MA. 139 (48.9%) patients were male, 145 (51.1%) underwent surgery, 156 (54.9%) received radiotherapy, and 173 (60.9%) developed metastasis. The mean age at diagnosis was 35.82±18.33 and the median OS was 9 months. 77 (27.1%) patients received platinum-based agents, 39 (13.7%) received taxanes, and 15 (5.3%) received BET inhibitors as part of their first-line regiment. Age at diagnosis, gender, and the aforementioned drugs did not significantly influence OS. Presence of metastasis was an independent predictor of poor survival, while radiotherapy and surgery were significantly associated with better survival (table 1).

Interpretation: NC is associated with poor survival. Surgery and radiotherapy appear to be more effective treatment strategies, while medical modalities may not play a major role in the treatment of NC.

Predictors of overall survival in NUT carcinoma patients. Parameter Hazard ratio 95% confidence interval P-value Age at diagnosis 0.99 0.99-1 0.35 BET inhibitors 0.61 0.28-1.15 0.16 Platinum-based agents 0.73 0.47-1.13 0.16 Taxanes 1.29 0.78-2.1 0.31 Surgery 0.41 0.29-0.58 <0.0001 Female gender 1.12 0.83-1.51 0.45 Metastasis 1.76 1.26-2.49 0.0011 Radiotherapy 0.48 0.36-0.67 <0.0001

Citation Format: Sameeha K. Abdulwali, Abduljalil M. El-Sibai, Saad S. Ali, Abdulaziz M. Alaklabi, Hytham M. Abdalla, Ahmad N. Sabbah, Areez Shafqat, Nader A. Fawzy, Belal N. Sabbah, Ahmed Badran, Tarek Z. Arabi. Predictive and prognostic factors in NUT carcinoma: A systematic review and individual patient data meta-analysis [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 3826.
Abstract 3859: HSP90 blockade activates antitumor immunity by suppressing tumor glycolytic flux in head and neck squamous cell carcinoma
Authors: Chen Fanghui , Tang Chris , Yang Fan , Ekpenyong Asari , Qin Richard , Saba Nabil F. , Teng Yong
Published: March 2024

Accumulating evidence suggests that failure of antitumor immunity may be due to dysregulation of energy metabolism. Head and neck squamous cell carcinoma (HNSCC) exhibits increased activity of two key enzymes, pyruvate kinase M2 (PKM2) and platelet phosphofructokinase (PFKP), which are central to the glycolytic pathway responsible for the conversion of glucose to ATP energy. HSP90 is a molecular chaperone that plays a critical role in the folding, stabilization, and regulation of a wide range of client proteins involved in various cellular processes, including metabolism. However, whether HSP90 signaling contributes to tumor metabolism rewiring and antitumor immune response remains unknown. Using ganetespib as a drug model for HSP90 inhibition and combining results from clinical trials and animal treatment, our study demonstrated that HSP90 inhibition causes an obstruction of glycolytic flux in HNSCC cells by simultaneously suppressing both PKM2 and PFKP at the transcriptional and post-translational levels. In addition, ganetespib enhances T cell-driven antitumor immune responses by promoting CD8+ T cell infiltration into the tumor. Mechanistically, ganetespib downregulates IL8 signaling by inhibiting PKM2 and PFKP-mediated glycolysis in HNSCC cells, which in turn contributes to ganetespib-mediated T cell tumor infiltration. These findings provide a novel molecular basis for the use of effective HSP90 inhibitors to improve the outcome of HNSCC patients.

Citation Format: Fanghui Chen, Chris Tang, Fan Yang, Asari Ekpenyong, Richard Qin, Nabil F. Saba, Yong Teng. HSP90 blockade activates antitumor immunity by suppressing tumor glycolytic flux in head and neck squamous cell carcinoma [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 3859.
Abstract 3866: Azvudine: An emerging immunomodulator in the treatment of cancer and viral infections
Authors: Li Pan , Jia Limin , Wang Zhaoyang , Du Jinfa
Published: March 2024

Azvudine (FNC) is a nucleoside analog that has secured approval from the CDE in China for the treatment of both AIDS and COVID-19. In these contexts, it has showed remarkable efficacy and safety when taken orally. Typically, nucleoside analog drugs function by integrating into DNA and impeding DNA synthesis, evident in drugs like 5-FU, Capecitabine, Ara-C, and Gemcitabine. Furthermore, FNC has been reported to exhibit robust anti-tumor properties, curbing cell proliferation, initiating G1 and S phase arrests, and advancing apoptosis across various human cancer cell lines. Grounded in this mode of action, we have ascertained that the anti-tumor effects of FNC intricately align with the expression of deoxycytidine kinase (dCK) both in vitro and in vivo. Remarkably, our studies delved into the effects and underlying mechanisms of FNC in enhancing the tumor microenvironment within solid tumors. Our findings, stemming from cell-based assays and in vivo animal experiments, elucidate the following: 1. FNC can trigger immunogenic cell death (ICD) in tumor cells. This is evidenced by the surface presentation and liberation of damage-associated molecular patterns (DAMPs) such as Calreticulin, HSP70, HSP90, Annexin A1, and HMGB1, which in turn stimulate both innate and adaptive immune responses. 2. FNC substantially reduces the population of monocytic-myeloid derived suppressor cells (M-MDSC) and Polymorphonuclear-myeloid derived suppressor cells (PMN-MDSC) in the tumor microenvironment. Concurrently, it boosts the infiltration and proliferation of CD8+T, CD4+T and NK cells. This instigates the transformation of the tumor microenvironment from a 'cold' state to a 'hot' one, enhancing the synergistic effects of PD-1 when used in tandem with FNC. This mechanism was substantiated through a high proportion of MDSCs observed in H22 and CT-26 syngeneic models, and contrastingly, a low proportion in MC38 and LL/2 in vivo syngeneic models. Notably, every animal subjected to combined FNC and PD-1 treatment in the H22 and CT-26 in vivo models witnessed complete tumor regression. Given these revelations, there's a compelling argument that FNC monotherapy possesses immense potential as an anti-tumor agent. The potent anticancer effects of FNC in vitro and in vivo warrants further investigation of its anticancer potential as immunomodulator.

Citation Format: Pan Li, Limin Jia, Zhaoyang Wang, Jinfa Du. Azvudine: An emerging immunomodulator in the treatment of cancer and viral infections [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 3866.
Abstract 391: Role of NRF2 in HIF-2α-mediated cancer stem cell phenotype
Authors: Kwak Mi-Kyoung , Hallis Steffanus P.
Published: March 2024

The acquisition of cancer stem cell (CSC) properties is influenced by the microenvironment, with tumor hypoxia playing a pivotal role. Elevated levels of nuclear factor erythroid 2-like 2 (NRF2), a redox balance-maintaining transcription factor, have been linked to enhanced tumor growth and therapy resistance. This study investigates the potential role of NRF2 in hypoxia-inducible factor-2α (HIF-2α) regulation in cancers. First, in a model of a 72-hour hypoxic incubation, chronic hypoxia led to CSC characteristics, including increased expression of KLF4 and OCT4, heightened cancer migration, and spheroid growth, which are associated with HIF-2α accumulation. NRF2 inhibition mitigated these effects, while NRF2 activation enhanced chronic hypoxia-induced CSC traits. Mechanistically, NRF2/miR181a-2 signaling emerged as a regulator of HIF-2α-mediated CSC phenotypes in chronic hypoxic conditions. Second, in clear cell renal cell carcinoma (ccRCC), characterized by pVHL gene mutation and constitutive HIF-2α elevation, the role of NRF2 in aggressive cancer phenotypes was explored. Silencing of NRF2 impaired aggressive phenotypes in multiple ccRCC cell lines with a reduction in HIF-2α expression. Promoter analysis elucidated that NRF2 directly upregulates HIF-2α expression through antioxidant response elements in the human HIF-2α gene. Collectively, our study suggests the involvement of NRF2/miR181a-2 signaling in the development of HIF-2α-mediated CSC phenotypes in sustained hypoxic environments and also proposes NRF2 as a promising target for mitigating HIF-2α-mediated CSC traits in ccRCC.

Citation Format: Mi-Kyoung Kwak, Steffanus P. Hallis. Role of NRF2 in HIF-2α-mediated cancer stem cell phenotype [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 391.
Abstract 3921: The aged tumor microenvironment limits CD8+ T cell control of cancer
Authors: Chen Alex C.Y. , Jaiswal Sneha , Martinez Daniela , Yerinde Cansu , Ji Keely , Miranda Velita , Fung Megan E. , Weiss Sarah A. , Zschummel Maria , Taguchi Kazuhiro , Garris Christopher S. , Mempel Thorsten R. , Sen Debattama R.
Published: March 2024

Aging is associated with progressive loss of immune function, which parallels the rise in cancer incidence. The etiology and impact of age-related CD8+ T cell dysfunction in cancer remain poorly understood. Here, we demonstrate that increased tumor growth in aged hosts is associated with reduced CD8+ T cell infiltration and function. The transfer of young antigen-specific CD8+ T cells fails to restore tumor control in aged hosts due to the rapid induction of CD8+ T cell dysfunction. The aged tumor microenvironment drives a novel age-associated dysfunctional state (TADys) that is functionally, transcriptionally, and epigenetically distinct from canonical CD8+ T cell exhaustion. Overall, this study focuses on understanding the cell-intrinsic and -extrinsic effects on CD8+ T cell immunity in aging and explores a proper strategy to improve CD8+ T cell control of cancer.

Citation Format: Alex C.Y. Chen, Sneha Jaiswal, Daniela Martinez, Cansu Yerinde, Keely Ji, Velita Miranda, Megan E. Fung, Sarah A. Weiss, Maria Zschummel, Kazuhiro Taguchi, Christopher S. Garris, Thorsten R. Mempel, Debattama R. Sen. The aged tumor microenvironment limits CD8+ T cell control of 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 3921.
Abstract 3930: The therapeutic implications of consensus genomic subtypes of gastric adenocarcinoma
Authors: Jeong Yun Seong , Eun Young-Gyu , Lee Sung Hwan , Kang Sang-Hee , Yim Sun Young , Kim Eui Hyun , Noh Joo Kyung , Sohn Bo Hwa , Lee Ju-Seog
Published: March 2024

Background: Gastric adenocarcinoma (GAC) is heterogeneous lethal disease in genomic and clinical level. Although the clinical relevance of genomic and molecular subtypes of GAC has been demonstrated, differences in classification methods have made it difficult to use these findings in clinical applications. We aim to examine a consensus of genomic subtypes and correlate them with clinical outcomes.

Method: We collected genomic data from 2527 GAC tumors and divided the data into discovery (n = 1427) and validation sets (n = 1100). A cluster of clusters approach (COCA) was used to find consensus subtypes of gastric tumors. We constructed the GAC predictor of the integrated consensus subtype with 120 genes (GPICS120) and applied it to the validation data set in order to validate the clinical significance of the new subtypes. By analyzing genomic and proteomic data we evaluated each subtype's potential response rate to standard and experimental treatments such radiation therapy, targeted therapy, and immunotherapy and further validated their functional significance in cell line models.

Results: We identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs) by integrating 8 previously established genomic subtypes. CGS1 is characterized by worst prognosis, remarkably high stem cell characteristics, high IGF1 expression, and low genomic alterations. CGS2 showed canonical epithelial gene expression patterns. CGS3 and CGS4 are characterized by high copy number alterations and low immune activity. CGS5 has highest mutation burden and moderately elevated immune activity that is characteristics of MSI-high tumors. The majority of CGS6 tumors have extremely high methylation, high immune activity, and are EBV-positive. The most intriguing finding is that CGS1 is the most responsive to immunotherapy whereas CGS3 is significantly associated with benefit of chemoradiation therapy due to high basal level of ferroptosis. Furthermore, we showed that ferroptosis inducer statin sensitized radiation-resistant GAC cells to ionizing radiation, suggesting that statin can be used to enhance the efficacy of chemoradiation in GAC and it would warrant further investigation in preclinical models.

Conclusion: Consensus subtype is robust classification system and can serve as the basis for future clinical trials as well as pre-clinical research into targeted subtype-based therapies.

Citation Format: Yun Seong Jeong, Young-Gyu Eun, Sung Hwan Lee, Sang-Hee Kang, Sun Young Yim, Eui Hyun Kim, Joo Kyung Noh, Bo Hwa Sohn, Ju-Seog Lee. The therapeutic implications of consensus genomic subtypes of gastric adenocarcinoma [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 3930.
Abstract 4014: Humanized mouse model to assess PBMC donor derived autologous CD19 CAR Ts for efficacy against Raji tumors and related cytokine release
Authors: Ramalingam Senthil , Cai Danying , Shopland Lindsay , Keck James G.
Published: March 2024

Immuno-oncology cell therapies engage the immune system to treat cancer. In recent years, adoptive T-cell therapy with CD19-specific chimeric antigen receptors (CARs) has shown promise for treatment of various malignancies, including acute lymphoblastic leukemia. However, CAR-T-cell therapies have been hampered by various adverse events, including cytokine release syndrome (CRS). To predict and minimize CRS effects from CAR-T therapies, a human immune preclinical murine model that combines efficacy and toxicity readouts is essential. Here, we describe the development of PBMC humanized mouse model based on the NSG-MHC I/II-DKO strain to study autologous CD19 CAR-T treatment related tumor growth inhibition and CRS in vivo. Three different PBMC donors were used to generate CAR-T (CD28-Cd3z) directed against a CD19 epitome. Our preliminary data demonstrate that CD19 CAR-T treatment stimulated dynamic and PBMC donor dependent cytokine release with IFN-g, IL-10, IL-4, IL-2, IL-6 and TNF. Our model showed elevation of shared proinflammatory cytokines (IFN-g, IL-10, IL-2 and TNF) observed in humans after CD19 CAR-T treatment. Currently, we are evaluating our PBMC based cytokine release model in CD19 CAR-T cells tumor control study. Our results to date indicate that PBMC-engrafted NSG-MHC I/II-DKO mouse models are vital platforms to screen adoptive T-cell therapy for potential CRS.

Citation Format: Senthil Ramalingam, Danying Cai, Lindsay Shopland, James G. Keck. Humanized mouse model to assess PBMC donor derived autologous CD19 CAR Ts for efficacy against Raji tumors and related cytokine release [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 4014.
Abstract 4028: Inhibition of IL25 IL17RA improves immune related adverse events of checkpoint inhibitors and reveals antitumor activity
Authors: Hu Xizi , Bukhari Shoiab , Tymm Carly , Adam Kieran , Lerrer Shalom , Henick Brian , Winchester Robert , Mor Adam
Published: March 2024

Immune checkpoint inhibitors (ICI) have improved outcomes and extended patient survival in several tumor types. However, ICI often induces immune-related adverse events (irAEs) that warrant therapy cessation, thereby limiting the overall effectiveness of this class of therapeutic agents. Currently, available therapies used to treat irAEs might also blunt the antitumor activity of the ICI themselves. Therefore, there is an urgent need to identify treatments that have the potential to be administered alongside ICI to optimize their use. Using a translationally relevant murine model of anti-PD-1 and anti-CTLA-4 antibodies-induced irAEs, we compared the safety and efficacy of prednisolone, anti-IL-6, anti-TNFɑ, anti-IL-25 (IL-17E), and anti-IL-17RA (the receptor for IL-25) administration to prevent irAEs and to reduce tumor size. While all interventions were adequate to inhibit the onset of irAEs pneumonitis and hepatitis, treatment with anti-IL-25 or anti-IL-17RA antibodies also exerted significant additional antitumor activity. Mechanistically, IL-25/IL-17RA blockade reduced the number of organ-infiltrating lymphocytes. These findings suggest that IL-25/IL-17RA may serve as an additional target when treating ICI-responsive tumors, allowing for better tumor control while suppressing immune-related toxicities.

Citation Format: Xizi Hu, Shoiab Bukhari, Carly Tymm, Kieran Adam, Shalom Lerrer, Brian Henick, Robert Winchester, Adam Mor. Inhibition of IL25 IL17RA improves immune related adverse events of checkpoint inhibitors and reveals antitumor activity [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 4028.