bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2448: Field cancerization proteomic analysis provides a novel class of functional risk biomarkers for non small cell lung cancer
Authors: Alhammad Rayan Ibrahim , Vuong Ngoc Bao , Zhou Weidong , Johann Donald J , Birkaya Barbara , Liotta Lance , Luchini Alessandra 
Published: March 2024

Abstract
Lung cancer carcinogenesis is the outcome of a field of premalignant changes that occur in the bronchial tree leading to the overt emergence of the malignant lung cancer (field cancerization). A tissue or blood proteomic signature of these premalignant changes represent a novel concept of risk biomarkers that can predict the probability of future emergence of Lung Cancer. In this study, we analyzed two independent cohorts of non-small cell lung cancer (NSCLC) patients. One cohort consisted of 18 patients who donated blood before and after tumor resection surgery and matched tissue samples (UAMS Medical Center). The second set derived from a longitudinal case-control study of plasma sample collected during the physician health study that were donated at different times prior to the diagnosis of Non-Small Cell Lung Cancer (N=272). We used affinity-enriched mass spectrometry analysis and statistical learning techniques to identify a set of common markers that discriminated plasma cases and controls and were conserved in different bronchial tissue compartments including tumor and adjacent tissue. The tumor microenvironment adjacent to and surrounding cancer cells undergoes to progressive stages of carcinogenesis during field cancerization. We identified 22 proteins involved in cell adhesion, protein folding, immune response, angiogenesis, and cancer proliferation. This is a novel class of functional risk biomarkers to determine the probability of NSCLC onset. In conclusion, our findings shed light on a new class of functional biomarkers that underly tumor pathogenesis mechanisms and can provide hints for new strategies of tumor prevention therapy or lifestyle modification.
Citation Format: Rayan Ibrahim Alhammad, Ngoc Bao Vuong, Weidong Zhou, Donald J Johann Jr, Barbara Birkaya, Lance Liotta, Alessandra Luchini. Field cancerization proteomic analysis provides a novel class of functional risk biomarkers for non small cell 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 2448.
Abstract 2529: Comparison of small cell lung cancer transcriptional factor expression by immunohistochemistry, multiplex immunofluorescence, and a targeted RNA expression panel
Authors: Ozakinci Hilal , Alontaga Aileen , Nguyen Jonathan V , Segura Carlos M Moran , Saeed-Vafa Daryoush , Gray Jhanelle , Haura Eric , Chiappori Alberto A , Boyle Theresa 
Published: March 2024

Abstract
Recent studies have identified distinct molecular subtypes of small cell lung cancer (SCLC) (SCLC-A, SCLC-N, SCLC-P, and SCLC-Y) based on ASCL1, NEUROD1, POU2F3, and YAP1 expression. In this study, we investigated the correlation between immunohistochemistry (IHC), multiplex immunofluorescence (mIF), and RNA Salah Targeted Expression Panel (RNA STEP) for ASCL1, NEUROD1, POU2F3, and YAP1 in formalin-fixed-paraffin-embedded (FFPE) samples from 14 SCLC samples collected under an IRB-approved protocol (MCC19163). For the mIF evaluation, FFPE samples were immunostained using the AKOYA Biosciences OPAL TM 7-Color Automation IHC kit on the BOND RX autostainer. For RNA STEP, nanoString nCounter TagSet chemistry was used to measure gene expression levels of test FFPE samples relative to a reference pooled human normal mRNA control. All three methods demonstrated significant correlation for ASCL1 levels (Table 1). IHC and RNA STEP NEUROD1 results exhibited significant correlation. However, mIF NEUROD1 results did not correlate with the results of other methods likely due to non-specific positivity of the NEUROD1 mIF antibody. No strong correlation was observed between any of the methods for POU2F3 and YAP1. Only 2 of the 14 samples displayed positive POU2F3 protein expression by IHC; one of these also had elevated POU2F3 expression by RNA STEP. Importantly, the sample with the highest POU2F3 protein expression by IHC also had the highest values by mIF and RNA STEP. All samples were negative for YAP1 by IHC and RNA STEP. Notably, ASCL1 staining was primarily observed in CD56+ POU2F3- cells by mIF. These findings highlight the reliability and utility of IHC and RNA STEP in assessing transcriptional factors in SCLC. Also, mIF presents an innovative method for the simultaneous analysis of multiple markers using a single tissue section, enabling the concurrent detection of multiple markers within individual cells.
Table 1. Statistical Significance (p-values) and Correlation Analysis (Spearman's Coefficients) IHC vs RNA STEP IHC vs mIF RNA STEP vs mIF p r P r p r ASCL1 0.021 0.62 &lt;0.0001 0.91 0.010 0.67 NEUROD1 0.002 0.78 0.517 -0.14 0.671 0.12 POU2F3 0.201 0.36 0.422 0.18 0.045 0.55 YAP1 0.299 0.30 0.364 0.20 0.295 0.30
Citation Format: Hilal Ozakinci, Aileen Alontaga, Jonathan V Nguyen, Carlos M Moran Segura, Daryoush Saeed-Vafa, Jhanelle Gray, Eric Haura, Alberto A Chiappori, Theresa Boyle. Comparison of small cell lung cancer transcriptional factor expression by immunohistochemistry, multiplex immunofluorescence, and a targeted RNA expression panel [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 2529.
Abstract 2563: Understanding the new subgroup- Her 2 low breast cancer
Authors: Kulkarni Radhika , Shahid Muhammad Ali , Castro Oscar Hinojosa , Patel Kunj , Lin Chun-Hui , Rose Courtney , Dabak Vrushali 
Published: March 2024

Abstract
Introduction: Outcomes have greatly improved for patients with HER2+ breast cancer. Recently, tumors with IHC 1+ or 2+/negative FISH have been classified as ‘HER2-low’. The development of novel HER2 agents has shown clinical benefit in this subset of patients. Information on the clinical characteristics of these patients which could be prognostic, and which could impact therapeutic options is limited.
Methods: This was an IRB-approved study. Relevant patient demographics, disease characteristics, and treatment details of patients with metastatic breast cancer seen at our center from 2018 to 2021 were collected by chart review. All data analyses were performed using R version 4.3.1, and a p-value ≤ 0.05 was considered statistically significant.
Results: A total of 102 patients with metastatic breast cancer were included. Patients were divided as HER2+, HER-, HER2 low ER+ and HER2 low ER -. 66.6% of patients had HER2 low disease. Patients with HER2 low ER- disease were more likely to have tumors that were of higher grade (grade 3, 71.4%, p=0.003), higher mean Ki67 (60%, p&lt;0.001), and of ductal histology (100%, p=0.006). There was a statistically significant difference in PFS among the four groups (p=0.001). Median survival was longer in patients with HER2 low ER+ compared to the HER2- group. (1.42 vs 0.58, p&lt;0.001, Table 1). Amongst HER2 low ER+ patients, there was a significant PFS difference in those treated with CDK4/6 inhibitors compared to chemotherapy (2.83 vs. 0.67, p=0.009). We found no difference in PFS between patients who were HER2 1+ ER+ and HER2 2+ ER+. In multivariate analysis, there was no significant association of race, grade, menopausal status, Ki67, histologic subtype, and metastatic sites with PFS.
Table 1. PFS Summary Group Total number Progression/Death Median Survival HER2- 13 13 0.58 HER2 low ER- 14 11 0.88 HER2 low ER+ 54 32 2.42 HER2+ 20 12 1.08
Conclusion: In this small single-center retrospective study, patients with metastatic HER2 low ER- breast cancer had higher-grade tumors. HER2 low ER+ patients had a better PFS compared to HER2- patients. This seems to suggest that the HER2 low group may have some inherent biologic differences. Larger studies are needed.
Citation Format: Radhika Kulkarni, Muhammad Ali Shahid, Oscar Hinojosa Castro, Kunj Patel, Chun-Hui Lin, Courtney Rose, Vrushali Dabak. Understanding the new subgroup- Her 2 low 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 2563.
Abstract 2618: BCG017, a bispecific ADC targeting PTK7 and EGFR exhibits anti-tumor efficacy in PDX models
Authors: Yao Sufei , Shang Chengzhang , Li Zhuolin , An Gao , Guo Chaoshe , An W. Frank , Yang Yi 
Published: March 2024

Abstract
EGFR is a favored target in various cancer therapies. However, EGFR-based treatments have been challenged by drug resistance and cytotoxicity. Targeting EGFR with an antibody-drug conjugate (ADC) is a promising new therapeutic strategy to address the drug resistance, due to the potent killing effects of the payload. Furthermore, we hypothesized that development of a bispecific ADC (bsADC) targeting EGFR and another tumor-associated antigen (TAA) might improve the tumor selectivity, thereby limiting the on-target off-tumor toxicity. One such TAA candidate is PTK7, which belongs to the same receptor tyrosine kinase family as EGFR, and is co-expressed with EGFR in multiple types of solid tumors, including lung, esophageal, head and neck, and colon cancers.
Herein, we developed a fully human anti-human PTK7 EGFR bsAb using our proprietary common light chain RenLite® mouse platform and knobs-into-holes technology. The anti-PTK7 EGFR bsAb demonstrates good purity by SEC-HPLC, and can cross-react with human and cynomolgus monkey antigens with favorable affinity. The PTK7 x EGFR bsAb demonstrated higher binding to various types of cancer cell lines, as well as enhanced internalization in vitro compared with PTK7 parental antibody. Next, the bsAb was conjugated with monomethyl auristatin E (MMAE) to generate an anti-PTK7 x EGFR bsADC, BCG017, with a drug-to-antibody ratio of approximately 4. BCG017 demonstrated superior anti-tumor activity compared to benchmarks and its PTK7 parental ADC in cell-derived non-small-cell lung cancer (NSCLC) xenografts, and showed enhanced anti-tumoractivity when compared to benchmark ADCs and parental ADCs in patient-derived breast and pancreatic ductal adenocarcinoma xenograft models. These results suggest that BCG017 have the potential to be a novel therapeutic alternative for PTK7 and EGFR co-expressing tumors.
Citation Format: Sufei Yao, Chengzhang Shang, Zhuolin Li, Gao An, Chaoshe Guo, W. Frank An, Yi Yang. BCG017, a bispecific ADC targeting PTK7 and EGFR exhibits anti-tumor efficacy in PDX models [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 2618.
Abstract 2640: HBI-2375, a first-in-class IND ready selective MLL1-WDR5 inhibitor, retains desirable preclinical characteristics in solid tumors and in leukemias to be pursued in clinical studies
Authors: Shojaei Farbod , Fang Che , Ricono Jill M. , Gillings Mireille 
Published: March 2024

Abstract
MLL1 (mixed lineage leukemia1) interaction with WDR5 (WD repeat domain 5) is critical for its histone methyl transferase (HMT) activity leading to transcriptional regulation of gene expression. MLL1 dysregulation such as its translocation at chromosome 11q23 results in generation of MLL1 fusion genes and leukemia development. Additionally, recent studies indicated a role for MLL1-WDR5 interaction in solid tumors progression via directly affecting cancer cells or by suppression of tumor immunity. Therefore, MLL1-WDR5 interaction is an important target in the discovery of anti-cancer drugs for both leukemia and solid tumors. We recently identified HBI-2375 as a selective inhibitor of MLL1-WDR5 interaction. HBI-2375 showed potent inhibition of WDR5 (IC50: 4.48nM) in biochemical assay and inhibited MV4-11 cellular proliferation (average IC50: 3.17µM) in CTG assays. In addition, HBI-2375 was stable in liver S9 and whole blood, with moderate to high plasma protein binding rates in multiple species, and acceptable hERG (IC50: 17µM). Furthermore, HBI-2375 displayed reasonable oral PK properties (Cmax, T1/2, AUC, and F%) in mouse, rat and dog and showed good safety profile in GLP tox studies. In pharmacology studies HBI-2375 showed significant dose dependent anti-tumor activity in MV4-11 AML model along with reduction in methylation of H3K4 in the tumors harvested from the treated animals demonstrating the targeted disruption of HMT activity in cancer cells by HBI-2375. Furthermore HBI-2375 in combination with PD-1 mAb significantly inhibited tumor growth in MC38, colorectal tumor model, and in 3LL lung carcinoma syngeneic tumor models. Flow cytometry and IHC showed significant increase in the infiltration of CD8+ CTLs in the combination group further providing immune-driven mechanisms for greater efficacy of combination therapy. Gene expression analysis also identified genes that are involved in promoting immune system activity in the combination group. Tissue distribution studies also showed greater accumulation of HBI-2375 in brain tissue indicative of a potential to target glioma and glioblastoma in clinical studies. Therefore, HBI-2375 represents a first-in-class MLL1-WDR5 inhibitor with promising characteristics for future testing in the clinic.
Citation Format: Farbod Shojaei, Che Fang, Jill M. Ricono, Mireille Gillings. HBI-2375, a first-in-class IND ready selective MLL1-WDR5 inhibitor, retains desirable preclinical characteristics in solid tumors and in leukemias to be pursued in clinical studies [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 2640.
Abstract 2654: HPK1 inhibits CD8+ T cell effector gene expression following T cell activation
Authors: Ames Rachel Y. , Zhao Rongqi , Mace Parker , Grant Adam , Xie Guorui , Milestone Heather , Grandcolas Molly , Fang Eva , Kiosea Nicolae , Wong Stephen , Brovarney Martin , Jacobson Scott , Nebalasca Danilo , Arguello Jorge , Gomez Blanca , Kandala Hiranmayee , Ko Michelle Y. , Nguyen Lan , Robles Omar , Shibuya Grant , Shakhmin Anton A. , Tivitmahaisoon Parcharee , Vu Vi-Anh , Younai Ashkaan , Zibinsky Mikhail , Subramanyam Babu , Poon Daniel , Ghomi Mohsen Sabouri , Wustrow David J. , Kassner Paul D. , Katibah George E. , Brockstedt Dirk G. 
Published: March 2024

Abstract
Hematopoietic progenitor kinase 1 (HPK1) has been shown to act as a negative regulator of T cell receptor signaling and of subsequent effector T cell function.  Inhibiting HPK1 to enhance T cell activity has emerged as a promising strategy for cancer immunotherapy. Upon T cell receptor engagement, the kinase domain of HPK1 is activated and targets components of the T cell receptor (TCR) signaling pathway for degradation, including SLP76. However, the molecular events connecting HPK1 kinase activity to observed T cell functions downstream of proximal TCR signaling are not well understood. Through transcriptional profiling of HPK1-kinase-dead (HPK1-KD) versus wild-type CD8+ T cells following an acute, attenuated Listeria monocytogenes infection, we observed increased expression of many genes associated with T cell activation and effector function, including changes in expression of several key transcription factors and their targets. Upon activation, HPK1-KD T cells, as well as T cells treated with our small-molecule HPK1 inhibitor, produce higher levels of a wide range of effector cytokines in vitro and in vivo.  Treatment of mice with the HPK1 inhibitor also inhibited tumor growth in several syngeneic tumor models.  These data expand our understanding of the role of HPK1 in inhibiting CD8+ T cell effector programs, and, importantly, the impact of HPK1 inhibitors on T cell function.
Citation Format: Rachel Y. Ames, Rongqi Zhao, Parker Mace, Adam Grant, Guorui Xie, Heather Milestone, Molly Grandcolas, Eva Fang, Nicolae Kiosea, Stephen Wong, Martin Brovarney, Scott Jacobson, Danilo Nebalasca, Jorge Arguello, Blanca Gomez, Hiranmayee Kandala, Michelle Y. Ko, Lan Nguyen, Omar Robles, Grant Shibuya, Anton A. Shakhmin, Parcharee Tivitmahaisoon, Vi-Anh Vu, Ashkaan Younai, Mikhail Zibinsky, Babu Subramanyam, Daniel Poon, Mohsen Sabouri Ghomi, David J. Wustrow, Paul D. Kassner, George E. Katibah, Dirk G. Brockstedt. HPK1 inhibits CD8+ T cell effector gene expression following T cell activation [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 2654.
Abstract 2689: Mass cytometry analysis of CXCR3 expression in tumor-infiltrated myeloid cells as a predictive biomarker For immunotherapy response
Authors: Valentin-Guillama Gabriel A. , Chatterjee Nandini , Alimadadi Ahmad , Hedrick Catherine C. 
Published: March 2024

Abstract
Monocytes have emerged as important regulators of cancer progression. We have recently found that CXCR3+ circulating monocytes in humans are associated with better response to immunotherapy. Here, we aimed to study the functions and heterogeneity of CXCR3+ monocytes in two different triple negative breast cancer (TNBC) tumors in mice, using either AT3 or EO771 tumor cell lines. AT-3 tumors exhibit higher resistance to anti-PD-1 and anti-CTLA-4 therapy in C57BL/6 breast cancer mouse models compared to EO771 tumors. We evaluated 36 surface protein markers on tumor-infiltrated myeloid cells in tumors isolated from each model using CyTOF mass cytometry. Analysis of monocytes, macrophages and dendritic cells in the tumors using unsupervised clustering identified 13 cell subsets. Significant differences were discovered between the two tumor types in frequencies of nine of 13 identified subsets. However, 3 of these subsets displayed relatively high expression of CXCR3 in EO771 tumors when compared to AT-3 tumors. The significant CXCR3 positive subsets were identified as CXCR3+ early macrophages, CXCR3+ Ly6C+CD11blo classical monocytes and Trem2+ CXCR3+ dendritic cells. We observed higher expression of CXCR4, Trem2, and CCR1 in CXCR3+ myeloid cells when compared to their CXCR3− counterparts in both tumor models. To elucidate the role of these CXCR3+ cells, we performed low-input bulk RNA sequencing of CD115+/CD11b+ cells from blood and spleen of EO771 tumor bearing mice with a wild type or CXCR3KO genotype. Ingenuity Pathway Analysis (IPA) of the differentially expressed genes suggests a significant inhibition of the IL-10 signaling pathway of CXCR3KO cells. These differentially expressed markers and genes suggest a functional importance in this subset in migration to the tumor and antigen presentation, both of which are anti-tumoral functions. Ongoing studies are aimed towards understanding the role of CXCR3+ myeloid cells in regulating response to immunotherapies.
Citation Format: Gabriel A. Valentin-Guillama, Nandini Chatterjee, Ahmad Alimadadi, Catherine C. Hedrick. Mass cytometry analysis of CXCR3 expression in tumor-infiltrated myeloid cells as a predictive biomarker For immunotherapy response [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 2689.
Abstract 2704: cGAS-STING drives myeloid inflammation in chromosomally unstable esophageal cancer
Authors: Beernaert Bruno , Erdal Erkin , Clark Rose , Liu Tong , Hammond Ester M. , Parkes Eileen E. 
Published: March 2024

Abstract
Esophageal adenocarcinoma (EAC) is an aggressive disease characterized by chromosomal instability (CIN), whereby cells continuously acquire chromosomal abnormalities that promote therapeutic resistance, immune evasion and metastasis. CIN in cancers also fuels the misplacement of genomic DNA in the form of structural abnormalities of the nucleus, such as micronuclei (MN), that lead to chronic activation of the cytosolic DNA sensing cGAS-STING pathway. However, how chronic cGAS-STING pathway activation is tolerated and shapes the tumor landscape of CINhigh EAC cancers is poorly understood. Using publicly available RNA-seq and genome sequencing data of EAC tumours and esophageal cancer cell lines as well as a panel of EAC cell lines, we demonstrate that the core cGAS-STING pathway machinery is rarely inactivated in EAC despite high levels of baseline CIN and aneuploidy. Through transcriptomic profiling of an isogenic EAC precursor cell line model of variable CIN and cGASKO/WT EAC cell lines we show that both chronic and transient CIN-driven cGAS-STING activation converge on the expression of CXCR1/2 ligands and other pro-inflammatory cytokines and chemokines rather than typical anti-tumor type I interferon signalling in EAC cells. Indeed, a novel transcriptional signature of cGAS+ micronuclear burden-correlated genes correlates with orthogonal measures of CIN in EAC tumours and esophagogastric cancer cell lines and is associated with an enrichment in myeloid-derived cells as well as poor prognosis. Correspondingly, using multiplexed immunofluorescence (IF) we find that a high preponderance of cGAS+MN and STING expression in human EAC samples is associated with decreased tumor purity, increased myeloid cell and macrophage infiltration, and increased peripheral blood neutrophil counts, indicative of tumor-promoting myeloid inflammation. Ongoing multiplexed IF and single-nuclei RNAseq analysis of cGAS+MNhigh and cGAS+MNlow EAC tumors will further help characterise the components that comprise the CIN EAC tumor microenvironment (TME) and the CIN- and cGAS-STING-dependent cell-cell interactions that govern it. Taken together, our findings provide an explanation for the observed maintenance of cGAS and STING in EAC and identify disruption of cGAS-STING-dependent myeloid cell inflammation and recruitment as a potential therapeutic target for CINhigh EAC.
Citation Format: Bruno Beernaert, Erkin Erdal, Rose Clark, Tong Liu, Ester M. Hammond, Eileen E. Parkes. cGAS-STING drives myeloid inflammation in chromosomally unstable esophageal 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 2704.