bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 6947: Exploring the single-cell dynamics of FOXM1 under cell cycle perturbations
Authors: Jawwad Tooba , Kamkaew Maliwan , Phongkitkarun Kriengkrai , Chusorn Porncheera , Sampattavanich Somponnat
Published: March 2024

The cell cycle plays a critical role in maintaining normal cellular functions and preventing abnormal cell growth. The transcription factor FOXM1 has emerged as a crucial regulator of cell cycle progression and has been implicated in various physiological and pathological processes. Notably, FOXM1 overexpression has been observed in numerous cancer types, including liver, prostate, breast, lung, and colon cancer. Despite its significance, our understanding of how FOXM1 dynamic behaves at the single-cell level under different cell cycle perturbations and its link to cell behavior heterogeneity remains limited. Here, we investigated the dynamic behavior of FOXM1 in individual cells exposed to various cell cycle perturbations, focusing on understanding heterogeneity in cell behavior and improving disease treatment. At the single-cell level, our investigation reveals six distinct dynamic features of FOXM1 in response to various therapeutic interventions, each of which corresponds to a unique cell phenotype. Our result further demonstrates that for cells exhibiting a high FOXM1 pattern, targeting aurora kinase and PLK1 may hold promise as a therapeutic approach for cancer suggesting that FOXM1 is a strong biomarker, and its pattern can be predictive of drug response, especially in cases with G1 checkpoint defects like Rb1 loss or p53 deficiency.

Citation Format: Tooba Jawwad, Maliwan Kamkaew, Kriengkrai Phongkitkarun, Porncheera Chusorn, Somponnat Sampattavanich. Exploring the single-cell dynamics of FOXM1 under cell cycle perturbations [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 6947.
Abstract 7: Ginsenoside Rb1 delays the senescence of CD8+ T cells to expand T cells with superior antitumor immunity
Authors: Ma Chunhong , Sheng Xue , Li Chunyang
Published: March 2024

Background and Objective: Immunosenescence represents a distinct state of T cell dysfunction in the TME, and plays crucial role in many age-related diseases including tumor. Senescent cell removal by senolytic agents or therapies that inhibit the SASP have demonstrated benefit in both preclinical and clinical models of geriatric decline and chronic diseases. Here, we aimed to screen anti-aging compounds to delay T-cell senescence in TME, and explore novel strategies of reversing tumor induced T-cell senescence to restore antitumor immunity.

Methods and Results: Using in vitro senescence inducing system, we screened ginsenoside Rb1 from 22 anti-aging compounds as the compound that had the most effective activity to reduce CD8+ T cell senescence, displayed as decreased β-gal, p16, and p21. Further analysis showed that ginsenoside Rb1 promoted anti-CD3/CD28-induced TCR signaling and the secretion of effector cytokines IFN-γ, TNF-α and IL -2 in OTI T cells. Intriguingly, ginsenoside Rb1 treatment significantly increased TCF-1 in CD8+ T cells, and ginsenoside Rb1 treated OT-I T cells significantly inhibited tumor growth. Moreover, ginsenoside Rb1 greatly enhanced the efficiency of CD19-CART cells to kill Namalwa tumor cells.

Conclusion: Ginsenoside Rb1 delays T cell senescence and enhances T cell antitumor activity. This data provides a new insight into T cell based antitumor therapy.

Citation Format: Chunhong Ma, Xue Sheng, Chunyang Li. Ginsenoside Rb1 delays the senescence of CD8+ T cells to expand T cells with superior antitumor immunity [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 7.
Abstract 7012: Studying mosaic epimutations at scale
Authors: Nikolaienko Oleksii , Lønning Per E. , Knappskog Stian
Published: March 2024

Mosaic epimutations (i.e., epigenetic gene inactivation) within the BRCA1 gene promoter occur in 5-8% of healthy individuals and are associated with a significantly elevated risk of breast and ovarian cancer. These epimutations arise prenatally and then serve as an underlying cause of cancer in adulthood, likely accounting for about 20% of triple-negative breast cancers. Similar mosaic epimutations have been detected in some other tumor suppressor genes as well, but the intraindividual and population frequencies of this phenomenon remain unknown. To address this gap, we have developed novel methodology for detection of mosaic epimutations. The experimental technique is a multiplexed, hybridization capture-based, targeted methylation sequencing assay covering gene regulatory areas. It allows cost-effective assessment of epimutations in established and emerging tumor suppressor genes. An accompanying tailored data analysis pipeline is designed to quantify epimutations. The pipeline is sensitive and robust to variance in methylation, sequencing errors and batch effects. We applied this method to a set of samples from healthy young males. Analysis uncovered significant interindividual epimutational heterogeneity and confirmed high sensitivity of the assay and its superiority compared to methylation profiling using microarrays. Here, we present details on the highly sensitive, scalable and robust methodology for analysis of mosaic epimutations together with the results on initial assessment of the prevalence of epimutations in healthy individuals. We anticipate that this method will become widely used for studies of epigenetic gene regulation and related cancer risk.

Citation Format: Oleksii Nikolaienko, Per E. Lønning, Stian Knappskog. Studying mosaic epimutations at scale [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 7012.
Abstract 7020: Prognostic implications of microRNA 181a 2 3p expression in association with tumor budding in patients with stage III lung squamous cell carcinoma
Authors: Lee Eunhyo , Kim Seoree , Kim Jeana , Lee Minho , Ko Yoonho , Chun Sang Hoon
Published: March 2024

Introduction: Tumor budding (Bd) has been known as an independent prognostic factor in various malignancies. MicroRNA (miRNA) are known to play an important role in regulating Bd. However, understanding the relationship between Bd and miRNA in Lung Squamous cell carcinoma (LUSC) remains limited.

Methods: 115 LUSC patients who underwent curative resection were included in the discovery cohort. Bd was verified through immunohistochemical (IHC) stain. Bd was classified according to a three tier system: Bd1 with 0-4 buds, Bd2 with 5-9 buds, and Bd3 with 10 or more buds. MiRNA expression profiles were analyzed through RNA sequencing. Differences in survival outcomes for miRNA, as identified in the discovery cohort, were confirmed using LUSC data of The Cancer Genome Atlas (TCGA) as a validation cohort.

Results: The relationship between Bd2 and the prolongation of recurrence-free survival (RFS) was statistically significant (p=0.0113), whereas Bd1 was correlated with Overall Survival (OS) (p=0.0468). Multivariate analysis indicated that both a high T stage (HR: 5.211, 95% CI: 1.168-23.250, p = 0.031; and HR: 5.107, 95% CI: 1.447-18.030, p < 0.011) and Bd3 (HR: 3.683, 95% CI: 1.370-9.900, p = 0.010; and HR: 1.600, 95% CI: 0.800-3.201, p = 0.018) are independently significant poor prognostic factors for both RFS and OS. MiRNA-181a-2-3p was identified through Differentially Expressed miRNA (DER) analysis. A higher expression of miRNA-181a-2-3p in stage III LUSC of the TCGA dataset was associated with OS (p=0.0463).

Conclusions: Our study demonstrates that the miRNA 181a 2 3p expression is associated with improved OS. This association may be attributed to its inhibitory effect on Bd in advanced stages of LUSC.

Citation Format: Eunhyo Lee, Seoree Kim, Jeana Kim, Minho Lee, Yoonho Ko, Sang Hoon Chun. Prognostic implications of microRNA 181a 2 3p expression in association with tumor budding in patients with stage III lung 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 7020.
Abstract 7035: Characterization of tissue-resident memory T cells in hepatocellular carcinoma through single-cell multi-omics
Authors: Park Mi-So , Cho Hyunbin , Kim Hyeree , Park Woong-Yang , Paik Yong-Han , Yoon Yeup , Kang Wonseok , Won Hong-Hee
Published: March 2024

As the fifth leading cause of cancer-related mortality, liver cancer imposes a global burden. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with a five-year overall survival rate of less than 20% for advanced-stage cases. Even the most advanced immunotherapy for HCC has disparate response rates in each patient with HCC, which has led to efforts to unravel the underlying factors in the progression of HCC using bioinformatic approaches. In recent decades, numerous studies have explored T-cell subtypes with tissue-specific residency, suggesting their early protective functions and therapeutic potential within tumor microenvironment (TME). This study aimed to understand inter-individual and intercellular TME through single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq) in five recurrent/non-recurrent HCC patients. We identified tumor-associated tissue-resident memory T (TA-TRM) cells and investigated the heterogeneous characteristics of two TRM clusters (CD69+ and CD103+). Whereas CD69+ TA-TRM showed high expression of genes associated with immunological activation, CD103+ TA-TRM exhibited upregulation of genes related to proliferation capacity. To validate the unique molecular patterns, we analyzed an independent HCC dataset (GSE140228) and observed high concordance of significant core marker genes for TA-TRM clusters between the two datasets. Moreover, we assessed the association of gene expression in TA-TRM cells with overall and recurrence-free survival by conducting survival analysis in two independent large-scale cohorts. The cross-validation approach was applied to estimate risk scores for patients with primary HCC tumors in The Cancer Genome Atlas (TCGA), and the trained model was evaluated using the International Cancer Genome Consortium (ICGC) data. The result of calculating the risk scores clearly indicates that TA-TRM cells are associated with survival in HCC. Therefore, our study characterized two distinct subtypes of TA-TRM cells in HCC, delineated their unique molecular signatures, and established their relevance to survival outcomes. The findings can potentially enhance the understanding of the roles of TA-TRM cells in the context of HCC.

Citation Format: Mi-So Park, Hyunbin Cho, Hyeree Kim, Woong-Yang Park, Yong-Han Paik, Yeup Yoon, Wonseok Kang, Hong-Hee Won. Characterization of tissue-resident memory T cells in hepatocellular carcinoma through single-cell multi-omics [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 7035.
Abstract 7039: Leveraging single cell RNA-seq for uncovering immune landscape of hepatocellular carcinoma
Authors: He Jian
Published: March 2024

The immune cell types as well as tumor microenvironment (TME) status may influence prognosis, metastasis, tumor progression, and clinical response to immunotherapies for cancer. Hepatocellular carcinoma (HCC) is a typical highly heterogeneous solid tumor with high morbidity and mortality worldwide, especially in China, however, the immune microenvironment of HCC, especially which caused by cancerogenic substance has not been clarified so far. In this study, we employed single-cell RNA sequencing (scRNA-seq) on diethylnitrosamine (DEN)-induced mouse HCC model to dissect the immune cell dynamics during tumorigenesis. Our findings reveal distinct immune profiles in both precancerous and cancerous lesions, indicating early tumor-associated immunological alterations. Notably, specific T and B cell subpopulations are preferentially enriched in the HCC TME. Furthermore, we identified a subpopulation of naïve B cells with high CD83 expression, correlating with improved prognosis in human HCC. These signature genes were validated in The Cancer Genome Atlas (TCGA) HCC RNA-seq dataset. Moreover, cell interaction analysis revealed that subpopulations of B cells in both mouse and human samples are activated and may potentially contribute to oncogenic processes. In summary, our study provides insights into the dynamic immune microenvironment and cellular networks in HCC pathogenesis, with a specific emphasis on naïve B cells. These findings emphasize the significance of targeting TME in HCC patients to prevent HCC pathological progression, which may give a new perspective on the therapeutics for the HCC.

Citation Format: Jian He. Leveraging single cell RNA-seq for uncovering immune landscape of 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 7039.
Abstract 7101: Remodeling of cancer cells by chemotherapy
Authors: Qian Gege , Schaffer Leah , Moon Kyung-Mee , Foster Leonard , Ideker Trey , Hu Mengzhou , Alkhairy Sahar , Lundberg Emma
Published: March 2024

Cisplatin is a commonly administrated chemotherapy drug for cancer treatment. Although the direct mechanism of cisplatin is largely well-defined, it is challenging to comprehensively assess its systemic effects. Cellular responses to perturbations are intricate processes involving modifications to protein complexes across diverse cellular compartments. Therefore, substantial research endeavors have been directed towards unraveling protein organization in cells. We recently built a multiscale integrated cell map, MuSIC, that combines fluorescence-stained images and interactions derived from affinity purification mass spectrometry to allow comprehensive characterization of cellular structure and functional networks of 5,254 proteins of the human bone osteosarcoma epithelial line (U2-OS). To exploit the biology of U2OS, we integrated dynamics into this map to determine the proteome reorganization upon cisplatin exposure. Thus, we developed a data-driven approach integrating high throughput size exclusion chromatography mass spectrometry (SEC-MS) data with large-scale cell maps built from static-state information to systematically map at all scales the remodeling of cell architecture in drug-treated cells. Here, we acquired drug-perturbed protein-protein interactions (PPIs) from the SEC-MS data by treating U2-OS with cisplatin. Integrating the differential interactions identified from SEC-MS PPIs with the scaffold large-scale hierarchy (MuSIC) allows retention of the upper cellular organization to systematically map drug impact on protein complexes in the cell. This pipeline serves as an explorative method to identify the drug-responsive organelles, alterations of hierarchical structures, and translocation of proteins. Apart from the well known alterations of DNA damage repair complexes, we also recapitulate remodeling in metabolism pathways, splicing, cAMP-dependent kinase activity, and histone modification. We identify 26 novel protein assemblies containing members that are previously associated with cisplatin biology. This pipeline exploits the potential of a well-established network by integrating the high throughput data modality, allowing for the screening of a range of chemical agents and stimuli to generate differential networks.

Citation Format: Gege Qian, Leah Schaffer, Kyung-Mee Moon, Leonard Foster, Trey Ideker, Mengzhou Hu, Sahar Alkhairy, Emma Lundberg. Remodeling of cancer cells by chemotherapy [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 7101.
Abstract 7114: Exploring the landscape of PARP and PARG inhibitor selectivity in live cells using NanoBRET™ target engagement assays
Authors: Michaud Ani , Teske Kelly , Wilkinson Jennifer , Zimprich Chad , Vasta James , Corona Cesear , Zhou Min , Dominguez Elizabeth , Dunn-Hoffman Kaitlin , Robers Matthew
Published: March 2024

The 17-member poly(ADP-ribose) polymerase (PARP) family of proteins mediate a number of cellular processes including gene transcription, cell-division and DNA-repair. PARPs catalyze the addition of poly- or mono- ADP-ribose chains on target proteins, modifying their function and/or recruitment in various pathways. Poly(ADP-ribose) Glycohydrolase (PARG) catabolizes PAR units and facilitates the recycling of PARP and other modified effector proteins. A number of PARPS are implicated in human disease, and PARP inhibitors (PARPi’s) have seen major clinical success, however, many PARPs (especially mono PARPs) are understudied and chemical tools for understanding cellular PARPi selectivity and potency across the entire family are lacking. Similarly, several PARG inhibitors have been developed to date, but tools for directly assessing target engagement in a cellular context are sorely needed. Here we describe the development and application of target engagement assays for characterizing PARP and PARG inhibitor selectivity and affinity in live cells. This method is based on the NanoBRET™ assay platform, which is a proximity-based probe displacement assay that operates in live cells. Using NanoBRET™ technology, we have developed a single probe that covers 12 out of 17 PARP family members. We explored the family-wide selectivity of a diverse panel of clinical and preclinical PARP inhibitors in live cells, representing the first family-wide, cell-based method for profiling PARP selectivity. We also describe the development of a second probe that reports on PARG target engagement. Target engagement of PARG was observed for three out of five tested inhibitors, suggesting a potential indirect mode of action for certain inhibitors on PARG glycohydrolase activity. These assays offer a complementary approach for studying target engagement within the PARylation cycle.

Citation Format: Ani Michaud, Kelly Teske, Jennifer Wilkinson, Chad Zimprich, James Vasta, Cesear Corona, Min Zhou, Elizabeth Dominguez, Kaitlin Dunn-Hoffman, Matthew Robers. Exploring the landscape of PARP and PARG inhibitor selectivity in live cells using NanoBRET™ target engagement assays [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 7114.
Abstract 7149: Discovery of a novel USP1 inhibitor: Targeted therapy for BRCA-mutated and PARPi-resistant cancers
Authors: Kim Jihye , Kim Sunkyu , Park Sejeong , Lee Sanghoon , Yoo Kiwoong , Lee Ho-Jeong , Kang Jaewoo , Lee Kwang-Ok
Published: March 2024

Harnessing synthetic lethality offers an innovative approach to targeted cancer treatment. USP1, a specific deubiquitinating enzyme, has gained attention as a potential synthetic lethality target for BRCA-mutated cancers. At AIGEN Sciences, Inc., we've integrated the advanced capabilities of our human-in-the-loop (HITL) AI drug discovery platform, AIGEN ChemTailor. This cutting-edge platform thrives on continuous learning enhanced by expert feedback, refining our approach to drug discovery. Using AIGEN ChemTailor, we synthesized a specific USP1 inhibitor. Its inhibitory capabilities were validated through the Ubiquitin-rhodamine 110 assay. Notably, our inhibitor presented remarkable anti-proliferative effects on BRCA1 mutant cells (MDA-MB-436) while showing no activity against BRCA wild-type cells (HCC1954), highlighting its specificity. The efficacy of our inhibitor was enhanced when combined with PARP inhibitors, such as olaparib or AZD5305, especially in UWB1.289 cells. Impressively, the USP1 inhibitor also effectively targeted PARPi-resistant cell lines, including A2780-ola, UWB1.289-nir, HCC38-ola, MDA-MB-468-ola, U251MG-ola, and OVCAR8-ola. Clonogenic assays with MDA-MB-436 and MCF-10A emphasized our inhibitor's selectivity towards BRCA mutant phenotypes. Subsequent studies demonstrated the compound's mechanism: inducing replication stress by impairing of DNA synthesis and activating DNA damage pathways via ATR signaling. Preclinical mouse studies highlighted favorable pharmacokinetics and involved the assessment of anti-tumor effects in animal models. In summation, our USP1 inhibitor, developed using AIGEN ChemTailor and advanced molecular modeling techniques, stands out as a potent therapeutic against BRCA-mutated cancers and PARP inhibitor-resistant strains.

Citation Format: Jihye Kim, Sunkyu Kim, Sejeong Park, Sanghoon Lee, Kiwoong Yoo, Ho-Jeong Lee, Jaewoo Kang, Kwang-Ok Lee. Discovery of a novel USP1 inhibitor: Targeted therapy for BRCA-mutated and PARPi-resistant cancers [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 7149.
Abstract 7155: Dichloroacetate reverses cisplatin resistance in ovarian cancer through promoting ROS production
Authors: Do Yen Thi , Lee Seungmee , Shin Changmin , Chung Hyewon , Kim Jin Young , Ha Eunyoung , Shin Sojin , Seo Ji Hae
Published: March 2024

Chemotherapy resistance and the high rate of ovarian cancer relapse pose major challenges in the treatment of ovarian cancer. The development of chemoresistance contributes to poor overall prognosis associated with ovarian cancer and high cancer-related mortality in women worldwide. Herein, we found that Dichloroacetate (DCA), a pan-pyruvate dehydrogenase kinase (PDK) inhibitor, is a potent agent to overcome Cisplatin (CP) resistance in ovarian cancer treatment. Firstly, we elucidated that phosphorylation of pyruvate dehydrogenase (pPDH) was elevated in CP-resistant ovarian cancer cells. Then, blockage of pPDH by DCA treatment significantly inhibited cell migratory and invasive capacity in CP-resistant ovarian cancer cells through the transition of motile mesenchymal phenotypes into epithelial characteristics. DCA markedly decreased the number of sphere formations and attenuated the stem cell-like properties in CP-resistant ovarian cancer cells. In combination with CP treatment, DCA effectively inhibited cell proliferation in chemoresistant ovarian cancer cells by triggering apoptosis. Collectively, we suggested that DCA is a promising drug to reverse CP resistance for ovarian cancer treatment. We further tested the underlying mechanisms of DCA to restore CP sensitivity in ovarian cancer. We found that CP treatment promoted reactive oxygen species (ROS) production to induce cell death in CP-sensitive ovarian cancer. However, CP-resistant ovarian cancer cells exhibited higher basal levels of ROS compared with sensitive cancer cells, and CP treatment failed to generate ROS production. That means ovarian cancer cells steadily adapted to elevated ROS levels, then becoming ROS-adapted ovarian cancer cells to survive. Interestingly, DCA treatment results in the buildup of ROS production, causing cell death in CP-resistant ovarian cancer. Therefore, our study suggests that ROS production can be an attractive target in DCA treatment to restore CP sensitivity in ovarian cancer.

Citation Format: Yen Thi Do, Seungmee Lee, Changmin Shin, Hyewon Chung, Jin Young Kim, Eunyoung Ha, Sojin Shin, Ji Hae Seo. Dichloroacetate reverses cisplatin resistance in ovarian cancer through promoting ROS production [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 7155.
Abstract 7169: A real-world toxicity-atlas shows that adverse events of combination-therapies commonly result in additive interactions
Authors: Küçükosmanoglu Asli , Scoarta Silvia I. , Westerman Bart
Published: March 2024

Purpose: Combination-therapies are a promising approach for improving cancer treatment, but it is challenging to predict their resulting adverse events in an real-world setting.

Experimental Design: We provide here a proof-of-concept study using 15 million patient records from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Complex adverse-event frequencies of drugs or their combinations were visualized as heatmaps onto a 2D UMAP grid. Adverse event frequencies were shown as colors to assess the ratio between individual and combined drug effects. To capture these patterns, we trained a convolutional neural network (CNN) autoencoder using 7,300 single-drug heatmaps. Additionally, statistical synergy analyses were performed based on BLISS independence or Chi-square testing.

Results: The trained CNN model was able to decode patterns, showing that adverse events occur in global rather than isolated and unique patterns. Patterns were not likely to be attributed to disease symptoms given their relatively limited contribution to drug associated adverse events. Pattern recognition was validated using trial data from ClinicalTrials.gov and drug combination data. We examined the adverse-event interactions of 140 drug combinations known to be avoided in the clinic and found that near all of them showed additive rather than synergistic interactions, also when assessed statistically.

Conclusion: Our study provides a framework for analyzing adverse events and suggest that adverse drug interactions commonly result in additive effects with a high level of overlap of adverse event patterns. These real-world insights may advance the implementation of new combination therapies in clinical practice.

Citation Format: Asli Küçükosmanoglu, Silvia I. Scoarta, Bart Westerman. A real-world toxicity-atlas shows that adverse events of combination-therapies commonly result in additive interactions [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 7169.
Abstract 7175: Web-based cross-database exploration of molecular pharmacology data from cancer cell lines and patient genomics
Authors: Reinhold William C. , Luna Augustin , Elloumi Fathi , Varma Sudhir , Taniyama Daiki , Mizunuma Makito , del Rivero Jaydira , Thomas Anish , Reilly Karyyne , Pacak Karel , Aladjem Mirit , Pommier Yves
Published: March 2024

CellMiner Cross-Database (CellMinerCDB, discover.nci.nih.gov/cellminercdb) allows integration and analysis of molecular and pharmacological data within and across cancer cell line datasets from the National Cancer Institute (NCI), Broad Institute, Sanger/MGH, MD Anderson Cancer Center (MDACC), and the National Center for Advancing Translational Sciences (NCATS, discover.nci.nih.gov/rsconnect/cellminercdb_ncats/). Altogether, our database spans over 1,700 distinct cell lines, over 1,000 clinically relevant drugs, ~25,000 experimental compounds, and molecular profiling data, such as gene/protein expression, molecular signatures including epithelial mesenchymal transition (EMT), replication stress (RepStress), neuroendocrine evaluation (NE), DNA copy, methylation, mutational status, and gene dependencies (Broad DepMap). This rich and growing set of cell lines and tested drugs allows for novel avenues for response determinant discovery and clinical translation that is facilitated by 1) common annotations (e.g., tissues of origin and matched drug names) across pharmacogenomic datasets and 2) various univariate and multivariate analyses tools. A major challenge to clinical translation occurs in relating pre-clinical models to patient samples. As part of this work, we show how the CellMinerCDB infrastructure additionally supports annotated patient multi-omics data to aid researchers to relate findings from cancer cell lines with patient data; we use data from small cell lung cancer (SCLC) and neuroendocrine tumors as illustrative examples. This work provides significant pharmacogenomic integration that allows exploration within a comprehensive dataset of cancer cell lines and to inter-relationships with patient-derived datasets; this is being developed to display and mine patient samples as part of the complementary web-based tool (PatientTumorMiner).

Citation Format: William C. Reinhold, Augustin Luna, Fathi Elloumi, Sudhir Varma, Daiki Taniyama, Makito Mizunuma, Jaydira del Rivero, Anish Thomas, Karyyne Reilly, Karel Pacak, Mirit Aladjem, Yves Pommier. Web-based cross-database exploration of molecular pharmacology data from cancer cell lines and patient genomics [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 7175.
Abstract 7207: Targeting hippo signaling pathway to overcome chemoresistance in glioblastoma
Authors: Wong Cheuk Lun Ethan , Kiang Mei Yee Karrie , Leung Ka Kit Gilberto
Published: March 2024

The study aims to investigate whether the Hippo signaling pathway contributes to temozolomide chemoresistance in glioblastoma, and to validate whether the combinational treatment of temozolomide and YAP inhibitor is effective against glioblastoma. Temozolomide-sensitive and temozolomide-resistant U87 and U251 GBM human cell lines were previously established. Temozolomide-resistant cells were maintained in low-dose temozolomide. Here, we investigate whether Hippo signaling contributes to temozolomide chemoresistance. By modulating the Hippo signaling pathway through YAP gene knockdown, the outcome on cell proliferation was studied by cell viability assay (in vitro) and mouse orthotopic xenograft (in vivo). Finally, the therapeutic effect of YAP inhibitor is studied in vitro and in vivo respectively. Our data showed that YAP is overexpressed in temozolomide-resistant glioblastoma cells. Nuclear translocation of YAP (which becomes its active state) is increased in temozolomide-resistant cells. In fact, YAP inhibition show decreased cell viability and higher susceptibility to temozolomide. In addition, mice with tumor injection of the YAP knockdown cells reduced tumor size with temozolomide treatment. Similarly, YAP inhibitor resensitizes temozolomide-resistant cells to temozolomide. Combinational treatment of YAP inhibitor and temozolomide is effective in shrinking tumor size in mouse xenograft models. In conclusion, our data suggest dysregulated Hippo signaling pathway contributes to temozolomide chemoresistance, thus targeting the Hippo signaling pathway resensitizes GBM cells to temozolomide. This research provides pre-clinical evidence on using YAP inhibitor for combinational therapy with temozolomide for the treatment of glioblastoma.

Citation Format: Cheuk Lun Ethan Wong, Mei Yee Karrie Kiang, Ka Kit Gilberto Leung. Targeting hippo signaling pathway to overcome chemoresistance in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7207.
Abstract 7253: Oncolytic virus therapy with two-factor authentication shows robust safety and efficacy in liver cancer
Authors: Moles Chad M. , Weijmarshausen Peter , Basu Rupsa , Ho Brenda , Farhat Manal , Flaat Taylor , Smith Bruce F. , Whitt Michael , Woodfield Sarah E. , Vasudevan Sanjeev A.
Published: March 2024

Background: Humane Genomics is pioneering multi-factored authenticated oncolytic virotherapy (OVT) using glycoprotein receptor matching and aptazyme technology to positively control replication in cytoplasm. Using VSV as a platform the OVTs show excellent safety and remain highly lytic. Sindbis virus glycoprotein was mutated to eliminate natural infectivity and retargeted to GPC3 with a codon optimized nanobody. An aptazyme was used to regulate viral replication. As far as we are aware, this was the first report of a functional ON switch using a cancer biomarker.

Methods: 293T cells were used for virus rescue and titration by TCID50. Identity was confirmed by Nanopore sequencing. We evaluated safety on off-target SK-Hep-1 and NCI-H28 cell lines, and efficacy on target HepG2 and patient derived HB17 cells. Cell health and GFP was measured at multiple timepoints up to 72 hours.

Results: Safety testing of HGI498 on SK-Hep-1 (GPC3 negative) and NCI-H28 (GPC3 negative, biomarker negative) showed no virus induced cell cytopathic effects in a range of 0.01 ≤ MOI ≤1. HGI498’s efficacy testing on HepG2 and HB17 showed tumor cytotoxicity at MOI 0.01 (p<0.001). Endpoint dilution assay showed a 159-fold and 316-fold difference between off-target NCI-H28 and on-target HepG2 and HB17, respectively. We incorporated an optimized aptazyme with the GPC3 targeted glycoprotein (HGI572), which was similarly rescued, titered, and evaluated for selectivity. HGI572 demonstrated approximately 1000-fold higher titer on target HepG2 and HB17 cells than off-target cells. Initial in vivo MTD study shows that both HGI498 and HGI572 are well tolerated, and are currently being investigated in vivo for efficacy on Hep3B in NSG mice. HGI498 has shown no seroprevalence (in vitro) and is stable at cryostorage for a minimum of 11 months.

Conclusion: We have successfully engineered a two-factor authentication enabled OVT to address an unmet need for a therapy for liver cancer. As far as we are aware, this is the first report of an ON switch using a cancer protein to control viral replication, and the ON/OFF control is the highest to date.

Citation Format: Chad M. Moles, Peter Weijmarshausen, Rupsa Basu, Brenda Ho, Manal Farhat, Taylor Flaat, Bruce F. Smith, Michael Whitt, Sarah E. Woodfield, Sanjeev A. Vasudevan. Oncolytic virus therapy with two-factor authentication shows robust safety and efficacy in liver 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 7253.
Abstract 7269: Karyopherin α-2, a nuclear export protein, promotes cancer progression in lung adenocarcinoma
Authors: Cheon Inyoung , Kim Seoree , Cho Sengran , Lee Heejin , Yoon Jung-Sook , Lee Ji Hyun , Chun Sang Hoon , Won Hye Sung , Hong Soon Auck , Ko Yoon Ho , Ahn Young-Ho
Published: March 2024

Introduction: Karyopherin α-2 (KPNA2), a nucleocytoplasmic transport protein, regulates the nuclear import of macromolecules and contributes to carcinogenesis. Actually, KPNA2 is upregulated in various types of cancer tissues and serum from cancer patients. In particular, it is associated with cancer invasiveness and poor prognosis in patient. Here, we tried to present the molecular mechanism and clinical significance of KPNA2 in lung cancer progression and metastasis.

Method: First, we retrospectively analyzed the data extracted from EMR for patients with non-small cell lung cancer receiving curative surgical resection in Uijeongbu and Bucheon St. Mary’s Hospitals (n=165). Immunohistochemistry staining was performed on the tumor microarray samples using antibodies against KPNA2. The functional assay and gene silencing was conducted.

Result: The clinical and pathological information of the experimental group is as follows. Based on the TMA staining, mean KPNA2 score was 36.5 [0-240] and median value was 10. Based on the TMA staining, patients with high KPNA2 expression were related to lymphatic invasion (p = 0.00782), advanced stage (p = 0.0202), and current smoker (p = 0.0074). KPNA2 expression was higher in squamous cell carcinoma than in adenocarcinoma histotype. Patients with high KPNA2 expression showed shorter survival than those with low KPNA2 (median OS (months), 72.8 vs 42.2, P < 0.0001; median RFS (months), 72.8 vs 32.1, P < 0.0011) and relevant to high recurrence (recurrence rate (%), 24.7 vs 44.7, p = 0.007). Further, high KPNA2 expression was associated with poor survival outcomes. Knockdown of KPNA2 in lung cancer cells suppressed the invasion and migration of lung cancer cells and inhibited metastasis in a mouse model of lung cancer. Inversely, KPNA2 overexpression promoted cancer cell growth, invasion, and migration. Moreover, ectopic expression of KPNA2 made lung cancer cells less sensitive to anticancer drugs, Talazoparib and Olaparib, indicating that KPNA2 enhances drug resistance in lung cancer cells.

Conclusion: Collectively, this study suggest that KPNA2 promotes invasiveness and metastasis and is associated with poor patient outcomes; therefore, KPNA2 will be a good therapeutic target or a biomarker in lung adenocarcinoma.

Citation Format: Inyoung Cheon, Seoree Kim, Sengran Cho, Heejin Lee, Jung-Sook Yoon, Ji Hyun Lee, Sang Hoon Chun, Hye Sung Won, Soon Auck Hong, Yoon Ho Ko, Young-Ho Ahn. Karyopherin α-2, a nuclear export protein, promotes cancer progression in 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 7269.
Abstract 7270: Combination targeting of SKP2 and KDM5B induces senescence in castration-resistant prostate cancer cells via AKT signaling
Authors: Brown LaKendria K. , Kanagasabai Thanigaivelan , Li Guoliang , Celada Sherly I. , Chen Zhenbang
Published: March 2024

Prostate cancer (PCa) is the second-leading cause of cancer mortalities and morbidities in the United States and is the most commonly diagnosed malignancy in men. Despite the fact that androgen deprivation therapy is the first-line option to initial responses, most PCa patients invariably develop castration-resistant prostate cancer (CRPC). CRPC is a lethal type of malignancy, therefore, novel and effective treatment strategies are needed. The goal of this study was to evaluate the combination treatment of small molecule inhibitors, SZL-P1-41, a SKP2 target and PBIT, a KDM5B target on PCa growth and progression; as well as to delineate the underlying mechanisms of suppressing CRPC. Literature reports that S-Phase Kinase Associated Protein 2 (SKP2) is upregulated in PCa and Lysine-specific demethylase 5B (KDM5B) serves as a histone demethylase with a crucial role in cancers. Studies showed that KDM5B is increased in human PCa and KDM5B knockout decreases carcinogenic properties of PCa cells. We previously reported that SKP2 loss partially decreases the growth of prostate tumors and that KDM5B levels are reversely regulated by SKP2 in PCa cells. However, the mechanisms of KDM5B and SKP2 interplay on PCa malignancy is unknown. We hypothesize that combination of PBIT and SZL-P1-41 treatment will enhance anti-cancer effects on PCa progression by inducing cellular senescence. Here, we showed that inhibition of KDM5B and SKP2 decreased the proliferation of PCa cells, and KDM5B KO cells were more vulnerable to SKP2 inhibition. More importantly, a combined inhibition of KDM5B and SKP2 significantly blocked malignant progression and migration of PCa cells. Mechanistically, combined inhibition of KDM5B and SKP2 in PCa cells abrogated AKT activation, resulting in an induction of cellular senescence, which was measured via Western blot analysis and senescence-associated β-galactosidase (SA-β-Gal) staining. Taken together, our results show that combined inhibition of KDM5B and SKP2 is more efficacious in inhibiting proliferation and migration in CRPC cells, and this regimen would be an ideal therapeutic approach for treating CRPC.

Citation Format: LaKendria K. Brown, Thanigaivelan Kanagasabai, Guoliang Li, Sherly I. Celada, Zhenbang Chen. Combination targeting of SKP2 and KDM5B induces senescence in castration-resistant prostate cancer cells via AKT signaling [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 7270.
Abstract 731: pHLIP targeted intracellular delivery of calicheamicin
Authors: DuPont Michael , Klumpp Craig , Iraca Marissa , Allababidi Dana , Visca Hannah , Engelman Donald , Andreev Oleg , Moshnikova Anna , Reshetnyak Yana
Published: March 2024

Calicheamicin is a potent, cell-cycle independent enediyne antibiotic that binds and cleaves DNA. Toxicity has led to its approved use in a targeted form as antibody-drug conjugates (ADC) for the treatment of liquid tumors. Mylotarg, one of the first such ADCs, was voluntarily withdrawn from the market due to safety concerns. However, Mylotarg was recently reapproved for acute myeloid leukemia based on new data that demonstrated efficacy with an acceptable safety profile. Besponsa, a related ADC, was approved for acute lymphocytic leukemia in 2017. In both agents, Mylotag and Besponsa, calicheamicin is conjugated to antibodies via an acid-labile hydrazone linker. We used a reduced calicheamicin to conjugate it to a single cysteine residue at the membrane-inserting end of a pH Low Insertion Peptide (pHLIP) via a disulfide bond to generate a linkerless cytoplasmic release. The cytoplasmic reduction of the disulfide releases the calicheamicin, which leads to its activation, DNA binding, and strand scission. pHLIP is a tumor-targeting agent now in clinical trials with imaging and therapeutic payloads. We studied the interaction of pHLIP-calicheamicin with liposomal and cellular membranes and demonstrated that the agent exhibits cytotoxic activity both in highly proliferative cancer cells and in non-proliferative immune cells, such as polarized M2 macrophages. In mice, treatment led to the growth inhibition of immuno-suppressive CT26 tumors with no signs of toxicity. Biodistribution studies confirmed tumor targeting with no accumulation of the agent in organs and tissues. The fluorescent version of the agent was observed within the tumor mass and tumor-stroma interface, where CD206+ M2 tumor-associated macrophages (M2-TAMs) reside. Treatment of tumors led to the depletion of M2-TAMs within the tumor core. Thus, pHLIP-calicheamicin could be developed into an effective therapeutic for the treatment of solid tumors with abundant immuno-suppressive M2-TAMs.

Citation Format: Michael DuPont, Craig Klumpp, Marissa Iraca, Dana Allababidi, Hannah Visca, Donald Engelman, Oleg Andreev, Anna Moshnikova, Yana Reshetnyak. pHLIP targeted intracellular delivery of calicheamicin [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 731.
Abstract 7319: Glycemic traits and colorectal cancer survival in a cohort of South Korean patients: A Mendelian randomization analysis
Authors: Jun So Yon , Cho Sooyoung , Kim Min Jung , Park Ji Won , Jeong Seung Yong , Shin Aesun
Published: March 2024

Background: Clinical diabetic traits have been reported to be associated with increased colorectal cancer risk (CRC) in observational studies. Using the Mendelian randomization (MR) analysis method, we examined the causal association between glycemic traits, such as fasting glucose (FG), fasting insulin (FI), and glycosylated hemoglobin A1c (HbA1c), and survival in a cohort of CRC patients.

Methods: We conducted a two-sample MR analysis among a cohort of patients with locally advanced CRC at Seoul National University Hospital. Single-nucleotide polymorphisms robustly associated (P<5 × 10−8) with the three glycemic traits were obtained from the Meta-Analyses of Glucose and Insulin-related traits Consortium, Asian Genetic Epidemiology Network, and Korea Biobank Array. Three-year and five-year overall survival (OS) and progression-free survival (PFS) were used as outcomes. Survival analysis was conducted using subgroup analysis by cancer stage and subsite in a multivariate Cox proportional hazards model adjusted for age and sex to examine whether glycemic traits affected survival.

Results: A total of 509 patients were included in our final analysis. MR analysis showed that HbA1c levels were associated with poor three-year OS (β=4.20, P=0.02). Sensitivity analyses did not show evidence of any violations of the MR assumptions. In the cancer subgroup analysis of the Cox proportional hazards model, pooled hazard ratios for FG were significantly associated with poor three-year OS and PFS regardless of cancer stage. FI was not significantly associated with any three-year survival endpoints. Among stage III patients, three glycemic traits were significantly associated with both five-year OS and PFS. Location-specific subgroup analysis showed a significant association between three glycemic traits and five-year PFS in patients with left-sided colon cancer. FG was associated with poor three-year survival for colon cancer but not rectal cancer.

Conclusions: Our results suggest that FG and HbA1c could be used to predict prognosis in CRC patients. Lifestyle and/or pharmacological interventions targeting glycemic traits could help improve survival for CRC patients.

Citation Format: So Yon Jun, Sooyoung Cho, Min Jung Kim, Ji Won Park, Seung Yong Jeong, Aesun Shin. Glycemic traits and colorectal cancer survival in a cohort of South Korean patients: A Mendelian randomization 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 7319.
Abstract 7368: Sentinel omics signatures: Comparative clinical and blood sample analysis from canine mammary tumor patients and their human guardian
Authors: Son Keun Hong , Nam A-Reum , Park Hyoung-Min , Kim HuiSu , Lee Jeong-Woon , Cho Je-Yoel
Published: March 2024

Breast cancer remains a leading cause of morbidity and mortality worldwide, necessitating innovative approaches for early detection and intervention. This study leverages the comparative biology paradigm, exploring the shared oncological pathways between humans and canines through a unique multi-omics approach. We have gathered a diverse cohort comprising healthy dogs, canine mammary tumor patients, and their respective human guardians, collecting comprehensive clinical data alongside blood samples. Employing RNA-seq, MBD-seq, and LCMS, we aim to construct a detailed transcriptomic, methylomic, and proteomic landscape to elucidate potential sentinel biomarkers indicative of an oncogenic environment shared between species. While results are forthcoming, the premise of our research rests on the hypothesis that environmental factors contributing to mammary cancer may manifest systemically, potentially affecting both canines and humans. By delineating these interspecies molecular signatures, we hope to advance the field of precision medicine, offering insights into early detection and the systemic nature of cancer pathobiology. This abstract presents the foundation and direction of our ongoing investigation, with a commitment to providing a comprehensive update, inclusive of significant findings, at the conference.

Citation Format: Keun Hong Son, A-Reum Nam, Hyoung-Min Park, HuiSu Kim, Jeong-Woon Lee, Je-Yoel Cho. Sentinel omics signatures: Comparative clinical and blood sample analysis from canine mammary tumor patients and their human guardian [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 7368.