bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 7273: Small molecule activation of PP2A in the treatment of melanoma
Authors: Johnson Hannah , Singh Amandeep , Raza Asif , Narayan Satya , Sharma Arun K. 
Published: March 2024

Abstract
Protein phosphatase 2A (PP2A) is a heterotrimeric holoenzyme functioning as a serine/threonine phosphatase, where it accounts for about 50-70% of all serine/threonine phosphorylation in the cell. Yet, PP2A is commonly inactivated in cancer, likely due to its role as a tumor suppressor. Due to the important role PP2A plays in many cellular processes, including those involved with tumor progression, there is a current need for novel therapeutics capable of targeting PP2A in cancer. Currently, none of the current PP2A modulators have made it into approved clinical use. As such, we have recently synthesized the PP2A activators, PPA24 and PPA27, using molecular docking and fragment-based drug design based on the structures of recently reported PP2A activators, iHAP1 and NSC49L. We were previously able to establish PPA24 as the lead compound in treating colorectal cancer (CRC) in vitro, compared to PPA27 and the parent compounds. Nevertheless, a single dose NCI-60 screen of both PPA24 and PPA27 indicated the cell selectivity present in both compounds and revealed the potential effect these compounds could have in other cancers. Further evaluation with an extended NCI-60 5-dose screen of PPA24 and PPA27 demonstrated a strong potential for both compounds in treating melanoma. Overall, the NCI-60 screen displayed PPA27 as most effective in melanoma across all cell lines screened, while PPA24 was found to be effective in both CRC and melanoma cell lines, agreeing with our previous findings. A cell viability screening of PPA24 and PPA27 in our laboratory across 5 melanoma cell lines (SK-MEL-2, SK-MEL-28, A375, Mel1241, and 451Lu) identified IC50 values in the range of 3.45-8.94 µM for PPA27 and 5.99-14.45 µM for PPA24. The parent compounds, iHAP1 and NSC49L, were also evaluated and NSC49L was found to be less effective in melanoma than previously found in CRC cells. Both PPA24 and PPA27 were found to be effective in cell lines with and without BRAFV600E mutation, though it appears the metastatic cell line, 451Lu, required an increased concentration for all compounds as compared to the IC50 values found in the other melanoma cell lines. Further evaluation revealed PPA24 and PPA27 as dose-dependently inducing apoptosis in cells with BRAFV600E (A375) and BRAF WT (SK-MEL-2). Together, these findings show the potential of PPA24 and PPA27 as therapeutic treatments for melanoma with or without BRAF mutations and are currently being further evaluated in several in vitro and in vivo melanoma models in our laboratory.
Citation Format: Hannah Johnson, Amandeep Singh, Asif Raza, Satya Narayan, Arun K. Sharma. Small molecule activation of PP2A in the treatment of melanoma [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 7273.
Abstract 7277: Discovery of INV-9956, an orally available and highly selective Cyp11A1 inhibitor for the treatment of castration-resistant prostate cancer with drug resistant AR mutations
Authors: Bai Chang , Chen Danqi , Xia Zilei , Huang Shujuan , Lin LIshan , Zeng Zhaopie , Su Jing , Sun Yongkui 
Published: March 2024

Abstract
Androgen Receptor (AR) signaling plays a profound role in prostate cancer and development. Efforts in harnessing androgen and AR axis for castration-resistant prostate cancer treatment have led to discovery of several therapeutics, including AR antagonists and Cyp17 inhibitors. However, resistance to these approved therapeutics has emerged, and remained a significant unmet medical need. Among the prominent resistance mechanisms of action are restored androgen signaling via AR amplification and overexpression, and gain-of-function mutations occurring at AR ligand binding domain that can be agonized by existing AR antagonists and/or non-androgenic steroids such as glucocorticoids. Targeting Cyp11A1 that catalyzes the formation of pregnenolone is effective to ablate biosynthesis of androgens and all steroids and thus holds promise to deliver coverage of a significant percentage of drug resistant AR mutations and benefit CRPC patients post treatment with AR antagonists or Cyp17 inhibitors. Here we present discovery and characterization of INV-9956, an orally available, selective, and potent Cyp11A1 inhibitor with well-acceptable pharmacokinetic properties. INV-9956 potently inhibits biosynthesis of pregnenolone and other androgens in H295R cells with IC50 at single-digit nanomolar, suppresses proliferation of prostate cancer cell lines harboring major clinically acquired drug resistant AR LBD mutations, such as AR L702H using coculture assays. Orally administered INV-9956 showed consistent dose dependent PK/PD correlations across animal species. Particularly, INV-9956 displayed pronounced tumor inhibition superior to known competitors in a CRPC VCaP xenograft model and in a “humanized” animal model. Furthermore, INV-9956 displayed a good tox profile in 14-day repeated dosing rat and dog studies, supported by a high selectivity to Cyp11A1 over other Cyp family members, clean hERG and mini-Ames, and no significant off-target activity in a safety panel screen. The promising preclinical profiles of INV-9956 lend strong support to its potentials in addressing unmet needs in CRPC treatments and warrant clinical development.
Citation Format: Chang Bai, Danqi Chen, Zilei Xia, Shujuan Huang, LIshan Lin, Zhaopie Zeng, Jing Su, Yongkui Sun. Discovery of INV-9956, an orally available and highly selective Cyp11A1 inhibitor for the treatment of castration-resistant prostate cancer with drug resistant AR mutations [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 7277.
Abstract 7287: High-grade serous ovarian carcinoma detected with TP53 mutation panel and SiMSen-Seq
Authors: Widjaja Amanda Olsson , Micallef Peter , Ulfenborg Benjamin , Lycke Maria , Gyllensten Ulf , Carlsson Therese , Österlund Tobias , Ståhlberg Anders , Linder Anna , Sundfeldt Karin 
Published: March 2024

Abstract
Background: Ovarian carcinoma (OC) has the highest mortality among gynecologic malignancies due to absent or unspecific symptoms. The high-grade serous ovarian carcinoma (HGSC) accounts for over 60% of the OC associated deaths. The most frequent genetic aberrations in HGSC are mutations in the TP53 gene, detected in approximately 96% of the tumors. Previous studies have proposed potential diagnostic utility of detecting mutations in circulating tumor DNA (ctDNA) from OC patients. However, the need for diagnostic methods capable of detecting asymptomatic HGSC is unmet.
Objectives: The primary aims of this study were to design a screening tool for identification of HGSC and to evaluate the suitability of various clinical specimen types for diagnostic applications.
Methods: In this study, we designed a highly sensitive and robust screening tool using the simple, multiplexed, PCR-based barcoding of DNA for sensitive mutation detection using sequencing (SiMSen-Seq) technique for identification of HGSC (n=11) by TP53 mutation profile in various clinical specimen for diagnostic applications. Specimens sampled included primary tumors, ascites, plasma, vaginal samples, and both liquid and solid samples from cyst-, endocervical-, and endometrial origin (n=94).
Results: The in-house designed panel amplified 17 regions, encompassing 619 nucleotide positions within the TP53 gene. Pathogenic variants were identified in 10/11 of the primary tumors, with a VAF ≥ 9% (range: 9-91). Preliminary data indicated that all (100%) paired samples obtained corresponding somatic mutations between two or more of the different compartments from the same patient.
In total 10/10 ascites-, 16/16 cyst-, 8/8 plasma-, 5/8 vaginal-, 17/22 endocervical-, and 14/19 endometrial samples showed somatic variants at a consensus read depth of 3 and a minimum VAF ≥ 0.1%.
Conclusion: The present study suggests that the TP53 mutation panel can identify somatic variants in a variety of non-invasive liquid biopsies. Additionally, the assessment of the TP53 mutation panel exhibits potential for forthcoming clinical utilization as a diagnostic tool.
Citation Format: Amanda Olsson Widjaja, Peter Micallef, Benjamin Ulfenborg, Maria Lycke, Ulf Gyllensten, Therese Carlsson, Tobias Österlund, Anders Ståhlberg, Anna Linder, Karin Sundfeldt. High-grade serous ovarian carcinoma detected with TP53 mutation panel and SiMSen-Seq [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 7287.
Abstract 7293: Serum fusion gene transcripts to predict liver cancer
Authors: Luo Jian-Hua , Yu Yan-Ping , Liu Silvia , Geller David 
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancers and one of the most lethal malignancies for human. Early diagnosis of HCC is crucial in reducing the mortality of the disease. In this report, we analyzed a panel of 9 fusion transcripts in the serum samples from 136 individuals (61 HCC patients and 75 individuals without HCC) using TaqMan qRT-PCR. Our results showed that 7 fusion genes were frequently detected in the serum samples of HCC patients, including MAN2A1-FER (100%), SLC45A2-AMACR (62.3%), ZMPSTE24-ZMYM4 (62.3%), Pten-NOLC1 (57.4%), CCNH-C5orf30 (55.7%), STAMBPL1-FAS (26.2%) and PCMTD1-SNTG1 (16.4%). We then divided the samples into training and testing cohorts based on the sample collection time: 82 individuals with samples collected before 2016 as the training cohort while 54 individuals with sample collected after 2015 as the testing cohort. Machine learning models was constructed based on the combination of different fusion genes with various cutoffs to predict the occurrence of HCC in the training cohort using leave-one-out-cross-validation approach. One of the machine learning models called 4-fusion genes logistic regression model (MAN2A1-FER&lt;40, CCNH-C5orf30&lt;38, SLC45A2-AMACR&lt;41, Pten-NOLC1&lt;40) produced a 91.5% accuracy, with a sensitivity of 87.1% and specificity of 94.1% in the training cohort. The same model generated an accuracy of 83.3%, with a sensitivity of 73.3% and specificity of 95.8% in testing cohort. When the training and testing cohorts were combined, the model produced an accuracy of 86%. When serum α-fetal protein (AFP) level was incorporated into the machine learning model, we found a 2-fusion gene+AFP logistic regression model (MAN2A1-FER&lt;40, CCNH-C5orf30&lt;38, AFP) generated an accuracy of 94.8% in the training cohort with a sensitivity of 93.5% and specificity of 96.3%. The same model generated 95% accuracy in both the testing cohort and the combined cohorts in the validation. Cancer treatment reduced most of the serum fusion transcript levels, reflecting the reduction of the tumor load. As a result, serum fusion gene machine learning models may serve as important tools in screening HCC and monitoring the impact of HCC treatment.
Citation Format: Jian-Hua Luo, Yan-Ping Yu, Silvia Liu, David Geller. Serum fusion gene transcripts to predict 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 7293.
Abstract 7297: Inhibition of lung tumorigenesis and potentiation of cancer preventive vaccines by a small molecule CA170 targeting the immune checkpoint protein VISTA
Authors: Zhang Qi , Pan Jing , Xiong Donghai , Wang Yian , Miller Mark S. , You Ming 
Published: March 2024

Abstract
The V-domain Ig Suppressor of T cell Activation (VISTA) is expressed on cells of the myeloid and lymphoid lineages and is an emerging target for cancer immunotherapy. Blocking VISTA activates both innate and adaptive immunity to eradicate tumors in mice. Furthermore, a tripeptide small molecule antagonist of VISTA, CA170, exhibited potent anticancer efficacy on carcinogen-induced mouse lung tumorigenesis. We have previously demonstrated that KRAS or EGFR vaccines are effective in preventing lung tumorigenesis driven by either KRAS or EGFR in a pure prevention setting but are less effective in mice carrying existing lesions. Here, we determined if combining an MHC class II-restricted multi-antigen vaccine targeting KRAS or EGFR with CA170 will provide enhanced efficacy in preventing lung cancer progression. Using tetracycline-inducible KRAS and EGFR transgenic mice, we found that lung tumor development was significantly suppressed when CA170, delivered by aerosol inhalation to minimize systemic toxicity, was combined with either KRAS or EGFR MHCII-directed peptide vaccines using a post-initiation model. Flow cytometry and single-cell RNA sequencing (scRNA-seq) revealed that CA170 significantly increases tumor infiltrating CD8+ T cells and enhances effector-memory T cell frequencies and functions of both CD4+ and CD8+ T cells. These changes coincide with significant reductions in G-MDSCs (granulocytic myeloid-derived suppressor cells) and Foxp3+ Treg populations within lung tumors from mice treated with CA170. We found that the KRAS and EGFR preventive vaccines primarily induced the expansion of CD4+ effector T cells. VISTA antagonism by CA170 revealed strong efficacy against lung tumorigenesis with broad immunoregulatory functions that influence effector, memory, and regulatory T cells, and drive an adaptive T cell tumor-specific immune response that enhances the efficacy of the KRAS and EGFR preventive vaccines in transgenic mouse models of lung cancer.
Citation Format: Qi Zhang, Jing Pan, Donghai Xiong, Yian Wang, Mark S. Miller, Ming You. Inhibition of lung tumorigenesis and potentiation of cancer preventive vaccines by a small molecule CA170 targeting the immune checkpoint protein VISTA [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 7297.
Abstract 7323: Tissue resident memory T cell abundances impact non-small-cell lung cancer immune microenvironment and patient prognosis
Authors: Shen Aidan , Garrett Aliesha , Mai Junhua , Zhu Yangzhi , Jiang Chongming 
Published: March 2024

Abstract
Tissue resident memory T cells (TRM) are a specialized subset of long-lived memory T cells that reside in peripheral tissues. However, whether TRM exerts any immunosurveillance role in the tumor immune microenvironment (TIME) and progression of non-small-cell lung cancer (NSCLC), which accounts for 85% of all lung cancers, remains unclear. Our comprehensive analysis of multiple independent single-cell and bulk RNA-seq datasets of patient NSCLC samples generated reliable, unique TRM signatures, through which we could infer the abundance of TRM in NSCLC. We discovered that TRM abundance is consistently positively correlated with CD4+ T helper 1 cells, M1 macrophages, and resting dendritic cells in TIME and significantly impacts the prognosis of NSCLC patients. In addition, TRM signatures are strongly associated with immune checkpoint genes and the prognosis of NSCLC patients, suggesting that TRM signatures are promising prognostic markers for immunotherapy in NSCLC. We then built a machine learning model to predict patient survival based on the TRM signatures and immune related genes. The accuracy of the model was validated by Kaplan-Meyer survival analysis, receiver operating characteristic curves, principal component analysis, and t-distributed random neighbor embedding. We developed a 4-gene risk score that effectively stratified patients into low-risk and high-risk categories. The patients with high-risk scores had significantly lower overall survival than patients with low-risk. The prognostic value of the risk score was independently validated by the Cancer Genome Atlas Program (TCGA) dataset and multiple independent NSCLC patient datasets. Notably, low-risk NSCLC patients with higher TRM infiltration exhibited enhanced T-cell activation, macrophage regulation, and other TIME immune responses related pathways, indicating a more active immune profile benefitting from immunotherapy. Altogether, this study provides valuable insights into the complex interactions between NSCLC TRM and TIME and their impact on patient prognosis, highlighting the importance of TRM in shaping the NSCLC microenvironment. The development of a simplified 4-gene risk score provides a practical prognostic marker for risk stratification.
Keywords: Tissue resident memory T cell, non-small-cell lung cancer, prognosis, tumor immune microenvironment, machine learning
Citation Format: Aidan Shen, Aliesha Garrett, Junhua Mai, Yangzhi Zhu, Chongming Jiang. Tissue resident memory T cell abundances impact non-small-cell lung cancer immune microenvironment and patient prognosis [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 7323.
Abstract 7348: CytoCellDB: A gold standard database for classification and analysis of extrachromosomal DNA in cancer
Authors: Brunk Liz 
Published: March 2024

Abstract
Extrachromosomal DNA (ecDNA), or double minute chromosomes, are established cytogenetic markers for malignancy and genome instability. More recently, the cancer community has gained a heightened awareness of the roles of ecDNA in cancer proliferation, drug resistance and epigenetic remodeling. A current hindrance to understanding the biological roles of ecDNA is the lack of available cell line model systems with experimental cytogenetic data that confirm ecDNA status. Although several recent landmark studies have identified numerous cell lines and tumor models with ecDNA, the current sample size limits our ability to detect ecDNA-driven molecular differences due to limitations in power. Increasing the number of model systems that are known to express ecDNA would provide new avenues for understanding the fundamental underpinnings of ecDNA biology and would unlock a wealth of potential targeting strategies for ecDNA-driven cancers. To bridge this gap, we created CytoCellDB, a resource that provides karyotype annotations, including ecDNA status, and leverages publicly available global cell line data from the Cancer Dependency Map (DepMap) and the Cancer Cell Line Encyclopedia (CCLE). We expanded the total number of cancer cell lines with ecDNA annotations to 632, or 34% of the cell lines in CCLE/DepMap. Of these, 154 cell lines express ecDNA, which is a 240% increase from the current sample size. We demonstrate that a strength of our framework is the ability to interrogate ecDNA, and the compendium of other chromosomal aberrations, in the context of cancer-specific vulnerabilities, drug sensitivities, and other multi-omic features (genomics, transcriptomics, methylation, proteomics). We anticipate that this resource will lower the barrier to systematic, population-scale discoveries related to ecDNA and will provide insights into strategies and best practices for determining novel therapeutics that overcome ecDNA-mediated drug resistance.
Citation Format: Liz Brunk. CytoCellDB: A gold standard database for classification and analysis of extrachromosomal DNA in 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 7348.
Abstract 7367: Dissecting cellular and molecular alterations in pre-invasive to invasive lung cancer progression at single-cell resolution
Authors: Yoffe Liron 
Published: March 2024

Abstract
Non-small cell lung cancer (NSCLC) accounts for most cancer-related deaths worldwide, largely due to diagnosis at advanced metastatic stages. Increased implementation of low-dose computed tomography (CT)-guided screening has led to the identification of non-solid lesions or ground-glass opacities (GGOs) that are not visible on plain chest radiography and can harbor very early-stage tumors. Growth of the lesions and/or development of a solid component can indicate more aggressive behavior. Using the low-dose CT reduced lung cancer mortality by &gt;20%, underscoring the need for early detection and intervention. However, the cellular and molecular determinants contributing to the malignant progression of those early preinvasive lesions remain poorly understood. To assess intratumoral heterogeneity and associated dynamic changes in the immune contexture during early lung carcinogenesis, we performed single-cell RNA-seq and Hyperion imaging on surgically resected freshly harvested tissues from 37 patients (matched solid and non-solid components of lesions and adjacent non-involved lungs), representing a spectrum from preneoplasia to invasive disease. Analysis of &gt;300K cells identified cellular, transcriptomic, and metabolic alterations as well as tumor-stroma cross-talk pathways. Specifically, preinvasive to invasive disease progression was associated with significant changes in the immune landscape determined by an increase in exhausted CD4/CD8 T-cells, suppressive T-regs, polymorphonuclear myeloid-derived suppressor cells, and M2-like macrophages; and a decrease in cytotoxic CD8 T-cells, NK cells, and inflammatory cDC2 cells, suggesting that activation of immunosuppressive/anti-inflammatory microenvironment and suppression of immune activation microenvironment may enable tumor progression.
Citation Format: Liron Yoffe. Dissecting cellular and molecular alterations in pre-invasive to invasive lung cancer progression at single-cell resolution [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 7367.