bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB271: Synergistic anti-tumor efficacy in olaparib-sensitive and -resistant models via simultaneously inhibition of USP1 and PARP
Authors: Yang Shuqun , Li Zhengtao , Zhou Lei , Zhou Feng , Qin Xiaokang , Xue Liting , Xu Piaopiao , Tang Jianxing , Wang Wendy , Tang Renhong 
Published: April 2024

Abstract
SIM0501 is a potent, orally bioavailable, specific inhibitor for USP1. We have explored its combination with olaparib, an approved PARP inhibitor, in both in vitro cancer cell lines and in vivo tumor models. Specifically, SIM0501 showed synergistic effect with olaparib on cell lines across different cancer types, including breast, ovarian, and prostate cancers. Most of these cell lines contain mutations in the homologous recombinational repair (HRR) pathway, which is likely the reason for their susceptibility to the combined inhibition on USP1 and PARP. In the in vivo efficacy studies, SIM0501 dose-dependently inhibited tumor growth when combined with olaparib, including BRCA1-mutated MDA-MB-436, BRCA-wildtype olaparib-resistant OVCAR3, and olaparib-resistant ovarian PDX models. Further, in the MDA-MB-436 model, delayed addition of olaparib to SIM0501 showed comparable efficacy with simultaneous combination treatment, suggesting the flexibility in add-on dosing strategy. Regarding the biomarker research, dose-dependent increase of Ub-PCNA was demonstrated by western blot (WB) following in vivo efficacy studies. Moreover, we have developed robust IHC detection method for Ub-PCNA, which correlated well with WB results. Since Ub-PCNA is a direct target of USP1, these results will facilitate the clinical assessment of target engagement by SIM0501. In summary, SIM0501 demonstrates strong synergistic anti-tumor growth effect in combination with PARP inhibitors in both in vitro and in vivo pharmacology studies, which supports the clinical testing of SIM0501, in combination with PARP inhibitors in patients harboring HRR mutations.
Citation Format: Shuqun Yang, Zhengtao Li, Lei Zhou, Feng Zhou, Xiaokang Qin, Liting Xue, Piaopiao Xu, Jianxing Tang, Wendy Wang, Renhong Tang. Synergistic anti-tumor efficacy in olaparib-sensitive and -resistant models via simultaneously inhibition of USP1 and PARP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB271.
Abstract LB293: O-GlcNAc transferase drives the proliferative state in adaptive drug tolerance
Authors: Menon Dinoop Ravindran , Hammerlindl Heinz , Gimenez Gregory , Zuegner Elmar , Magens Christoph , Eccles Michael , Fujita Mayumi , Schaider Helmut 
Published: April 2024

Abstract
Drivers of the drug tolerant proliferative persister (DTPP) state have not been well investigated. Histone H3 lysine-4 trimethylation (H3K4me3), an active histone mark, might enable slow cycling drug tolerant persisters (DTP) to regain proliferative capacity. This study aimed to determine H3K4me3 transcriptionally active sites identifying a key regulator of DTPPs in melanoma. Deploying a model of adaptive cancer drug tolerance H3K4me3 ChIP-seq data of DTPPs guided identification of top transcription factor binding motifs. These suggested involvement of O-linked N-acetylglucosamine transferase (OGT), which was confirmed by metabolomics analysis and biochemical assays. OGT impact on DTPPs and adaptive resistance was explored in vitro and in vivo. H3K4me3 remodeling was widespread in CPG island regions and DNA binding motifs associated with O-GlcNAc marked chromatin. Accordingly, we observed an upregulation of OGT, O-GlcNAc and its binding partner TET1 in chronically treated cancer cells. Inhibition of OGT led to loss of H3K4me3 and downregulation of genes contributing to drug resistance. Genetic ablation of OGT prevented acquired drug resistance in vivo. Our findings uncover a fundamental mechanism of adaptive drug resistance that governs cancer cell reprogramming towards acquired drug resistance, a process that can be exploited to improve response duration and patient outcomes.
Citation Format: Dinoop Ravindran Menon, Heinz Hammerlindl, Gregory Gimenez, Elmar Zuegner, Christoph Magens, Michael Eccles, Mayumi Fujita, Helmut Schaider. O-GlcNAc transferase drives the proliferative state in adaptive drug tolerance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB293.
Abstract LB300: RNA splicing variants of the novel long non-coding RNA, CyKILR, exhibit distinct possess divergent biological functions in lung cancer
Authors: Xie Xiujie , Macknight Patrick H. , Lu Amy L. , Chalfant Charles E. 
Published: April 2024

Abstract
The cyclin-dependent kinase inhibitor 2A (CDKN2A) gene encodes the tumor suppressors, p16(INK4A) and p14(ARF), and is found inactivated or deleted in non-small cell lung cancer at a high percentage. In this study, a novel, uncharacterized long non-coding RNA (lncRNA) (ENSG00000267053) located on chromosome 19p13.12 was found overexpressed in non-small cell lung cancer (NSCLC) cells with a wild-type and active CDKN2A gene. The expression of this Cyclin-Dependent Kinase Inhibitor 2A-regulated lncRNA (CyKILR) was also associated with the expression of the tumor suppressor, Liver kinase B1 (LKB1), a product of the STK11 gene. Characterization of CyKILR identified distinct RNA splicing variants classified into two groups based on their exon 3 inclusion/exclusion status, CyKILRa (exon 3 included) and CyKILRb (exon 3 excluded). The CDKN2A and STK11 gene products not only regulated the expression of CyKILR mRNA in non-transformed cells, but also the interplay between these genes synergistically regulated inclusion of exon 3 into the mature CyKILR RNA as shown by dramatic loss of exon 3 inclusion when mRNAs from both tumor suppressor genes were downregulated by siRNA. Functionally, CyKILRa predominantly localized to the nucleus, and targeted downregulation of the CyKILRa using antisense RNA oligonucleotides (ASOs) significantly enhanced cellular proliferation, migration, and clonogenic survival in mechanistic studies. In contrast, CyKILRb predominantly localized to the cytoplasm, and downregulation of CyKILRb using siRNA significantly reduced cell proliferation, migration, and clonogenic survival. Additionally, downregulation of CyKILRb, in stark contrast to CyKILRa, reduced tumor growth in vivo. Interrogation of cell signaling pathways by transcriptomics analyses demonstrated that CyKILRa suppressed key mitogenic pathways further demonstrating the tumor suppressive role of this CyKILR variant. On the other hand, CyKILRb induced key survival pathways further corroborating the oncogenic nature of this variant. Taken together, our findings shed light on the complexity of lncRNA expression and the alternative RNA splicing of lncRNAs as well as their roles in cell signaling and tumorigenesis.
Citation Format: Xiujie Xie, Patrick H. Macknight, Amy L. Lu, Charles E. Chalfant. RNA splicing variants of the novel long non-coding RNA, CyKILR, exhibit distinct possess divergent biological functions in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB300.
Abstract LB307: The role of tumor microenvironment derived growth factors in pediatric brain tumors
Authors: Cruz Andrea , Johnson Brenden , Gatesman Taylor , Halbert Mathew , Taori Suchet , Hu Baoli , Kohanbash Gary , Pollack Ian F. , Agnihotri Sameer 
Published: April 2024

Abstract
Introduction: Children with H3K27-altered diffuse midline gliomas (DMG-H3K27a), have a 5-year survival rate of only 2% following diagnosis. While in-depth genomic characterization has been performed in DMG-H3K27a, very few druggable targets have been identified. A common feature of DMG-H3K27a is infiltration of microglia, macrophages, other myeloid cells, collectively referred to as GAMs. Cellular crosstalk between non-tumor and tumor cells in the tumor microenvironment (TME) can both promote and or inhibit tumor growth, thus representing an opportunity in the pursuit of novel therapeutics. We have recently determined that DMG-H3K27a tumor cells stimulate microglial secretion of pro-tumor growth factors.
Hypothesis: Microglial-derived growth factors activate receptor tyrosine kinases (RTKs) via paracrine signaling in DMG-H3K27a.
Methods: We used scRNA-seq and RNA-seq datasets and, in parallel, in vitro studies, such as co-culture studies, ELISA assays, western blotting, and growth assays to test our hypothesis. In addition, we are developing a mouse-human chimeric neutralizing antibodies of our top targets for in vivo studies.
Preliminary Results: Microglial cells secrete growth factors into the TME, which promotes DMG-H3K27a cell proliferation and growth. Targeting growth factors with neutralizing antibodies attenuates glioma cell proliferation in co-culture studies.
Conclusion: This research uncovers an important signaling network between GAMs and DMG-H3K27a that can be therapeutically targeted.
Citation Format: Andrea Cruz, Brenden Johnson, Taylor Gatesman, Mathew Halbert, Suchet Taori, Baoli Hu, Gary Kohanbash, Ian F. Pollack, Sameer Agnihotri. The role of tumor microenvironment derived growth factors in pediatric brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB307.
Abstract LB347: PLA2G2D/PGD2-PTGDR signaling deficiency restricts the melanoma progression and lung metastasis
Authors: Dhakal Hima , Zheng Jian 
Published: April 2024

Abstract
Normal 0 false false false EN-US KO X-NONE/* Style Definitions */table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin-top:0in; mso-para-margin-right:0in; mso-para-margin-bottom:8.0pt; mso-para-margin-left:0in; line-height:107%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi; mso-font-kerning:1.0pt; mso-ligatures:standardcontextual;} Melanoma is a serious form of skin cancer with an approximate incidence more than 160,000 cases and 41,000 melanoma-associated death per annual globally. Malignant Melanoma is more dangerous because of its rapid spread and metastasis if it were not treated at an early stage. The high mortality of malignant melanoma incites an urgent need to refine the current treatments. Phospholipase A2 group IID (PLA2G2D) is an inducible enzyme expressed in myeloid cells, positively associated with immune infiltration through producing anti-inflammatory prostaglandin D2 (PGD2). The aging-related increase of PLA2G2D and PTGDR, a PGD2 receptor, makes them attractive targets for treating aged-related diseases, such as chronic inflammation and cancer diseases. In this study, by using Pla2g2d-/- and Ptgdr-/- mice, we found that PLA2G2D or PTGDR deficiency effectively restricted the in-situ growth and lung metastasis of subcutaneously implanted melanoma B16F10. These benefits are associated with the early enrichment of γδ-T cells in the tumor mass. The activation and accumulation of γδ-T cells can be induced in B16F10-bearing WT mice by the adoptive transfer of Pla2g2d-/- or Ptgdr-/- DCs. Pro-inflammatory characteristics of Pla2g2d-/- or Ptgdr-/- DCs, especially the production of IL-1b, contribute to γδ-T cells recruitment. These tumor-restraining effects were further confirmed in DC-specific PTGDR deficient (zDCcrePtgdrfloxp ) mice. Taken together with the prominent expression of PLA2G2D and PTGDR in human lung cancer tissue, this study demonstrates the potential of PLA2G2D-PGD2/PTGDR signaling-targeted therapy in treating melanoma and lung metastasis.
Citation Format: Hima Dhakal, Jian Zheng. PLA2G2D/PGD2-PTGDR signaling deficiency restricts the melanoma progression and lung metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB347.
Abstract LB374: The microbial landscape of colorectal cancer across 11 countries
Authors: Abbasi Ammal , Alexandrov Ludmil 
Published: April 2024

Abstract
Colorectal cancer (CRC) is the second most frequent cause of cancer-related deaths globally. CRC is influenced by the colorectal microbiome, which plays a pivotal role in inflammation, DNA damage, and production of cancer-promoting metabolites. Most prior CRC microbial studies have identified multiple microbes enriched in tumor samples, but these examinations have generally focused on CRC from a specific country and have not accounted for CRC patient’s tumor site, sex, diet, or geographical location. Further, the interconnection between somatic alterations and microbiome composition has not been comprehensively explored. Here, we examine the microbiome profiles of 963 whole-genome sequenced CRC and their matched-normal blood from 11 different countries with highly varying age-standardized incidence rate (ASR) for colorectal cancer. Matched normal blood samples exhibited a strong intra- and inter-microbial heterogeneity across the 11 countries. In contrast, while CRC tumors exhibited a higher microbial diversity when compared to their matched-normal samples, the top 10 most abundant CRC taxa were strikingly similar across all countries, suggesting a global convergence of the CRC microbiome composition. Moreover, a positive correlation was observed between the colorectal cancer ASR across 11 countries and the CRC microbial diversity (rho=0.91, p-value: 0.0002), suggesting that countries with high incidence rates also have high microbial diversities. After accounting for age, shipment batch, sex, and country-specific effects on the microbiome composition, we observed a core set of five microbial species enriched in CRC across all countries, which included Bacteroides fragilis,Phocaeicola Vulgatus, Faecalibacterium Prausnitzii, Fusobacterium Nucleatum, and Escherichia Coli. A strong correlation (rho=0.84, p-value: 0.0013) was observed between Bacteroides fragilis and a novel mutational signature characterized by A/T[C&gt;G]T and T[T&gt;G]N substitutions. No association was observed between polyketide synthase gene complex (pks)+ microbe and the presence of the pks-derived colibactin mutational signatures. Furthermore, additional associations were observed between the microbiome and other mutational signatures and driver genes. Overall, this study delivers a global atlas of the microbial landscapes of CRC genomes across 11 countries and their links with genetic changes and epidemiological risk factors.
Citation Format: Ammal Abbasi, Ludmil Alexandrov. The microbial landscape of colorectal cancer across 11 countries [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB374.
Abstract LB434: Rapid and reproducible expansion of rare tumor cells: The R3CE platform for personalized medicine
Authors: Kuo Wen-Hung , Huang Yen-Jang , Chen Jia-Yang , Wu Yi-Chun , Chen Chia-Chun , Pegram Mark D. , Chang Ying-Chih 
Published: April 2024

Abstract
We have developed a novel single-cell derived 3D organoid culture platform, Rapid, Reproducible, Rare Cell 3D Expansion (R3CE), capable of generating 3D organoids from solid tumors and normal tissues obtained via surgical tissues and needle biopsies within one week. This method demonstrates over 90% success in banking for at least two passages with over 106 cells across various cancer types, including breast cancer, colorectal cancer, hepatoma cancer, and ovarian cancer. The organoids maintain high fidelity to original tissues, as evidenced by H&E staining, WES, and protein marker analysis across generations. Notably, the R3CE platform can also cultivate circulating tumor cells (CTCs) from peripheral blood. The drug sensitivity profiles of RCE-cultured CTCs closely mirrored clinical outcomes in breast cancer patients. For a patient with stage IV HER2-positive breast cancer, our real-time assay results led to an adjustment in treatment from lapatinib/5-FU to lapatinib/Trastuzumab emtansine (TDM-1), which resulted in substantial clinical improvement. To our knowledge, the R3CE platform is the first 3D organoid system that does not require aggregation or 3D scaffold such as matrigel system. These advancements position the R3CE platform as a promising tool for personalized medicine, offering a rapid and accurate method for drug screening and therapeutic response prediction to guide clinical decision-making in cancer treatment.
Citation Format: Wen-Hung Kuo, Yen-Jang Huang, Jia-Yang Chen, Yi-Chun Wu, Chia-Chun Chen, Mark D. Pegram, Ying-Chih Chang. Rapid and reproducible expansion of rare tumor cells: The R3CE platform for personalized medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB434.
Abstract LB447: Drug delivery and efficacy testing using vascularized tumor-on-a-chip
Authors: Kim Da-Hyun 
Published: April 2024

Abstract
The inhibition of tumor angiogenesis is considered a promising strategy to impede cancer progression, as the vasculature associated with tumors plays a crucial role in supplying blood and facilitating metastasis. Therefore, the in vitro replication of vascularized tumors is essential for comprehending cancer pathology and discerning the mechanisms governing tumor cell proliferation, metastasis, and response to pharmaceutical interventions. In this study, we fabricated vascularized tumor-on-a-chip to recapitulate the pathological features of solid tumors. We first developed hybrid spheroids consisting of tumor and endothelial cells, resulting in self-assembled intratumoral vessels. This approach enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids composed of only cancer cells. RNA sequencing analysis revealed that the tumor-EC hybrid spheroids exhibited expression profiles associated with aggressive behaviors, such as cancer progression, invasion and metastasis. The blood vessels sprouting around the hybrid spheroids on the chip displayed the distinctive characteristics of leaky tumor vessels. We further validated the suppressive effects of axitinib on tumor growth and angiogenesis, depending on exposure dose and time. Notably, we successfully induced both lymphangiogenesis and angiogenesis around the tumor hybrid spheroids by promoting interstitial flow. In summary, our findings demonstrated that vascularized tumor-on-a-chip reproduces various characteristics of vascularized tumors. Consequently, our model stands as a valuable platform for investigating interactions between within tumor microenvironments and exploring therapeutic strategies in cancer.
Citation Format: Da-Hyun Kim. Drug delivery and efficacy testing using vascularized tumor-on-a-chip [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB447.
Abstract NG06: Tracing the developmental origins of group 3 medulloblastoma
Authors: Saulnier Olivier 
Published: April 2024

Abstract
Citation Format: Olivier Saulnier. Tracing the developmental origins of group 3 medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr NG06.
Abstract PL03-02: From microniches to single cells: Understanding the impact of intratumoral microbes on spatial and cellular heterogeneity in cancer
Authors: Bullman Susan 
Published: April 2024

Abstract
The tumor microenvironment (TME) is a dynamic network that includes a variety of non-malignant cells such as endothelial cells, fibroblasts, and immune cells, which play a crucial role in tumor behavior. Advances in molecular analysis have recently identified the presence of intratumoral microbiota in several solid cancer types. However, the specific ways these microorganisms interact with human cells within the TME and contribute to disease progression are not yet fully understood. Our recent research provides new insights into how bacterial components of the intratumoral microbiota contribute to tumor heterogeneity, particularly in head and neck and colorectal cancers. To investigate these interactions, we have adapted and applied emerging technologies in spatial transcriptomics, spatial proteomics, and single-cell sequencing (INVADEseq). Our spatial analyses show that the intratumoral microbiota are not distributed randomly within human tumors; instead, they localize to distinct microniches that promote immune and epithelial cell functions supportive of cancer progression. These bacterial-colonized microniches are characterized by myeloid cell infiltration, upregulation of MAPKs and immune checkpoint proteins, and reduced T-cell levels. Furthermore, INVADEseq single-cell RNA sequencing has enabled us to identify the dominant host cell-associated bacteria, the human cell types they infect, and their impact on the transcriptional programs of infected cells from patient tumor specimens. In oral squamous cell carcinoma, Fusobacterium and Treponema species have been identified as the dominant cell-associated bacterial taxa, primarily infecting subsets of macrophages and aneuploid cancer epithelial cells and upregulating pathways associated with cancer progression. Our findings offer insights into the complex interplay between intratumoral microbiota and human components of the TME, emphasizing their role in supporting intratumoral heterogeneity and influencing cancer progression. Understanding these dynamics holds significant promise for the development of targeted therapeutic strategies aimed at disrupting bacterial-human spatial and cellular interactions within the TME.
Citation Format: Susan Bullman. From microniches to single cells: Understanding the impact of intratumoral microbes on spatial and cellular heterogeneity in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr PL03-02.