bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1121: Patient-centric Discovery by Active Learning (PeDAL) platform to predict drug response in a heterogeneous patient population
Authors: Montgomery Robert J. , Gilkey Aaron W. , Kangas Joshua D. , Murphy Robert F. , Uihlein Arlette H. 
Published: June 2023

Abstract
Even after thorough preclinical testing, only 5% of oncology drug candidates entering clinical trials ultimately get approved for use in patients. To find one drug that will be effective in the clinic, drug developers have to test 20 agents, 19 of which will ultimately prove ineffective. Such high attrition rates drive up the cost of treatment and delay getting effective drugs to the market. Here we describe the Patient-centric Discovery by Active Learning (PeDAL) platform and present results of a study that shows it can predict the effectiveness of a drug or a set of drugs in a patient population with 92% accuracy in only 11 weeks while only performing in vitro assays on a fraction of the drug-patient combinations. The power of PeDAL is derived from a combination of AI technology, an extensive drug response and biomarker database, and a biobank of 150,000 tumor samples from 137 tumor types. The study consists of two phases, the first demonstrates that PeDAL’s predictive model efficiently reveals drug-response patterns that provide insight into the treatment of ovarian cancers. The second phase focuses on the in vitro validation of the accuracy of the predictions. The experimental space was 175 FDA-approved drugs and 130 primary ovarian tumor samples. PeDAL’s active machine learning algorithm iteratively optimizes predictive models by learning from in vitro experiments which take into account tumor-stromal interactions and cellular heterogeneity. Importantly, the ability to model patient-drug combinations across a diverse population of primary samples adds a patient heterogeneity dimension to the generated drug response predictions. After performing 720 high throughput experiments, PeDAL was able to make drug-response predictions for an additional 4,600 drug/tumor predictions. Additional in vitro validation experiments confirm the reproducibility and accuracy of the high-confidence predictions generated by PeDAL with area under the curve (AUC) values &gt;0.95. These results have strong implications not only for the new drug discovery process, but also for identifying opportunities for drug repurposing. We demonstrate that the PeDAL platform is a highly efficient tool to make confident predictions about drug-tumor pairings allowing the discovery of many more drug-tumor responses than are practical to test in vitro.
Citation Format: Robert J. Montgomery, Aaron W. Gilkey, Joshua D. Kangas, Robert F. Murphy, Arlette H. Uihlein. Patient-centric Discovery by Active Learning (PeDAL) platform to predict drug response in a heterogeneous patient population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1121.
Abstract 1122: Pan-cancer analysis reveals roles of retrotransposon-fusion RNAs
Authors: Lee E. Alice , Lee Boram , Choi Yoonjoo , Park Junseok , Voshall Adam , Maury Eduardo , Kang Yeeok , Kim Yeon Jeong , Lee Jin-Young , Shim Hye-Ran , Kim Si-Cho , Chu Hoang Bao Khanh , Kim Da-Won , Kim Minjeong , Choi Eun-Ji , Ha Kyungsoo , Choi Jung Kyoon , Kim Yongjoon , Park Woong-Yang 
Published: June 2023

Abstract
Transposons comprise half of the human genome and some create novel insertions in human germ cells and somatic tissues of healthy and diseased individuals. These genetic elements may be an abundant yet underexplored source of immunogenic molecules that create chimeric transcripts composed of transposons and non-transposons. However, it remains challenging to accurately identify such transposon-fusion events from short RNA-seq reads mainly due to the repetitive nature of transposon sequences and error-prone read alignment near exon-intron junctions, and there are few existing methods for such detection. We developed a computational pipeline, rTea (RNA Transposable Element Analyzer) to detect transposons-fusion transcripts from RNA-seq data. Using rTea, we performed a pan-cancer analysis of 10,257 cancer samples across 34 cancer types as well as 2,994 normal tissue samples from the TCGA/ICGC, our unpublished colorectal cancer cohort, and the GTEx consortia. Among normal human tissues, higher fusion loads were found most notably in the testis and to a lesser extent in other tissues that have been characterized as immune-privileged. Somatic fusions found in cancer were enriched in known cancer genes, implicating their contribution to tumorigenesis. We also found distinct epigenetic and tumorigenic mechanisms underlying fusions from different transposon families. Through in silico immunogenicity modeling and experimental validation, we confirmed the MHC-I binding and CD8+ T cell activation by peptides derived from transposon fusions to the extent comparable to EBV viruses. Our findings highlight endogenous retroelements as novel therapeutic targets and a significant source of neoantigens.
Citation Format: E. Alice Lee, Boram Lee, Yoonjoo Choi, Junseok Park, Adam Voshall, Eduardo Maury, Yeeok Kang, Yeon Jeong Kim, Jin-Young Lee, Hye-Ran Shim, Si-Cho Kim, Hoang Bao Khanh Chu, Da-Won Kim, Minjeong Kim, Eun-Ji Choi, Kyungsoo Ha, Jung Kyoon Choi, Yongjoon Kim, Woong-Yang Park. Pan-cancer analysis reveals roles of retrotransposon-fusion RNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1122.
Abstract 1217: The FAM72 gene family promotes cancer development by disabling the base excision repair system
Authors: Feng Yuqing , Thakur Bhupesh , Bruce Jeffery , Mamand Sami , Shirdarreh Melika , Wong Matthew , Silvester Jennifer , Han Ming , Kashem Mohammad , Zia Amin , Cescon David , Pugh Tervor , Pezo Rossanna C. , Martin Alberto 
Published: June 2023

Abstract
Genetic lesions are central contributors to cancer development and progression, and understanding the sources of these lesions will provide a better understanding of the mechanisms of carcinogenesis. Our previous work showed that the uncharacterized murine Fam72a gene promotes mutagenic DNA repair during antibody maturation by causing the degradation of Uracil DNA glycosylase 2 (UNG2), a component of the base excision repair (BER) system. Humans encode four almost identical paralogues of FAM72 called FAM72A-D, which are absent in all other mammalian genomes, including those of non-human primates. The role of these four paralogues in human biology is unknown. Intriguingly, a previous report showed that FAM72A is over-expressed in many cancers. Since FAM72A promotes mutagenesis by degradation of UNG2, we hypothesized that overexpression of the FAM72 gene family might promote cancer development and progression. Here we show that FAM72A-D is overexpressed in many human cancers and inversely correlates with UNG2 protein levels in tumorigenic tissue. However, FAM72A but not FAM72B-D causes degradation of UNG2. Consistent with this effect, FAM72 expression correlates with a higher mutation load in many tumor types. Since genetic mutations are associated with cancer development and progression, we tested whether FAM72 expression is associated with disease outcomes. Indeed, we found that high FAM72 expression was associated with poorer survival in several cancers. To directly test if Fam72a is sufficient to promote cancer, we generated transgenic mice that overexpress Fam72a in multiple tissues. We observed that Fam72a overexpression promotes increased colonic polyps in the Apcmin background compared to controls. These data show that the novel FAM72 gene family are drivers of cancer development in both mice and humans and advances our understanding of the underlying molecular mechanisms that precipitate cancer development and progression. This work is supported by a grant from the CIHR (PJT-180269).
Citation Format: Yuqing Feng, Bhupesh Thakur, Jeffery Bruce, Sami Mamand, Melika Shirdarreh, Matthew Wong, Jennifer Silvester, Ming Han, Mohammad Kashem, Amin Zia, David Cescon, Tervor Pugh, Rossanna C. Pezo, Alberto Martin. The FAM72 gene family promotes cancer development by disabling the base excision repair system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1217.
Abstract 1238: Loss of HSPD1 induces cellular plasticity in triple-negative breast cancer cells
Authors: Khodary Muhammad G. , Yirsaw Alehegne W. , Samuel Temesgen , Yates Clayton , Bedi Deepa 
Published: June 2023

Abstract
Abstract Background Unlike Breast cancer (BRCA) luminal subtypes, Triple negative breast cancer (TNBC) subtype lacks expression of estrogen receptor-α (ERα/ESR1), progesterone receptor (PGR) and/or epidermal growth factor (EGF) family receptor HER2/ERBB2 where patients do not benefit from endocrine and HER2 based therapies in addition to its poor differentiation that results in greater aggressiveness and poorer prognosis. The 60 KD Heat shock protein (HSP60) is a Mitochondrial protein that plays a role in stabilizing and refolding proteins and is regulated by HSPD1 gene. In normal cells, HSPD1 gene expression is controlled, however in TNBC, HSPD1 overexpression is common and is associated with poor cancer-specific survival. This study aims to understand downstream signaling pathways dependent on the function of HSPD1 in TNBC. Method To understand downstream signaling pathways dependent on the function of HSPD1, we analyzed the transcriptomic profiles of metastatic MDA-MB-231-WT and HSPD1-KD cells. Results Bioinformatics data analysis shows that HSPD1 is overexpressed in TNBC, particularly in basal subtype. High expression of HSPD1 related to low survival in breast cancer patients. HSPD1 KD in MDA-MB-231 cells identified several differentially regulated genes (DEG) as compared to WT MDA-MB-231 cells by RNA-seq analysis. Pathway analysis of DEG showed downregulation of mitochondrial respiration, thermogenesis, citric acid cycle, PD-1 signaling while upregulation of estrogen dependent gene expression, estrogen mediated signaling, nuclear receptor transcription pathway. These suggests that HSP60 overexpression in TNBC promotes basal type phenotype. Downregulation of HSP60 expression upregulated hormone receptors, particularly estrogen receptor (ESR1) and androgen receptor (AR) expression, thus inducing basal to luminal switch in MDA-MB-231 cells. These findings suggest that loss of HSPD1 significantly Induces plasticity in TNBC. Conclusion Our results suggest that loss of HSPDI in the context TNBC cells may promotes oncogenic transformation to an intermediary luminal progenitor phenotype that gains differentiation plasticity based on the upregulation of Estrogen-receptors signaling pathways. Ongoing analyses will be performed to identify the possible links between loss of HSPD1 and key transcription factors that define mammary epithelial cell differentiation.
Citation Format: Muhammad G. Khodary, Alehegne W. Yirsaw, Temesgen Samuel, Clayton Yates, Deepa Bedi. Loss of HSPD1 induces cellular plasticity in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1238.
Abstract 1242: Single cell multiomic map reveals regulatory landscape of human brain metastases
Authors: Klotz Remi , Zukowski Alexis , Kamal Mohamed , Attenelo Frank , Ramachandran Srinivas , Yu Min 
Published: June 2023

Abstract
Capturing comprehensive brain metastasis landscape is critical to the establishment of effective anti-tumor strategies. This study took advantage of single-cell multiomics sequencing to profile the molecular and cellular dynamics in tumor cells and associated microenvironment during brain metastasis. Among different primary cancer types, our data suggest that there are conserved yet distinct tumor cell subpopulations, governed by specific changes in gene expression, chromatin accessibility and tumor-stroma interactions. We characterized the conserved tumor subpopulations of brain metastasis with features of: (1) dormancy, (2) enhanced translation and migration, (3) cell death and (4) high proliferation rate. Dormant tumor cells in brain metastasis appear to limit cell-cell interactions with the surrounding microenvironment. In line with previous observations, dormant cells exhibit distinct stimulation for interferon, oxidative phosphorylation and HIPPO signaling. Despite a pronounced cell plasticity, trajectory analysis uncovered a cell progression pattern and its major sequential states and driving genes. Importantly, the tumor trajectory provides new insights into the regulatory landscape controlling the transition from dormant to proliferating tumor cells. Our findings also point to a valuable use of matched isolated circulating tumor cells and cell-free DNA to map the molecular and cellular dynamics of brain metastases. This work demonstrated that despite a pronounced intratumoral heterogeneity, brain metastases present conserved tumor subpopulations regardless of the patient and primary type. A novel and key finding in this study is the multiomics characterization of the regulatory landscape shaping human brain metatastases. Thus, we believe further understanding of these key regulatory elements could lead to novel tumor targets with broad translational potential.
Citation Format: Remi Klotz, Alexis Zukowski, Mohamed Kamal, Frank Attenelo, Srinivas Ramachandran, Min Yu. Single cell multiomic map reveals regulatory landscape of human brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1242.
Abstract 1244: Examining the differential roles of OSM and IL-6 in varying subtypes of breast cancer for novel therapeutic treatment
Authors: Wolf Cody L. , Tawara Ken , Jorcyk Cheryl L. 
Published: June 2023

Abstract
Breast cancer remains the second leading cause of cancer-related death in women, in large part due to distant metastasis to organs such as bone, lung, liver, and brain. Our laboratory has demonstrated that the IL-6-family cytokine oncostatin M (OSM) increases circulating tumor cell (CTC) numbers and metastases to lung in vivo, and that OSM stays active when bound to proteins in the extracellular matrix, thus “bioaccumulating” in the tumor microenvironment. These published findings are supported by our results demonstrating that OSM strongly promotes expression and secretion of IL-6 from breast cancer cells. Interestingly, the increased production of IL-6 by OSM occurs only in estrogen receptor-negative (ER-) cells. It is well known that patients with ER- breast cancer, specifically triple negative breast cancer (TNBC; ER- PR- HER2-), have limited therapeutic options. However, the divergent role OSM plays in ER+ and ER- breast cancer and the mechanism by which this occurs has yet to be fully understood. Thus, we aimed to fully elucidate the difference between OSM in ER+ versus ER- breast cancer. First, we performed RNA-Seq analysis on OSM-treated human ER+ T47D cells and ER- TNBC MDA-MB-231 cells and discovered significant differences in gene expression between both cell lines upon treatment with OSM, including alteration in DNA-replication and cell cycle pathway genes. Next, to better understand the mechanism by which OSM-mediated IL-6 secretion is repressed, we utilized a computational modeling approach and evaluated the direct inhibition of STAT3 and ER to identify theoretical dimerization complex for future studies. This research aims to elucidate the unique role OSM plays in ER+ and ER- breast cancer and will provide a molecular understanding of how this occurs and will provide detailed information on which patients will benefit most from anti-OSM therapeutics.
Citation Format: Cody L. Wolf, Ken Tawara, Cheryl L. Jorcyk. Examining the differential roles of OSM and IL-6 in varying subtypes of breast cancer for novel therapeutic treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1244.
Abstract 1307: The effect of circulating CXCL10 on osteosarcoma metastasis using orthotopic xenograft mouse models
Authors: Chen Xiang , Clement Margaret , Hicks John , Man Tsz Kwong 
Published: June 2023

Abstract
Osteosarcoma is the most common malignant bone tumor in children. Despite the use of chemotherapy and surgery, the survival of patients with metastasis is still dismal. We have previously reported that a high serum level of CXCL10 is associated with a poor prognosis and metastasis in osteosarcoma, suggesting that the chemokine may affect the development of metastasis. Nonetheless, the effect of endocrine signaling of CXCL10 is largely unknown. It is unclear if the prognostic effect of circulating CXCL10 is due to its metastasis-promoting effect or if CXCL10 is merely a biomarker. In this study, we employed orthotopic xenograft mouse models to examine the effect of circulating CXCL10 with respect to metastasis. We first injected luciferase-labeled 143B osteosarcoma cells into the tibia of NOD/SCID mice to generate an orthotopic xenograft mouse model. When the tumor was detectable by bioluminescence, we injected 1.5ug of CXCL10 protein or saline intravenously via the tail vein every day for two weeks. The development of pulmonary metastasis was monitored by bioluminescence. The mice were sacrificed at the endpoint when bioluminescence was detected in the lungs. The mouse lungs were then resected and examined by H&E staining for the detection of metastatic nodules. The mice in the experimental and control groups that developed lung metastases were compared. The results showed that no significant difference was observed between the two groups. The experiment was repeated one more time and similar results were observed. To investigate the influence of the cell line background, we analyzed another osteosarcoma cell line, MG63.3. No significant difference in metastasis development was observed between the mice injected with CXCL10 and the mice injected with saline. The results indicate that a higher level of circulating CXCL10 alone was not sufficient to promote pulmonary metastases in the orthotopic xenograft mouse models. We also showed that AKT phosphorylation was upregulated in the osteosarcoma cell lines incubated with CXCL10, ruling out that the CXCL10 protein used was biologically inactive. In summary, our results suggest that although an increased circulating level of CXCL10 is associated with a poor prognosis in osteosarcoma patients, it does not promote the development of pulmonary metastasis in xenograft mouse models. Circulating CXCL10 may only act as a prognostic biomarker, but not a metastatic driver. Alternatively, the CXCL10-CXCR3 axis may be necessary, but not sufficient, to cause metastasis.
Citation Format: Xiang Chen, Margaret Clement, John Hicks, Tsz Kwong Man. The effect of circulating CXCL10 on osteosarcoma metastasis using orthotopic xenograft mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1307.
Abstract 1435: A GABP dominant negative approach to targeting tumor cell immortality
Authors: Stevers Nicholas O. , Collins Sara A. , Wu Samuel H. , Kasahara Noriyuki , Costello Joseph F. 
Published: June 2023

Abstract
Immortality is a hallmark of human cancer cells and therapeutic reversal is of great interest. Telomerase Reverse Transcriptase promoter (TERTp) mutations reactivate TERT expression, the rate limiting step in telomerase activity and cellular immortality. While prior telomerase blocking therapies lack tumor selectivity and were poorly tolerated, TERTp mutations and their regulation offer a unique opportunity for tumor specific reversal of cellular immortality. TERTp mutations are the most common non-coding mutation across all cancers, including glioblastoma (GBM), melanoma, urothelial carcinoma, and many others. The mutations generate a de novo E26 Transformation Specific (ETS) binding motif that recruits the GA-Binding Protein (GABP) multimeric complex to reactivate TERT expression. While GABP can form both a dimeric and tetrameric complex, we found that the tetrameric complex is responsible for reactivation of the mutant TERTp, suggesting selectively targeting the tetramer may induce telomere shortening and tumor cell death. However, through knocking out the tetramer, we found that the GABP dimer is sufficiently upregulated to maintain TERT expression. In the absence of the dimer and the tetramer isoform, many tumor cells senesce or undergo cell death. However, some escape this fate via upregulation of a second tetramer forming GABP paralogue that maintains TERT expression. Therefore, we devised a transactivation domain null GABP subunit that we hypothesized would act in a dominant negative manner to block the GABP dimer and both GABP tetramers. Introduction of the dominant negative construct into TERTp mutant GBM, meningioma, medulloblastoma, oligodendroglioma, and urothelial carcinoma cells significantly reduced TERT expression while not altering expression in TERTp wildtype GBM cells. Furthermore, the dominant negative is able to shorten telomere length in TERTp mutant GBM cells. While therapeutic targeting of the three GABP complexes seems particularly challenging, our initial dominant negative appears to do so. Ultimately the dominant negative could be delivered directly into tumors via clinically approved viral delivery systems such as retroviral replicating vectors.
Citation Format: Nicholas O. Stevers, Sara A. Collins, Samuel H. Wu, Noriyuki Kasahara, Joseph F. Costello. A GABP dominant negative approach to targeting tumor cell immortality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1435.