bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3175: Dear ABBIE, edit that colon cancer
Authors: Aguilar David C. , Gallegos Alfred 
Published: March 2024

Abstract
Genome editing has exciting potential for gene therapy of cancers. Colorectal cancer is the third most occurring cancer in both men and women. The current treatments for colon cancers include surgery, radiofrequency ablation, chemotherapies and immunotherapies. These either involve removal of intestinal tissue that can alter the quality of life of the patient, or require doses of drugs that generally result in various side effects. ABBIE (A Binding Based Integrase Enzyme) genome editing can insert operational gene sequences into a chosen site in the genomic DNA of cells via its targetability and integrase activity. The ABBIE system offers ease of use, faster time to a readout and decreased time per genome editing experiment. SW480 and Caco-2 colon adenocarcinoma cells were used with the ABBIE system to integrate a GFP donor sequence into a safe harbor locus of the genome. Integration is to be confirmed with fluorescence microscopy and DNA sequencing. The colon cancer cell line will then be edited with the ABBIE genome editing system to include a gene cassette that overexpresses caspase genes into the genomic DNA of these cells. ABBIE-Edited colon cancer cell lines are expected to exhibit increased apoptosis as compared to non-edited controls or controls edited with DNA that do not have the caspase genes. This strategy will help lead to novel and more targetable treatments for colon cancer.
Citation Format: David C. Aguilar, Alfred Gallegos. Dear ABBIE, edit that colon 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 3175.
Abstract 3202: Investigating the induction of ferroptosis by nano drug delivery system
Authors: Jacob Eden M. , Kim Sarah Y. , Sirohi Parul , Wang Mu-En , Davis Meredith L. , Bawcom Alyssa R. , Chilkoti Ashutosh , Wiesner Mark R. , Huang Jiaoti , Chen Ming 
Published: March 2024

Abstract
Prostate cancer is the second leading cause of cancer-related death in U.S. men. Genomic and clinical associations have identified loss of RB function as a dominant mechanism driving prostate cancer lethality. We recently demonstrated that ferroptosis induction in vivo by ferroptosis inducers blocks RB1-deficient prostate tumor growth and metastasis and leads to improved survival of the mice. As all ferroptosis inducers are newly discovered, there is a great need to improve their therapeutic potential through different avenues, including innovative drug delivery systems. Poly Lactic-co-glycolic acid (PLGA) is an FDA-approved biodegradable polymer. Due to their strong biocompatibility and consistent release, PLGA-based nanotherapeutics are an attractive carrier for small molecule drugs. This study aims to further improve the efficacy of ferroptosis induction against lethal RB1-deficient prostate cancer through PLGA-based ferroptosis-induced nanoparticles (NPs). The PLGA NPs encapsulating JKE-1674 were synthesized using the solvent evaporation method. The NPs were characterized using dynamic light scattering (DLS) and scanning electron microscopy (SEM) to assess the physicochemical properties of the NPs. The cell-killing efficacy of free-form or PLGA NP encapsulated JKE-1674 was then evaluated in vitro. Our analyses showed that the particle size and polydispersity index (PDI) of JKE-1674 PLGA NPs were 160.8 nm and 0.049, respectively. SEM images of JKE-1674 PLGA NPs further validated the DLS data. These findings suggest that encapsulation of JKE-1674 within the PLGA NPs results in a stable and biocompatible formation. Critically, JKE-1674 encapsulated by PLGA NPs is as potent as JKE-1674 in its free form to induce ferroptosis and associated lipid peroxidation in various human prostate cancer cell lines. This study presents the first effort to develop and validate PLGA-based ferroptosis-induced nanotherapeutics. Based on our in vitro data, we will test the in vivo efficacy of JKE-1674 PLGA NPs against lethal RB1 deficient prostate cancer.
Citation Format: Eden M. Jacob, Sarah Y. Kim, Parul Sirohi, Mu-En Wang, Meredith L. Davis, Alyssa R. Bawcom, Ashutosh Chilkoti, Mark R. Wiesner, Jiaoti Huang, Ming Chen. Investigating the induction of ferroptosis by nano drug delivery system [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 3202.
Abstract 3209: Antibody mediated targeted drug delivery approach for pancreatic cancer
Authors: Dan Nirnoy , Setua Saini , Shaji Poornima , Kumari Sonam , Yallapu Murali Mohan , Khan Sheema S. , Chauhan Subhash 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinomas, originating from the epithelial cell lining of ducts, account for approximately 95% of tumors in this category, showcasing a survival rate of less than 5-7%. Unfortunately, little progress has been seen in the outcomes of patients with PDAC as tumor develops high desmoplasia and chemo-resistance to chemotherapeutic drugs, such as gemcitabine (Gem). The therapies are unable to penetrate to the fibrotic tumors leading to insufficient availability of the therapeutic drugs at the tumor site. We and others have shown that MUC13 is aberrantly expressed in pancreatic tumors but not in normal pancreas, which makes MUC13 as an excellent protein for specifically targeting pancreatic tumors. Herein, we demonstrate a unique ability of our in-house generated mouse and humanized monoclonal antibody of MUC13 to penetrate and target pancreatic cancer. These antibodies have been conjugated with our recently developed novel patented superparamagnetic iron oxide nanoparticles (SPIONS) to deliver therapeutics specifically to pancreatic tumors. In this study, we are using curcumin that depletes tumor microenvironment and gemcitabine to investigate the efficacy of the MUC13 conjugated SPION in delivery of therapeutic drugs. Our results demonstrate that enhanced uptake of MUC13-SPION formulation in MUC13 positive (MUC13+) PanCa cells, compared with MUC13 null (MUC13-) cells as demonstrated by immunofluorescence, Prussian blue staining and flow cytometry experiments. Interestingly, the formulation resulted in sustained delivery of curcumin (CUR), enhanced inhibition of cell proliferation, migration and invasion in MUC13+ cells as compared with MUC13- cells, which suggests the targeting efficacy of the formulation. In PanCa orthotopic mice model, MUC13-SPION efficiently targeted pancreatic tumors resulting in significant tumor accumulation. We observed inhibition of tumor volume, metastasis, gem resistance and improved survival in mice treated with the formulation. Additionally, the tumor tissues from treated mice showed extensive downregulation of PCNA and expression of key proteins in SHH pathway, such as SHH, Gli-1, Gli-2, Patched 1, SMO, which has been associated with cancer progression and drug resistance. In conclusion, the results indicate high therapeutic significance of MUC13-SPIONS for achieving pancreatic tumor specific delivery of drugs.
Citation Format: Nirnoy Dan, Saini Setua, Poornima Shaji, Sonam Kumari, Murali Mohan Yallapu, Sheema S. Khan, Subhash Chauhan. Antibody mediated targeted drug delivery approach for pancreatic 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 3209.
Abstract 3264: Characterization of EGFR ectodomain mutation in acquired resistance to cetuximab in colorectal cancer
Authors: Joshi Neeraj , Deal Ramona Graves , Bogatcheva Galina , Higginbotham James N. , Ramirez Marisol , Brown Benjamin P. , Liu Qi , Meiler Jens , Singh Bhuminder 
Published: March 2024

Abstract
Colorectal cancer (CRC) remains the second leading cause of cancer-related deaths in the United States (US). Individuals with surgically unresectable stage four CRC have a five-year overall survival rate of 13%. Targeting of the receptor tyrosine kinase (RTK), EGF receptor (EGFR) with therapeutic monoclonal antibodies (cetuximab, panitumumab) is approved for use in wild-type (WT) KRAS/NRAS/BRAF (RAS/RAF) advanced CRC. However, these antibodies as a single agent have response rates of 12-17% and expected progression-free survivals of only 3-4 months. Accordingly, resistance may be present at the outset (de novo resistance) or develop during treatment (acquired resistance). Here, we report the identification of an EGFR ectodomain missense mutation acquired in vitro in response to treatment with anti-epidermal growth factor receptor (EGFR) antibody cetuximab. Using 2D and 3D drug sensitivity assays, our results demonstrate that this EGFR ectodomain mutation in addition to being resistant to cetuximab and panitumumab, also could not be targeted by the oligoclonal antibody cocktail MM-151. To determine whether this EGFR ectodomain mutation is necessary and sufficient to impart cetuximab resistance, we engineered CRC lines to inducibly overexpress mutant EGFR and showed that this was sufficient to induce cetuximab resistance. Further structural, and functional characterization is underway for this ectodomain mutation that confers resistance to cetuximab and will be shared during the meeting. These findings necessitate the need for additional treatment strategies for a subset of subjects with mCRC who do not respond to treatment with cetuximab/panitumumab and MM-151.
Citation Format: Neeraj Joshi, Ramona Graves Deal, Galina Bogatcheva, James N. Higginbotham, Marisol Ramirez, Benjamin P. Brown, Qi Liu, Jens Meiler, Bhuminder Singh. Characterization of EGFR ectodomain mutation in acquired resistance to cetuximab in colorectal 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 3264.
Abstract 33: Revitalizing CAR-T cells for TNBC: Targeting phosphorylation of TCF7 to overcome T cell exhaustion
Authors: Jiang Zhou , Chu Yu-Yi , Lee Heng-Huan , Hung Mien-Chie , Yang Liuqing , Lin Chunru 
Published: March 2024

Abstract
Breast cancer stands as the second leading cause of cancer-related deaths among women in the United States, with triple-negative breast cancer (TNBC) representing the most aggressive subtype. Although immune checkpoint inhibitors (ICI) demonstrated durable response in some TNBC patients, the added benefit of current FDA-approved ICI in combination with chemotherapy is estimated to be only around 10%. Fortunately, TNBC displays the highest number of tumor-infiltrating lymphocytes (TILs), compared to other BC subtypes, indicating an optimal context for the survival of T cells. Therefore, CAR-T therapy emerges as a promising therapeutic option for TNBC patients. Expanding the application of CAR-T therapies to solid tumors, including breast cancer, remains challenging. One of the key hurdles lies in the immunosuppressive tumor microenvironment, where the T cell receptor experiences long-term exposure to tumor antigens, leading to T cell exhaustion. This state impedes the T cells' capacity to efficiently target and eliminate cancer cells. Identifying key regulatory mechanisms downstream of the T cell receptor holds the potential to revolutionize existing immunotherapeutic strategies.
In our study, we discovered that the presence of the master transcriptional factor of T cell stemness, TCF1, in CD8+ T cells, is essential for controlling TNBC tumors. TCF1 undergoes phosphorylation by LCK, a crucial component of initiating T cell receptor signaling, upon T cell activation. We found this phosphorylation site is indispensable for TCF1's transcriptional activities, inhibiting the downstream program of T-cell persistence and causing T-cell exhaustion. Reversing this process, either through LCK inhibition or introducing a non-phosphorylated form of TCF1, results in a more sustained CAR-T cell-mediated anti-tumor response. Our findings reveal the significance of TCF1 post-translational modification in the development and longevity of stem-like CD8+ T cells, bridging the gap between TCR signaling and transcriptional and epigenetic programs of stem-like CD8+ T cells. This insight contributes to a potential cure for TNBC by maintaining T cell persistence.
Citation Format: Zhou Jiang, Yu-Yi Chu, Heng-Huan Lee, Mien-Chie Hung, Liuqing Yang, Chunru Lin. Revitalizing CAR-T cells for TNBC: Targeting phosphorylation of TCF7 to overcome T cell exhaustion [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 33.
Abstract 3367: R-loop type determines the orientation of transcription-replication conflicts attenuated by transcription factor IIS
Authors: Duardo Renée C. , Marinello Jessica , Russo Marco , Morelli Sara , Pepe Simona , Guerra Federico , Gomez-González Belen , Aguilera Andrés , Capranico Giovanni 
Published: March 2024

Abstract
During human Topoisomerase I (Top1) catalytic activity, a transient Top1-DNA cleavage complex (Top1cc) forms to allow DNA relaxation. Top1ccs can be stabilized by antitumor Top1 poisons, such as clinically-effective camptothecin analogs. Camptothecin-stabilized Top1ccs can lead to R-loop-dependent transcription-replication conflicts (TRCs), single-end DNA double-strand breaks (seDSBs) and genome instability in cancer cells. To define the genomic location of TRCs and the underlying mechanisms, we integrated genomic maps of Top1cc-induced DNA cleavage by END-seq and DNA:RNA hybrids by DRIP, determined the cell-cycle specificity of micronuclei formation and the effects of elongation transcription factor IIS (TFIIS). We have defined the genomic sites of both seDSBs and increased R-loop levels (gains) induced by Top1ccs. seDSBs are highly enriched at regions with R-loop gains at highly-transcribed genes in early replicating zones. Kinetics analyses of R-loops and genomic ChIP data of RNA polymerase II (RNAPII) revealed that R-loop gains can either be upstream or downstream of RNAPII. TFIIS effects showed that downstream R-loop gains can follow RNAPII backtracking and arrest. seDSB strandness showed that co-directional TRCs occur mainly at downstream hybrid-associated RNAPII, whereas head-on TRCs occur mainly at upstream hybrid-associated RNAPII. Therefore, Top1ccs can increase two structurally-different R-loops and R-loop-associated backtracked RNAPII causes co-directional TRCs at higher rate than head-on collisions. Moreover, Top1ccs trigger micronuclei formation at G1/early S, but not late S/G2, which are attenuated by TFIIS. Thus, our findings establish a role of RNAPII backtracking at highly-transcribed genes in Top1cc-induced co-directional TRCs and micronuclei formation. The findings can accelerate the development of new effective strategies to treat cancer patients. (Supported by Associazione Italiana per la Ricerca sul Cancro, Milan, Italy - IG 2019 - ID. 23032 to C.G. and by the European Union - NextGenerationEU through the Italian Ministry of University and Research under PNRR - M4C2-I1.3 Project PE_00000019 "HEAL ITALIA" to G.C., CUP J33C22002920006).
Citation Format: Renée C. Duardo, Jessica Marinello, Marco Russo, Sara Morelli, Simona Pepe, Federico Guerra, Belen Gomez-González, Andrés Aguilera, Giovanni Capranico. R-loop type determines the orientation of transcription-replication conflicts attenuated by transcription factor IIS [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 3367.
Abstract 3407: Physical activity and post-menopausal breast cancer in the Multiethnic Cohort Study
Authors: Gill Jasmeet K. , Maskarinec Gertraud , Park Song-Yi , Wilkens Lynne , Marchand Loic Le 
Published: March 2024

Abstract
Much research has been conducted on the relationship between physical activity and breast cancer, with meta-analyses showing 10 – 21% reduction in breast cancer risk for postmenopausal women with high compared to low level of physical activity. However, few studies have explored this relationship in non-Caucasian women. We analyzed data from 74,177 post-menopausal African American, Caucasian, Japanese American, Latina, and Native Hawaiian women in the Multiethnic Cohort in Hawaii and California. Data on physical activity (hours and metabolic equivalents (METs)) was based on a self-administered questionnaire at baseline (1993–1996). Multivariate Cox proportional hazards models provided estimates of hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for risk factors. We observed no associations between breast cancer risk and hours of moderate/vigorous activity per week (HR=1.01, 95% CI: 0.91-1.10, Ptrend=0.71), MET-hours of moderate/vigorous activity per week (HR=1.03, 95% CI: 0.94-1.13, Ptrend=0.92), and total METs-measured as average MET level per day multiplied by 7 (HR=0.94, 95% CI: 0.86-1.03, Ptrend=0.37) when comparing the highest quartile to the lowest. When examining the data across race/ethnicity, we observed a reduction in risk of breast cancer for total METs (HR=0.75, 95% CI: 0.61-0.94, Ptrend=0.05) among Latina women. Analysis across strata of BMI showed no differences across subgroups. In this study, we did not observe any consistent protective association between physical activity and breast cancer risk.
Citation Format: Jasmeet K. Gill, Gertraud Maskarinec, Song-Yi Park, Lynne Wilkens, Loic Le Marchand. Physical activity and post-menopausal breast cancer in the Multiethnic Cohort Study [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 3407.
Abstract 3454: Cell-free DNA methylation and fragmentomic signatures identify tissue damage and predict cancer risk
Authors: Cheng Nicholas , Skead Kimberly , Oullette Tom , Bratman Scott , De Carvalho Daniel , Soave David , Awadalla Philip 
Published: March 2024

Abstract
Cell-free DNA (cfDNA) epigenetic and fragmentomic profiling has emerged as prominent non-invasive approaches for early cancer detection and subtyping. However, owing to difficulties in observing the early development of human malignancies, most cancer biomarker and evolution studies to date have primarily examined biologics following a diagnosis. Utilizing cfDNA as a screening tool for early disease detection requires assessment of blood plasma samples collected from asymptomatic individuals prior to the diagnosis of cancers. Here, we leverage the Ontario Health Study (OHS), a prospective longitudinal population cohort, to assess cfDNA profiles in blood plasma collected from participants that developed breast (n=476), prostate (n=342) and pancreatic (n=32) cancers throughout the study follow up time between 2009 and 2019. We performed cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) on baseline plasma samples from incident cancer cases up to eight years prior to diagnosis, in addition to matched controls (n=404) with no history of cancer through follow-up. Genome-wide plasma cfDNA differential methylation analysis revealed significantly hypermethylated regions, particularly among CpG island and shore regions, were predictive of early breast cancers, and overlapped hypermethylated regions in solid cancer tissues relative to adjacent normal tissues and peripheral blood leukocytes. Using a repeated cross-validation strategy we found that as few as 200 hypermethylated regions can identify individuals with breast cancer in blood up to seven years prior to diagnosis among discovery set samples (AUC=0.725) and are highly generalizable to samples processed in separate batches (AUC = 0.650). Remarkably, integrating biomarker hypermethylated regions with fragmentomic features including fragment length and 5’ tetranucleotide motif proportions further increased accuracy for detecting individuals with early prostate cancers (AUC=0.804). In addition, we observed shared genome-wide cfDNA methylome changes associated with aging and heavy alcohol consumption in cfDNA. We identified increased shedding of tissue-specific methylation markers from liver and pancreatic tissue among individuals consuming more than three drinks a week relative to non-drinkers, reflective of potential signatures of tissue damage.
Citation Format: Nicholas Cheng, Kimberly Skead, Tom Oullette, Scott Bratman, Daniel De Carvalho, David Soave, Philip Awadalla. Cell-free DNA methylation and fragmentomic signatures identify tissue damage and predict cancer risk [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 3454.
Abstract 3500: Refining diagnosis of renal cell carcinoma subtypes through single-cell resolution transcriptomic signatures
Authors: Kim Minjun , Madrigal Ariel , Mehrjoo Zohreh , Glennon Kate I. , Arseneault Madeleine , Park Morag , Brimo Fadi , Tanguay Simon , Najafabadi Hamed S. , Riazalhosseini Yasser 
Published: March 2024

Abstract
A remaining challenge in the field of renal cell carcinoma (RCC) is diagnosis of rare or mixed subtypes, which hampers the delivery of the most effective healthcare to patients. While a new classification scheme, integrating molecular characteristics of tumors, is emerging, it requires a deep understanding of the tumor heterogeneity and etiopathogenesis of each subtype. We have generated and analyzed single-cell transcriptome profiles of 38 human RCCs and normal kidneys 16 RCCs with diverse histological subtypes and established gene signatures specific to each cell type. We have applied these gene signatures to bulk RNA-sequencing data of 1000 RCC tumors with different histological subtypes and normal kidneys from The Cancer Genome Atlas (TCGA) to characterize different cancer types and cellular origins. Unsupervised clustering analysis of TCGA data shows diagnostic discrepancies for 9.3% cases and subclassifies each major subtype (clear cell, papillary and chromophobe) into clusters with differential clinical outcomes.[KM1]. The pathological marker expression in misdiagnosed tumors is consistent with clustering-based classification, not their original diagnosis. Notably, using unique and subtype-specific gene signature patterns, we identified clear cell papillary renal cell tumor (ccpRCT), which is a newly classified benign entity and the main tumor type representing the mis-diagnosed tumors. These observations have further been confirmed by reviewing histological images of the tumors by an experienced genitourinary pathologist. Interestingly, our gene signatures reveal that ccpRCT does not originate from proximal tubule cells unlike clear cell and papillary RCCs. Taken together, our approach suggests a potential new classification method connected to clinical behaviors and drug responses based on overall transcriptomic differences.
Citation Format: Minjun Kim, Ariel Madrigal, Zohreh Mehrjoo, Kate I. Glennon, Madeleine Arseneault, Morag Park, Fadi Brimo, Simon Tanguay, Hamed S. Najafabadi, Yasser Riazalhosseini. Refining diagnosis of renal cell carcinoma subtypes through single-cell resolution transcriptomic signatures [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 3500.