bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6390: Chromosome arm aneuploidies as genetic vulnerabilities of triple-negative breast cancer
Authors: Dandage Rohan , Schwartz Michael , Karam Lynn , Hart Traver , Kuzmin Elena 
Published: June 2022

Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer which lacks the expression of key biomarkers, namely Estrogen and Progesterone receptors and HER2. Therefore, it lacks targeted therapies, resulting in the worst prognosis compared to other breast cancer subtypes. Chromosome 4p (chr4p) loss is recurrent in TNBC, correlates with poor prognosis, is an early event in tumor evolution, and confers a proliferative advantage onto cells. Here, we propose that chr4p loss can be leveraged as a genetic vulnerability of TNBC by identifying its specific synthetic lethal (SL) genetic interactions. An SL interaction occurs when the inactivation of individual genes is tolerated, however, the combined inactivation of the corresponding genes leads to a loss of cellular viability. SL interactions offer promising avenues for precision oncology therapeutic strategies of TNBC. We leveraged the publicly available CRISPR-mediated genome-wide gene inactivation screens (DepMap project) dataset to computationally predict pairwise SL interactions that are specific to individual genes within chr4p, as well as complex SL genetic interactions involving multiple genes spanning large segments of chr4p and the entire chromosome arm. We developed regression models to compare the inactivation effect of a given SL partner gene, between cell lines that harbor chr4p loss and those characterized by a copy-neutral status of chr4p, while effectively accounting for potential confounding effects. We integrated the putative SL interactions identified from these regression models with those identified using other methods, drugZ and MAGECK, therefore, resulting in a robust set of putative SL interactions. We have prioritized the SL interactions for their subsequent experimental validation in TNBC PDX-derived 2D and 3D cell models, which we will carry out using CRISPR-based gene editing. The prediction model and collective set of SL candidates identified in this study is a unique resource for the development of SL-based therapeutic strategies for TNBC and other cancers harboring chr4p loss.
Citation Format: Rohan Dandage, Michael Schwartz, Lynn Karam, Traver Hart, Elena Kuzmin. Chromosome arm aneuploidies as genetic vulnerabilities of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6390.
Abstract 6391: Scalable colorectal cancer (CRC) diagnosis model with arterial and unenhanced phases of KRAS mutational status using Apache Spark
Authors: Adewunmi Mary Adetutu 
Published: June 2022

Abstract
The exponential increase in Medical data and Computer-aided diagnostic tools has made it easier for Machine Learning (ML) Researchers to extract valuable insights from medical images resulting in better patient outcomes during Medical Summarization. According to current statistics, 8.8 million people died every year due to cancer death. It is therefore imperative to use these available image datasets for better diagnosis, increased patient outcomes and recovery from deadly diseases. As a result, this study proposes a Colorectal Cancer classification model for detecting KRAS mutation status of Patients through their Radiomic images using the transfer learning of a deep learning pipeline on Apache Spark. The datasets will be curated from National Cancer Institute (NCI), features extraction or classification of Computed tomography(CT) images into CT- based handcrafted radiomic signatures with a Convolutional Neural Network(CNN) using the Apache Spark framework, the system uploads the segmented scanning images to the High Distributed File System (HDFS), Confidence Interval(CI), Area Under Curve(AUC), Precision and Recall for Validation cohort, Docker for app deployment and containerization of the model developed for reproducibility, transfer learning and model reuse. The result would be a real-time model using Deep learning pipelines with Apache Spark and Keras Tensor flow for KRAS Mutation detection using Colorectal Cancer images. In conclusion, this research project would produce a scalable and reproducible model for the faster diagnosis of Colorectal Cancer through the KRAS mutation status of CRC Patients.
Citation Format: Mary Adetutu Adewunmi. Scalable colorectal cancer (CRC) diagnosis model with arterial and unenhanced phases of KRAS mutational status using Apache Spark [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6391.
Abstract 647: Association between adrenal-restrictive HSD3B1 inheritance and hormone independent subtypes of endometrial and breast cancer
Authors: McManus Jeffrey M. , Vargas Roberto , Bazeley Peter , Sabharwal Navin , Sharifi Nima 
Published: June 2022

Abstract
Breast and endometrial cancer are both malignancies that can be classified into subtypes based on their hormone dependence, such as estrogen receptor (ER)-positive vs. ER-negative breast cancer and low-grade vs. high-grade endometrial cancer. The gene HSD3B1 encodes the steroid metabolism enzyme 3β-hydroxysteroid dehydrogenase 1, which catalyzes a critical step in conversion of adrenal precursor steroids to potent androgens and estrogens. Associations between the missense-encoding germline variant rs1047303 in HSD3B1 have been described to affect outcomes of castration-resistant prostate cancer and associated with ER positivity in postmenopausal breast cancer. The adrenal-permissive 1245C allele enables greater production of androgens and estrogens from adrenal precursors, whereas the adrenal-restrictive 1245A allele limits this reaction pathway. Using data from The Cancer Genome Atlas’s TCGA-UCEC and TCGA-BRCA projects, we interrogated whether the adrenal-restrictive rs1047303 genotype was associated with less hormone-driven genomic clusters of endometrial and breast cancer. We determined the genotype frequencies for different tumor subtypes, as classified by the genomic analysis of Sanchez-Vega, et al. (2018). The adrenal-restrictive HSD3B1(1245A) allele was associated with the copy number (CN) high cluster of endometrial cancer (OR 1.59, 95% CI 1.12-2.26, p = 0.0098), notably composed of serous and high-grade endometrioid endometrial cancers which are less estrogen-dependent than low-grade endometrioid tumors. Similarly, the adrenal-restrictive HSD3B1(1245A) was associated with the basal subtype of breast cancer (OR 1.54 [1.13-2.09], p = 0.0057), a subtype that is largely ER-negative and is known to share genomic features with serous-type endometrial cancers. Lastly, we interrogated overall survival of endometrial cancer patients in the UK Biobank and found that patients homozygous for the adrenal-restrictive HSD3B1(1245A) had worse overall survival (HR 1.39 [1.16-1.68], p = 0.00049) and cancer-specific survival (HR 1.39 [1.14-1.70], p = 0.0013), a finding consistent with the A allele being enriched in the more aggressive CN-high subtype of endometrial cancer. Taken together, these findings suggest a role for adrenal-restrictive vs. adrenal-permissive steroidogenesis, by way of rs1047303 genotype, in the development of and/or outcomes from at least three different commonly hormone-associated types of cancer: prostate, breast, and endometrial.
Citation Format: Jeffrey M. McManus, Roberto Vargas, Peter Bazeley, Navin Sabharwal, Nima Sharifi. Association between adrenal-restrictive HSD3B1 inheritance and hormone independent subtypes of endometrial and breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 647.
Abstract 667: Inhibition of protein-protein interaction between STING and TRIM29 is a new approach to enhance anti-tumor immune response
Authors: Park Seung Bum , Cho Wansang , Chan Won Sol , choi young il , Ahn Sungoh , Lee Dong-Sup 
Published: June 2022

Abstract
Introduction: STimulator of INterferon Genes (STING) has been reported to be essential for antitumor immunity by inducing type I IFN expression, resulting in activation of both innate and adaptive immunity. Thus, pharmacological activation of STING pathway is actively being tested in many clinical studies. However, the clinical efficacy was not that clear, probably due to the limited expression of STING protein, which is tightly regulated by TRIM29 (E3 ligase)-mediated protein degradation pathway. Here, we present a novel small-molecule drug candidate with strong antitumor response in murine syngeneic model by upregulating cellular levels of STING through the inhibition of protein-protein interaction.
Methods: The inhibitors of STING-TRIM29 interaction were identified using luciferase-complementation high-throughput screening system. Target protein of the inhibitor was identified in cellular thermostability shift assay. Their immunological activity was tested in Raw264.7 and A431 cells as well as CT26 murine syngeneic model.
Results: The lead compound, SB24011, bound to STING and upregulated cellular levels of STING by inhibiting ubiquitin-mediated degradation. Together with STING agonist, SB24011 synergistically enhanced the inflammatory cytokine expression in cell lines as well as in CT26 syngeneic animal model. Intratumoral injection of SB24011 showed strong abscopal activity as single agent as well as synergistic antitumor responses with anti-PD1 antibody in CT26 syngeneic animal model.
Conclusions: We identified novel small-molecule drug candidate, SB24011, which prevents the degradation of both murine and human STING proteins, resulting in enhanced immune responses together with STING agonist, cGAMP. SB24011 showed strong abscopal antitumor activity as single agent and synergistic antitumor activity as combination agent with other IO agents in CT26 syngeneic models.
Citation Format: Seung Bum Park, Wansang Cho, Won Sol Chan, young il choi, Sungoh Ahn, Dong-Sup Lee. Inhibition of protein-protein interaction between STING and TRIM29 is a new approach to enhance anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 667.
Abstract 675: Facilitating G-quadruplex formation in the KRAS promoter with polypurine reverse Hoogsteen oligonucleotides
Authors: Psaras Alexandra Maria , Valiuska Simonas , Noe Veronique , Ciudad Carlos J. , Brooks Tracy A. 
Published: June 2022

Abstract
KRAS is a GTPase involved in the proliferation signaling of a number of growth factors, such as epidermal growth factor. The protein is mutated or upregulated in an array of cancers, including pancreatic and ovarian cancers, where it correlates with more aggressive and chemoresistant disease. Within the promoter of KRAS lies a G-rich region capable of forming the higher order non-canonical DNA structure, the G-quadruplex (G4). Stabilization of G4 formation in the mid-region of the KRAS promoter downregulates transcription and facilitates decreased growth and chemo-sensitization of pancreatic and ovarian cancer cells with aberrant KRAS signaling. Our collaborative team designed Polypurine Reverse Hoogsteen (PPRH) hairpin oligonucleotides that establish Watson Crick bonds with the pyrimidine strand within the KRAS-mid-G4-forming region to enhance G4 formation, downregulate KRAS transcription and mediate an anti-proliferative effect. In particular, two PPRHs were designed to interact with the 3’ and 5’ ends of the G4-forming region, along with two correlating W:C, and one scramble, controls. The binding of these oligonucleotides to the G4-forming region was verified by gel electrophoresis, and the cell activity was examined in vitro both by luciferase and in pancreatic and ovarian cancer cells. Using a luciferase construct driven by the KRAS promoter, only the PPRHs, and none of the control oligonucleotides, significantly decreased activity. Cytotoxicity experiments in KRAS dependent and independent cell lines demonstrated that PPRHs, but not control oligonucleotides, selectively suppressed proliferation only in the dependent pancreatic and ovarian cancer cell lines. Correlation of the cytotoxic effects of these potential therapeutic PPRHs with transcriptional downregulation is under investigation. PPRH also demonstrated synergistic activity with a KRAS promoter selective G4-stabilizing compound in KRAS-dependent pancreatic cells, and sensitization to standard chemotherapeutic regimens is also being studied. These designed PPRH oligonucleotides selectively stabilize G4 formation within the KRAS mid promoter region, and represent an innovative approach both for G4-stabilization and KRAS modulation with potential for development into novel therapeutics.
Citation Format: Alexandra Maria Psaras, Simonas Valiuska, Veronique Noe, Carlos J. Ciudad, Tracy A. Brooks. Facilitating G-quadruplex formation in the KRAS promoter with polypurine reverse Hoogsteen oligonucleotides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 675.
Abstract 694: E-slice: A novel 3D culture platform for precision medicine
Authors: Gopalan Archana , Gallup Thomas D. , Wood Stephanie , Maldonado Jose , Margain Corina , Esnaola Nestor F. , Kim Min P. , Kopetz E. Scott , Yun Kyuson 
Published: June 2022

Abstract
The need for personalized medicine in oncology is widely accepted but translating this important concept into clinical practice has been challenging. Currently, the dominant platform for precision medicine utilizes genomics/sequencing-based assays to measure the expression and/or mutational profiles and then infer patient responses to therapies based on previous knowledge; however, this approach benefits less than 10-15% of patients with profiled tumors. Recognizing the inherent limitations of these inference-based methods, functional assays (e.g., organoids and PDX models) have been developed; however, these approaches also have significant limitations including high cost and time required to establish the models, low “take rates”, and destruction of the native tumor microenvironment (TME). To overcome these challenges, EMPIRI uses a novel 3D ex vivo tumor slice culture method (E-slices) that enables rapid, personalized drug sensitivity testing in intact patient tumor tissues. Major differentiators of the E-slice platform from other ex vivo methods include the use of chemically defined, serum-free medium, longitudinal viability measurements from the same tissue, tracking of dynamic responses to treatment over 2-3 weeks, and retention of the native TME and tissue architecture, unlike other approaches. In addition, E-slices can be generated from any solid tumor tested thus far (breast, lung, colorectal, pancreas, brain, head 7 neck, and others) from patient tumors directly and PDX and genetically engineered mouse models. In addition, because E-slices retain tumor-infiltrating immune cells in their native microenvironment and spatial topography of all cell types in the endogenous configuration, it sustains immune cell survival and proliferation and measures immunotherapy responses ex vivo. The E-slice method is compatible with biopsies as well as surgical samples. Importantly, it has been shown to accurately predict individual patient treatment responses to chemotherapies and targeted therapies in 4-12 days, paving the way for evidence-based personalized treatment selections in a clinically actionable time frame. In summary, we present a novel ex vivo 3D human tumor tissue drug sensitivity platform that faithfully replicates the patient tumor tissues and provides personalized treatment responses in a clinically actionable time frame.
Citation Format: Archana Gopalan, Thomas D. Gallup, Stephanie Wood, Jose Maldonado, Corina Margain, Nestor F. Esnaola, Min P. Kim, E. Scott Kopetz, Kyuson Yun. E-slice: A novel 3D culture platform for precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 694.
Abstract 715: Targeting the mTOR pathway for the prevention of er-negative breast cancer
Authors: Mazumdar Abhijit , Hill Jamal , Tahaney William , Ma Yanxia , Contreras Alejandro , Sei Shizuko , Mohammed Altaf , Brown Powel 
Published: June 2022

Abstract
Background: Triple-Negative breast cancer (TNBC) is an aggressive cancer that lacks expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. These cancers have a poor prognosis and are treated predominantly with chemotherapy. Therefore, we are working to find preventive therapies for these potentially lethal cancers. Dysregulation of PI3K-mTOR pathway is commonly associated with TNBC and other ER-negative breast cancers. We hypothesized that targeting mTOR may prevent development of ER-negative breast cancers and in this study tested whether the mTOR inhibitor, everolimus, prevents cancer in several mouse models of ER-negative breast cancer.
Methods: MMTV-erbB2 mice were purchased from the Jackson Laboratory. C3(1)/SV40TAg and BRCA1co/co;MMTV-Cre;p53+/- were generated through breeding. P53-null and p53-mutant mammary gland mice were generated by transplanting p53-null or p53-mutant mammary glands into cleared fat pads of p53-wild type mice. The mice were treated with either control or everolimus (5mg/kg), administered by oral gavage daily (5X/week). All mice develop palpable mammary tumors within 8-12 months. Mice were observed daily for tumor formation and drug toxicity. The percentage of tumor free mice was recorded, and time to tumor development was visualized using Kaplan-Meier curves and analyzed using the generalized Wilcoxon test.
Results: Treatment with everolimus significantly increased median survival of all mouse models. Everolimus treatment was also able to completely prevent mammary tumor formation in 27% of C3(1)/SV40Tag mice and 44% p53-mutant mammary gland mice. In p53-null mammary gland mice, 46% of control mice had developed tumors after 420 days, compared to 7% of everolimus treated mice. Long term treatment of everolimus was associated with mild toxicity that includes slight weight loss (&lt;10%) and skin changes (matted hair, skin erythema).
Conclusions: Everolimus significantly delayed mammary tumorigenesis in all five breast cancer mouse models. Our results suggest that everolimus is a promising cancer preventive drug for ER-negative tumors, and that further studies of everolimus in combination with other targeted therapies are warranted. In the future, clinical trials of the everolimus should be considered for the prevention of breast cancer in high-risk patients. Supported by NCI PREVENT Cancer Preclinical Drug Development Program (HHSN-2612015000-18I (PB).
Citation Format: Abhijit Mazumdar, Jamal Hill, William Tahaney, Yanxia Ma, Alejandro Contreras, Shizuko Sei, Altaf Mohammed, Powel Brown. Targeting the mTOR pathway for the prevention of er-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 715.
Abstract 740: Obesity promotes liver pro-oxidative and DNA damage in mammary tumor of Zucker rats
Authors: Hakkak Reza , Melnyk Stepan , Korourian Soheila 
Published: June 2022

Abstract
Obesity is a major health problem in the US and world. Obesity is associated with the risk of cardiovascular disease, type 2 diabetes, and certain types of cancers such as breast cancer. Our laboratory reported that obesity increased mammary tumor model using obese Zucker rat model. However, the effects of obesity in the liver in regard to oxidative stress and DNA reaction is less known. In present study, we used a DMBA induced-mammary tumor model to further investigate the effects of obesity on creation of pro-oxidative environment in liver and oxidative DNA reaction. Lean and obese female rats were at 50 days of age received 7,12-dimethylbenz(α)anthracene (DMBA) and were sacrificed 20 weeks later. HPLC-ECD, HPLC-UV and LC-MS were used. Obesity capable significantly modify methylation status in liver caused higher (p &lt; 0.001) SAM/SAH ratio (know as “methylation ratio”) and increased (p &lt; 0.05) global DNA methylation. Also, obesity decrease GSH/GSSG ratio (known as “oxidative stress ratio”) with p &lt; 0.0001 inducing higher oxidative stress and as results, increase presence both oxidized guanosine (8-OH-Guanosine) with p &lt; 0.001 and oxidized 5metylCytosine (5hmCytosine) p&lt;0.04 in liver DNA. 8-OH-Guanosine/5hmCytosine ratio was not significantly affected. Obesity caused significant oxidative stress in liver, causing oxidative DNA damage and change of DNA methylation pattern. These changes may contribute to the development of fatty liver in breast cancer models.
Citation Format: Reza Hakkak, Stepan Melnyk, Soheila Korourian. Obesity promotes liver pro-oxidative and DNA damage in mammary tumor of Zucker rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 740.
Abstract 796: Dual inhibition of NHEJ and MMEJ induces synthetic lethality in TP53 mutant cancers
Authors: Patterson-Fortin Jeffrey , Bose Arindam , Tsai Wei-Chih , Grochala Carter , Nguyen Huy , Zhou Jia , Parmar Kalindi , Lazaro Jean-Bernard , Liu Joyce , McQueen Kelsey , Shapiro Geoffrey I. , Kozono David , D'Andrea Alan D. 
Published: June 2022

Abstract
DNA repair pathway inhibitors are a new class of anti-cancer drugs that are advancing in clinical trials. While inhibitors of targets in the Non-Homologous End Joining (NHEJ) DNA repair pathway, such as DNA-dependent protein kinase (DNA-PK), are available for clinical use, it remains unclear which cancers are vulnerable to these agents. In a genome-wide CRISPR knockout screen with the DNA-PK inhibitor M3814, we identify loss of POLQ, encoding polymerase theta, and other genes in the microhomology-mediated end-joining (MMEJ) pathway as key predictors of sensitivity to DNA-PK inhibition, whereas loss of TP53 conferred resistance to DNA-PK inhibition. Inhibition of DNA-PK led to increased DNA double strand break end-resection, increased expression of polymerase theta, and activation of MMEJ repair. Combined DNA-PK inhibition by M3814 and polymerase theta inhibition by novobiocin resulted in synthetic lethality mediated by the accumulation of resected DNA and apoptosis. Significantly, this drug combination efficiently killed TP53-deficient human patient-derived xenografts and the corresponding tumor organoids. Taken together, our results provide a rationale for the combination of an inhibitor of DNA-PK mediated NHEJ and an inhibitor of polymerase theta mediated MMEJ in an anti-cancer trial. If DNA-PK is inhibited, cancers develop a hyper-dependence on MMEJ and an upregulation of DNA double strand break end resection and polymerase theta expression. Similarly, P53-deficiency which confers resistance to DNA-PK inhibition, also leads to a hyper-dependence on MMEJ and an upregulation of polymerase theta expression. Thus, a combination of DNA-PK and polymerase theta inhibitors may provide a precision treatment strategy for TP53-mutant solid tumors, known to account for 50% of newly diagnosed cancers.
Citation Format: Jeffrey Patterson-Fortin, Arindam Bose, Wei-Chih Tsai, Carter Grochala, Huy Nguyen, Jia Zhou, Kalindi Parmar, Jean-Bernard Lazaro, Joyce Liu, Kelsey McQueen, Geoffrey I. Shapiro, David Kozono, Alan D. D'Andrea. Dual inhibition of NHEJ and MMEJ induces synthetic lethality in TP53 mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 796.