bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1694: Loss ofZNF251stimulates NHEJ resulting in PARP inhibitor resistance inBRCA1-mutated cancer cells
Authors: Huang Jian , Skorski Tomasz 
Published: June 2023

Abstract
The poly (ADP-ribose) polymerases (PARPs) inhibitors are an exciting new class of agents that have shown efficacy in treating various cancers, especially those harboring BRCA1/2 mutations. The cancer associated BRCA1/2mutations disrupt DNA double strand break (DSB) repair by homologous recombination (HR). PARP inhibitors (PARPi) have been applied to trigger synthetic lethality in BRCA1/2-mutated cancer cells by promoting the accumulation of toxic DSBs. Unfortunately, PARPi resistance is common and develops through multiple mechanisms. Restoring HR and/or stabilizing replication forks are two major mechanisms of PARPi resistance in BRCA1/2-mutated cells. To further understand the mechanisms of drug resistance to PARPi, we took an unbiased approach with a CRISPR-pooled genome-wide library to screen new genes whose loss-of-function confers resistance to PARPi olaparib. We identified ZNF251, a transcription factor, and found that its loss-of-function led to the PARPi resistance in multipleBRCA1-mutated breast and ovarian cancer lines. Elevated activities of both HR and non-homologous end joining (NHEJ) repair were detected in cancer cells harboring BRCA1 mutation and ZNF251 deletion (BRCA1mut+ZNF251del) and were associated with enhanced expression of RAD51 and Ku70/Ku80, respectively. Furthermore, we showed that a DNA-PKcs inhibitor restored sensitivity of BRCA1mut+ZNF251del cells to PARPi ex vivo and in vivo. Taken together, our study discovered a novel gene ZNF251 whose loss-of-function conferred resistance to PARPi in BRCA1-mutated breast and ovarian cancers and identified DNA repair pathway responsible for this effect.
Citation Format: Jian Huang, Tomasz Skorski. Loss ofZNF251stimulates NHEJ resulting in PARP inhibitor resistance inBRCA1-mutated 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 1694.
Abstract 2309: Unlocking the proteome of metastatic prostate cancer circulating tumor cells
Authors: Drake Justin M. , Sychev Zoi , Horrmann Alec , Smith Kaylee J. , Galeano-Garces Catalina , Arafa Ali , Heller Nicholas , Ahmadi Mahdi , Hong Jiarong , Ludwig Megan , Hwang Justin , Antonarakis Emmanuel S. , Parthasarathy Jayant 
Published: June 2023

Abstract
In recent years, liquid biopsies have emerged to provide improved insights on the current disease state of a patient, but they generally rely on a small number of protein markers from immunofluorescent staining or cell-free DNA, which provides limited information especially around drug targets. As more targeted and immune therapies enter the market, selecting the optimal drug target could improve patient outcomes drastically. One way to achieve this goal is to generate multi-omic datasets from the cancer cells in circulation, known as circulating tumor cells (CTCs). In this study, Astrin Biosciences’ patented isolation technology was used to enrich CTCs with high purity from the blood of metastatic castration resistant prostate cancer (mCRPC) patients. The enriched CTCs and a patient matched control sample consisting primarily of white blood cells were divided such that RNA and protein could be interrogated from the same patient. Label free unbiased mass spectrometry was used to identify proteins and marks the first time a global proteomic assessment has been performed in CTCs from cancer patients. Initial analysis identified over 1,500 peptides corresponding to greater than 500 proteins with increased epithelial cell markers in the CTC-enriched sample and increased WBC markers in the control sample. Hallmarks of androgen response and detection of the androgen receptor were also identified in the CTC proteome. In addition to the proteome, RNA sequencing will also be performed to generate a multi-omic platform to detect cancer signaling mechanisms and biomarkers. Overall, this study was designed to show the feasibility of obtaining multi-omic data from a liquid biopsy and future studies will provide more insight into the clinical utility of such data. As we analyze more patients, we plan to compare the protein and RNA signatures across mCRPC patients and eventually be able to map patient outcomes and correlate them with drug response with the overall goal to improve treatment selection and patient outcomes.
Citation Format: Justin M. Drake, Zoi Sychev, Alec Horrmann, Kaylee J. Smith, Catalina Galeano-Garces, Ali Arafa, Nicholas Heller, Mahdi Ahmadi, Jiarong Hong, Megan Ludwig, Justin Hwang, Emmanuel S. Antonarakis, Jayant Parthasarathy. Unlocking the proteome of metastatic prostate cancer circulating tumor 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 2309.
Abstract 2736: Locoregional modified vaccinia ankara (MVA) encoding a single-chain IL-12 achieves efficacy antitumor immune response in peritoneal carcinomatosis
Authors: Bella Ángela , Arrizabalaga Leire , Trani Claudia Augusta Di , González-Gomariz José , Cirella Assunta , Olivera Irene , Alvarez Maite , Teijeira Álvaro , Langbein Cigdem Atay , Medina-Echeverz José , Hinterberger Maria , Hochrein Hubertus , Melero Ignacio , Berraondo Pedro , Aranda Fernando 
Published: June 2023

Abstract
Peritoneal carcinomatosis is an advanced stage of cancer developed in the peritoneal cavity without effective treatment. In order to restore antitumor immunity subverted by tumor cells, we evaluated in this study intraperitoneal administration of vaccinia virus Ankara (MVA) genetically modified to express the proinflammatory cytokine single-chain interleukin 12. MVA encoding scIL-12 was evaluated in peritoneal carcinomatosis models based on intraperitoneal administration of tumor cells. The immune response was evaluated by ELISpot, flow cytometry, intravital microscopy, and depleting monoclonal antibodies. Safety was assessed by measuring body weight and a hemogram test. Tissue tropism after intravenous or intraperitoneal administration was determined by bioluminescence analysis after the administration of MVA encoding luciferase.
Intraperitoneal or locoregional administration, but not other routes of administration, elicited a potent immune response characterized by increased levels of tumor-specific T CD8 lymphocytes. The antitumor immune response was detectable not only in the peritoneal cavity but also systemically. As a result, a single intraperitoneal administration of MVA encoding scIL-12 completely eradicates MC38 cells implanted in the peritoneum, protecting cured mice from a subcutaneous rechallenge with MC38 cells. The safety profile of intraperitoneal administration was also superior to that of intravenous administration since there was no weight loss or hematological toxicity when the vector was infused into the peritoneal cavity.
In conclusion, intraperitoneal administration of MVA vectors encoding scIL-12 induces a potent tumor-specific immune response that leads to the eradication of peritoneal metastasis.
Citation Format: Ángela Bella, Leire Arrizabalaga, Claudia Augusta Di Trani, José González-Gomariz, Assunta Cirella, Irene Olivera, Maite Alvarez, Álvaro Teijeira, Cigdem Atay Langbein, José Medina-Echeverz, Maria Hinterberger, Hubertus Hochrein, Ignacio Melero, Pedro Berraondo, Fernando Aranda. Locoregional modified vaccinia ankara (MVA) encoding a single-chain IL-12 achieves efficacy antitumor immune response in peritoneal carcinomatosis [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 2736.
Abstract 3157: Prediction of adverse drug reactions of anti-breast cancer drugs using machine learning
Authors: Seongmo Kang , Lee Suehyun , Shin Hyunah , Kim Hyun Uk 
Published: June 2023

Abstract
Chemotherapy is a representative treatment option for cancers, but one of the challenges during the course of cancer treatment is the possible occurrence of adverse drug reactions (ADRs) caused by an anticancer drug. For example, ADRs such as encephalopathy, radiation recall dermatitis, acute cardiogenic shock and febrile neutropenia have been reported for 5-fluorouracil, an anticancer drug used to treat several cancer types. These ADRs may be caused by a single drug or by interactions with other drugs. Unfortunately, it is extremely difficult to predict potential ADRs a priori because the occurrence of ADR depends on the patient’s genetics and health condition as well as a combination of drugs taken together. To address this problem, we use electric health record (EHR) data of breast cancer patients as a proof-of-concept demonstration to develop a machine learning model that predicts ADRs. For this, administrations of breast cancer patients, diagnostic records, and additional personal information (e.g., age and gender) were used as input data. To deal with high sparsity of EHR data, which has categorical information, factorization machine was applied. Factorization machine can effectively capture key information in an sparse environment. The model classifies whether a patient shows one of pre-defined ADRs as an output. The machine learning model developed in this study can be useful for predicting potential ADRs of various drugs by taking into account a patient’s health condition.
Citation Format: Kang Seongmo, Suehyun Lee, Hyunah Shin, Hyun Uk Kim. Prediction of adverse drug reactions of anti-breast cancer drugs using machine learning [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 3157.
Abstract 3209: Metabolic characterization of radiation-induced cardiotoxicity
Authors: Elliott Sarah C. , Sharma Jayesh , Zhang-Velten Elizabeth R. , Elnwasany Abdallah , Vidal Chantal , Szweda Luke , Alluri Prasanna 
Published: June 2023

Abstract
Background: Approximately 50% of all cancer patients receive radiation therapy as a component of their cancer care. While radiation therapy has demonstrable benefit in improving survival in patients, radiation-induced heart disease (RIHD) is a major contributor to morbidity and mortality in cancer survivors with history of thoracic radiation. Understanding metabolic changes underlying RIHD may enable development of novel diagnostic and therapeutic approaches for early detection and treatment of RIHD. The high energetic demands of the heart require properly functioning mitochondria to meet the ATP production needs. Fatty acids are the primary metabolic substrates for energy production in a healthy heart. However, under conditions of stress, the cardiac metabolism shifts towards increased glucose utilization. In this study, we characterize the impact of radiation of cardiac substrate utilization and energy production.
Methods: Pre-clinical RIHD models were established by administering whole heart radiation (8Gy x 5) in mice and rats followed by structural and biochemical characterization. Transmission electron microscopy and western blot analyses were used to characterize structural and biochemical changes in the heart in response to radiation. Spectrophotometric assays and Western blot analyses were used to characterize changes in pyruvate dehydrogenase (PDH) activity and function in the heart in response to radiation.
Results: Our studies identified myocardial mitochondrial dysfunction as an early event following exposure of heart to radiation. Cardiac irradiation resulted in increased mitochondrial fusion and higher expression of MFN1, a key protein that mediates mitochondrial fusion. The pathological structural and biochemical changes in the myocardial mitochondria are associated with reduced glucose metabolism due to impaired PDH activity. This decline was mediated by increased phosphorylation of PDH in irradiated hearts, which inhibits its activity.
Conclusion: Cardiac irradiation results in early metabolic dysregulation, especially in glucose metabolism, which may be exploited for early detection and mitigation of radiation-induced cardiotoxicity.
Citation Format: Sarah C. Elliott, Jayesh Sharma, Elizabeth R. Zhang-Velten, Abdallah Elnwasany, Chantal Vidal, Luke Szweda, Prasanna Alluri. Metabolic characterization of radiation-induced cardiotoxicity [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 3209.
Abstract 3628: RAC1 aberrations in head and neck cancer affect immune microenvironments
Authors: Chan Helen Hoi Yin , Liu Yuchen , Ngan Hoi Lam , Lui Vivian Wai Yan 
Published: June 2023

Abstract
RAC1 is a Rho GTPase well-identified as an oncogene overexpressed in various cancer types. RAC1 amplification or gain account for ~40% of head and neck squamous cell carcinoma (HNSCC) while mutation of RAC1 occurs at ~3% according to TCGA-HNSCC cohort. HNSCC patients with RAC1 aberrations, including RAC1 mutations and amplification or gain, are associated with poor overall and disease-free survival in HNSCC. Significantly higher tumor mutational burden is observed in RAC1-mutated group (p=0.0336) or in RAC1-amplified/gain group (p=0.0109) vs. wildtype patients in TCGA-HNSCC cohort. As increases in TMB are often associated with immune cell infiltration in cancers, we hypothesized that RAC1 aberrations impact the tumor immune microenvironment (TIME) of HNSCC, potentially contributing to disease progression.PD-L1 (CD274) is an important immunosuppressive immune checkpoint molecule expressed in tumor cells. Here, we first reported that ectopic overexpression of RAC1 p.P29S and p.A159V mutations in a human HNSCC cell line (PECAPJ41 clone D2, ATCC, USA) could cause upregulation of PD-L1 at both mRNA (by RNA-seq) and protein levels (by Western blotting), first demonstrating a direct effect of RAC1 mutations on potential HNSCC TIME modulation via PD-L1. Furthermore, by tumor immune estimation resources (TIMER) analysis, we found that RAC1-mutated tumors have significantly higher level of neutrophils immune infiltration of 38.63% (p=0.027) compared to the wildtype tumors. From the CIBERSORTx analysis, M2 Macrophages was significantly increased by 40.42% in RAC1-mutated tumors vs wildtype in the TCGA-HNSCC cohort (p=0.031). We also validated this finding by immunofluorescent staining of PD-L1 and M2 Macrophages in immunocompetent mouse HNSCC xenografts models expressing RAC1 p.P29S and p.A159V mutations as compared to controls.
Our in silico, in vitro and in vivo findings first uncover an important role of RAC1 aberrations in HNSCC TIME immunosuppression by regulating PD-L1 expression, neutrophil and M2 macrophages infiltrations. Clinical activities of PD-L1 inhibitors in RAC1-mutated HNSCC patients worth future investigations.
Acknowledgement: This research is funded by the General Research Fund (Ref. No.:14168517) and the Research Impact Fund (Ref. No.: R4015-19) from the Research Grants Council in Hong Kong. VWYL is supported by Start-up Fund, Georgia Cancer Center, Medical College of Georgia at Augusta University.
Citation Format: Helen Hoi Yin Chan, Yuchen Liu, Hoi Lam Ngan, Vivian Wai Yan Lui. RAC1 aberrations in head and neck cancer affect immune microenvironments. [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 3628.
Abstract 3656: A multi-scale approach to quantitatively evaluate the SMAD signaling pathway
Authors: Heimsath Ernest , Arvidson Lisa , Prioli Reginaldo , Wood Antony 
Published: June 2023

Abstract
Angiogenesis and cell proliferation are fundamental biological processes whose pathologic states represent two hallmarks of cancer. Central to controlling both processes is the TGF-β/BMP signaling pathway, for which the SMAD proteins serve as major downstream effector molecules. Upon ligand-binding, TGF-β or BMP type I/II receptor heterotetramers phosphorylate receptor-regulated SMADs (R-SMADs). TGF-β-receptor binding leads to SMAD2/3 phosphorylation, whereas BMP-receptor binding induces phosphorylation of SMADs 1/5/8. Phosphorylated SMADs (pSMADs) then form a complex with the co-SMAD SMAD4 at which point they undergo nuclear translocation, where they function as transcriptional modulators of target genes. The magnitude of SMAD phosphorylation and functional output (e.g., stimulated angiogenesis or attenuated cell proliferation) depends on both the ligand concentration, as well as the duration of exposure. In this study, we quantitatively evaluate the phosphorylation states of R-SMADs, as well as their downstream biological effects at three different biological scales: 1) biochemical, 2) cellular, and 3) tissue/3D models. At the biochemical level, the temporal and dose-dependent phosphorylation of R-SMADs in response to growth factor stimulation can be quantified using a quantitative ELISA approach. Growth factor stimulation can be quantified at the cellular level by high content imaging of SMAD phosphorylation and nuclear translocation, while simultaneously monitoring cell proliferation rates. Lastly, high-resolution confocal imaging can be employed to observe developmental consequences of phospho-SMAD signaling using a HUVEC-based 3D angiogenesis model system.
For Research Use Only. Not for use in diagnostic procedures.
Citation Format: Ernest Heimsath, Lisa Arvidson, Reginaldo Prioli, Antony Wood. A multi-scale approach to quantitatively evaluate the SMAD signaling pathway. [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 3656.
Abstract 4168: BALB/c-CD3EDG HuGEMMTM mouse model for evaluation of CD3-targeted tumor immunotherapy
Authors: Liu Demi Xiaojuan , Lian Kaixia , Yan Xuefei , Lin Jie , Zheng Lei , Xiaoyu An Annie , Xu Xiaoxi , Bourre Ludovic , Wang Jingjing 
Published: June 2023

Abstract
Introduction: T cell immune response plays critical roles in cancer immunotherapy. CD3 complex, composed of CD3ε, CD3δ and CD3γ chains, is an essential component of TCR-CD3 complex mediating TCR signaling. Targeting CD3 complex has therefore become a popular strategy for manipulation of T cell function. Clinically relevant animal models for proper evaluation of human CD3 antibodies is in great demand in the field. Currently, adoptive transfer of human CD3+ T cells or transplantation of human hematopoietic stem/precursor cells to immunodeficient mice are usually employed. However, these mouse models are not fully immunocompetent. In this study we have evaluated in vitro CD3 EDG functionality and in vivo therapeutic efficacy, in BALB/c-hCD3EDG knock-in mouse in which all the three components of the CD3 complex — Cd3ε, Cd3δ, and Cd3γ— are replaced by their human counterparts, CD3E, CD3D, and CD3G.
Methods: A humanized CD3EDG mouse model (HuGEMM) on BALB/c background was generated by replacing the entire mouse CD3EDG with its human counterpart through ES cell-based gene targeting. The cell surface expression of CD3E and intracellular expression of CD3D and CD3G were confirmed by FACS. Naïve CD3+ T cells were isolated from the splenocytes of homozygous CD3EDG HuGEMM and activated by anti-hCD3 antibody. T cell proliferation was demonstrated by CFSE dilution assay. To validate the TCR functionality of humanized CD3EDG in vivo, we evaluated bispecific antibody anti-hCD3/hEpCAM5 in BALB/c-CD3EDG HuGEMM bearing CT26-hEpCAM5.
Results: The expression of human CD3E, CD3D and CD3G were confirmed by flow cytometry. hEpCAM5 antigen expression was confirmed in CT26 cell line in vitro and tumor in vivo by flow cytometry. The TCR functionality was detected by in vitro T cell activation assays using anti-hCD3 antibody. In vivo efficacy was demonstrated using a bispecific antibody that simultaneously binds to human CD3 and human tumor associated antigen EpCAM5 in human CD3 EDG knock-in mice engrafted with CT26-hEpCAM5 tumor. The therapeutic efficacy of the bispecific antibody showed 32% tumor growth inhibition compared to control treatment. No significant body weight loss was recorded in any of the animals.
Conclusion: This study showed the successful establishment of humanized CD3 knock-in BALB/c mouse models providing a full immunocompetent model for human CD3-targeted tumor immunotherapies evaluation.
Citation Format: Demi Xiaojuan Liu, Kaixia Lian, Xuefei Yan, Jie Lin, Lei Zheng, Annie Xiaoyu An, Xiaoxi Xu, Ludovic Bourre, Jingjing Wang. BALB/c-CD3EDG HuGEMMTM mouse model for evaluation of CD3-targeted tumor immunotherapy. [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 4168.
Abstract 5254: Topical inhibition of UV-induced PD-L1 expression and inflammatory signaling by the small molecule inhibitor BMS-202
Authors: Vaishampayan Prajakta , Jandova Jana , Ai Yuchen (Ella) , Kirschnerova Viktoria , Curiel-Lewandrowski Clara , Wondrak Georg T. , Dickinson Sally E. 
Published: June 2023

Abstract
Immune evasion is a molecular hallmark of cancer, and overexpression of the immune checkpoint protein PD-L1 (CD274) has been documented in several tumors including cutaneous squamous cell carcinoma (cSCC). Notably, while baseline levels of PD-L1 in normal human epidermis are low, acute solar-simulated light (SSL) exposure increases the expression of this protein in epidermal keratinocytes, an effect which can be replicated in cultured keratinocytes and in mouse models. While current immunotherapies targeting the PD-1/PD-L1 axis using monoclonal antibodies are providing therapeutic benefits in many cancers including cSCC, small molecule inhibitors are also being developed to target PD-L1 which may be amenable for topical formulation and therefore early intervention with reduced systemic exposure. We have recently tested one such molecule, BMS-202, in vitro and in vivo. BMS-202 application to keratinocytes in culture inhibits UV-induced PD-L1 RNA and protein expression. Notably, exposure to this inhibitor also reduced UV-induced stress signaling as measured by AP-1 luciferase assay in cultured keratinocytes. Topical application of BMS-202 to immunocompetent SKH-1 mouse skin resulted in significant inhibition of SSL-induced epidermal PD-L1 as determined by immunoblot analysis. NanoString nCounter Pathway™ transcriptomic analysis of full-thickness SKH-1 mouse skin shows strong inhibition of SSL-induced inflammatory responses, chemokine activity, innate immune response and NF-κB activation in BMS-202 treated samples compared to SSL-only controls. Our results indicate that early intervention against PD-L1 expression/activity could be a viable target for skin cancer photochemoprevention. Topical application of small molecule PD-L1 inhibitors such as BMS-202 may provide novel treatment options for populations at high risk for cSCC.
Citation Format: Prajakta Vaishampayan, Jana Jandova, Yuchen (Ella) Ai, Viktoria Kirschnerova, Clara Curiel-Lewandrowski, Georg T. Wondrak, Sally E. Dickinson. Topical inhibition of UV-induced PD-L1 expression and inflammatory signaling by the small molecule inhibitor BMS-202. [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 5254.