bluuebunny/crossref_metadata_2025 huggingface dataset:
PPARG: A Promising Therapeutic Target in Breast Cancer and Regulation by Natural Drugs
Authors: Li De-Hui , Liu Xu-Kuo , Tian Xiao-Tong , Liu Fei , Yao Xu-Jiong , Dong Jing-Fei
Published: June 2023

Breast cancer (BC) is the most common type of cancer among females. Peroxisome proliferator-activated receptor gamma (PPARG) can regulate the production of adipocyte-related genes and has anti-inflammatory and anti-tumor effects. Our aim was to investigate PPARG expression, its possible prognostic value, and its effect on immune cell infiltration in BC, and explore the regulatory effects of natural drugs on PPARG to find new ways to treat BC. Using different bioinformatics tools, we extracted and comprehensively analyzed the data from the Cancer Genome Atlas, Genotype-Tissue Expression, and BenCaoZuJian databases to study the potential anti-BC mechanism of PPARG and potential natural drugs targeting it. First, we found that PPARG was downregulated in BC and its expression level correlates with pathological tumor stage (pT-stage) and pathological tumor-node-metastasis stage (pTNM-stage) in BC. PPARG expression was higher in estrogen receptor-positive (ER+) BC than in estrogen receptor-negative (ER−) BC, which tends to indicate a better prognosis. Meanwhile, PPARG exhibited a significant positive correlation with the infiltration of immune cells and correlated with better cumulative survival in BC patients. In addition, PPARG levels were shown to be positively associated with the expression of immune-related genes and immune checkpoints, and ER+ patients had better responses to immune checkpoint blocking. Correlation pathway research revealed that PPARG is strongly associated with pathways, such as angiogenesis, apoptosis, fatty acid biosynthesis, and degradation in ER+ BC. We also found that quercetin is the most promising natural anti-BC drug among natural medicines that upregulate PPARG. Our research showed that PPARG may reduce BC development by regulating the immune microenvironment. Quercetin as PPARG ligands/agonists is a potential natural drug for BC treatment.
Balanced Translocation Disrupting JAG1 Identified by Optical Genomic Mapping in Suspected Alagille Syndrome
Authors: Zhang Yi-Qiong , Gao Peng-Fei , Yang Jing-Min , Zhang Jing , Lu Yu-Lan , Wang Jian-She
Published: June 2023

We report the clinical and genetic features of a Han Chinese boy who presented with disease suspect for Alagille syndrome (ALGS). Multiple genetic analyses (panel sequencing, multiplex-ligation-dependent probe amplification, and whole genome sequencing) failed to uncover a causative variant. Optical genomic mapping detected a reciprocal translocation between chromosomes 4 and 20, interrupting JAG1. Long-range polymerase chain reaction and targeted sequencing identified the exact breakpoints. Sanger sequencing and reanalysis of genome sequencing raw data further confirmed the result. This translocation is expected to generate aberrant JAG1 transcripts that lead to complete loss of JAG1 expression. This is the first t(4;20)(q22.1;p12.2) balanced translocation detected by optical genomic mapping and characterized at base-pair resolution in ALGS. Our approach permitted precise diagnosis and genetic counseling.
Changes in Breast Cancer Presentation during COVID-19: Experience in an Urban Academic Center
Authors: Diskin Brian , Pourkey Nakisa , Schnabel Freya , Miah Pabel , DiMaggio Charles , Axelrod Deborah , Shapiro Richard , Guth Amber A.
Published: June 2023

The COVID-19 pandemic strained healthcare systems worldwide, delaying breast cancer screening and surgery. In 2019, approximately 80% of breast cancers in the U.S. were diagnosed on screening examinations, with 76.4% of eligible Medicare patients undergoing screening at least every two years. Since the start of the pandemic, many women have been reluctant to seek elective screening mammography, even with the lifting of pandemic-related restrictions in access to routine healthcare. We describe the effect of the COVID-19 pandemic on breast cancer presentation at a tertiary academic medical center greatly impacted by the pandemic.
Coverage Maximization of WSNs in 3D Space Based on Hybrid Lion Swarm Optimization
Authors: Wu Chen-Yin , Huang Zi-Lin , Lin Geng , Ke Chen-Qi , Lan Tian-Chen
Published: June 2023

The wireless sensor network (WSN) collects all the physical information required by the user for the target area and transmits the data to the sink or base station via multihop communication. With a limited number of nodes, it is important to reduce the overlapping area between nodes to improve coverage. However, increasing the coverage rate tends to create isolated points, which reduces the connection efficiency. Therefore, considering coverage and connection efficiency simultaneously is a challenging optimization task. In order to solve the above problems, this paper proposes a spatial configuration optimization strategy based on the hybrid lion swarm optimization (HLSO) algorithm. The proposed algorithm is experimented on a large number of benchmark graphs. The experimental results prove very competitive with and even better than different algorithms. Finally, in order to avoid isolated points in the node deployment process, the optimal deployment scheme of the nodes is found by considering both conditions of node coverage and connection efficiency at the same time.
Photovoltaic Module Fault Detection Based on Deep Learning Using Cloud Computing
Authors: Naveen Venkatesh S. , Arun Balaji P. , Chakrapani Ganjikunta , Annamalai K. , Aravinth S. , Anoop P. S. , Sugumaran V. , Mahamuni Vetriselvi
Published: June 2023

The performance of photovoltaic modules (PVMs) degrades due to the occurrence of various faults such as discoloration, snail trail, burn marks, delamination, and glass breakage. This degradation in power output has created a concern to improve PVM performance. Automatic inspection and condition monitoring of PVM components can handle performance-related issues, especially for installed capacity where no trained personnel are available at the location. This paper describes a deep learning-based technique involving convolutional neural networks (CNNs) to extract features from aerial images obtained from unmanned aerial vehicles (UAVs) and classify various types of fault occurrences using cloud computing and Internet of things (IoT). The algorithm used demonstrates a binary classification with high accuracy by comparing individual faults with good condition. Efficient and effective fault detection can be observed from the results obtained.
Diabetes and Prostate Cancer Outcomes in Men with Nonmetastatic Castration-Resistant Prostate Cancer: Results from the SEARCH Cohort
Authors: Sergeyev Andrei , Gu Lin , De Hoedt Amanda M. , Amling Christopher L. , Aronson William J. , Cooperberg Matthew R. , Kane Christopher J. , Klaassen Zachary , Terris Martha K. , Guerrios-Rivera Lourdes , Freedland Stephen J. , Csizmadi Ilona
Published: June 2023

Background:

The prognosis of diabetic men with advanced prostate cancer is poorly understood and understudied. Hence, we studied associations between diabetes and progression to metastases, prostate cancer–specific mortality (PCSM) and all-cause mortality (ACM) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC).

Methods:

Data from men diagnosed with nmCRPC between 2000 and 2017 at 8 Veterans Affairs Health Care Centers were analyzed using Cox regression to determine HRs and 95% confidence intervals (CI) for associations between diabetes and outcomes. Men with diabetes were classified according to: (i) ICD-9/10 codes only, (ii) two HbA1c values > 6.4% (missing ICD-9/10 codes), and (iii) all diabetic men [(i) and (ii) combined].

Results:

Of 976 men (median age: 76 years), 304 (31%) had diabetes at nmCRPC diagnosis, of whom 51% had ICD-9/10 codes. During a median follow-up of 6.5 years, 613 men were diagnosed with metastases, and 482 PCSM and 741 ACM events occurred. In multivariable-adjusted models, ICD-9/10 code-identified diabetes was inversely associated with PCSM (HR, 0.67; 95% CI, 0.48–0.92) while diabetes identified by high HbA1c values (no ICD-9/10 codes) was associated with an increase in ACM (HR, 1.41; 95% CI, 1.16–1.72). Duration of diabetes, prior to CRPC diagnosis was inversely associated with PCSM among men identified by ICD-9/10 codes and/or HbA1c values (HR, 0.93; 95% CI, 0.88–0.98).

Conclusions:

In men with late-stage prostate cancer, ICD-9/10 ‘code-identified’ diabetes is associated with better overall survival than ‘undiagnosed’ diabetes identified by high HbA1c values only.

Impact:

Our data suggest that better diabetes detection and management may improve survival in late-stage prostate cancer.
Abstract 1051: Liquid biopsy in the detection of genetic biomarkers in gastrointestinal cancer
Authors: Gomes-Fernandes Bianca , Carneiro Juliana Garcia , da Silva Rodrigo Gomes , de Marco Luiz , Bastos-Rodrigues Luciana
Published: June 2023

Colorectal cancer (CRC) is one of the leading causes of morbidity and mortality worldwide. Detection prior to metastasis and appropriate therapeutic application lead to greater patient survival and quality of life. However, the diagnosis and postoperative surveillance are surrounded by limitations. Genetic biomarkers are influential factors that contribute to favorable clinical outcomes. To better understand the molecular basis associated with CRC, we investigated KRAS, NRAS, BRAF, EGFR and TP53 genes in the DNA of tumor and healthy cells using Sanger sequencing. The most frequent alteration, present only in the tumor DNA (somatic), was used to investigate, by Digital PCR (ddPCR), the detection and analysis of circulating tumor DNA (ctDNA) in the plasma. Altogether, 42 subjects made up the study, most of them male (59.5%), with a mean age of 63 years and tumors located in the right colon (21.4%). transversal (2.4%), left (4.8%), sigmoid (33.3%) and straight (38.1%). Germline and somatic allelic variants were found in the KRAS, EGFR and TP53 genes. The most frequent somatic alteration in the study was rs121913529, which showed an association with alcohol consumption (p = 0.002). Patients with a somatic mutation in TP53 are ten times more likely to die, compared with the chance of those without a mutation in this gene (OR 11.2; 95% CI 1.25 - 245). The applicability of these somatic changes in the liquid biopsy technique was demonstrated by ddPCR. Therefore, the results obtained expand the understanding of the molecular basis of CRC and present an optimization of the liquid biopsy, timely for clinical practice.

Citation Format: Bianca Gomes-Fernandes, Juliana Garcia Carneiro, Rodrigo Gomes da Silva, Luiz de Marco, Luciana Bastos-Rodrigues. Liquid biopsy in the detection of genetic biomarkers in gastrointestinal cancer [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 1051.
Abstract 1081: Co-targeting CK1epsilon and PIK3CB/p110beta to treat glioblastoma
Authors: Xu Eileen
Published: June 2023

The purpose of this study is to determine whether co-inhibition of CK1epsilon and PIK3CB/p110β is an effective therapeutic treatment for Glioblastoma (GBM). GBM is the most common and malignant primary brain cancer in adults. GBM has a dismal prognosis of death within 6 months if left untreated, thus there is a clinically unmet need for new and effective treatments. CK1epsilon has been identified as a GBM survival kinase gene. CK1epsilon promotes growth of GBM cells by inhibiting β-catenin. However, blocking CK1epsilon alone fails to completely block tumor growth perhaps because β-catenin can be regulated by other kinases. PIK3CB/p110β is another GBM survival kinase gene which also acts upstream of β-catenin. As seen with CK1epsilon, blocking PIK3CB/p110β alone also fails to completely block tumor growth. It is possible that blocking either CK1epsilon or PIK3CB/p110β alone does not substantially activate β-catenin to induce massive GBM cell death, thus limiting their therapeutic efficacy as a single agent. It is therefore imperative to investigate if co-targeting CK1epsilon and PIK3CB/p110β yields a synergistic inhibitory effect on GBM cell growth.

GBM cells were treated with either DMSO (control), IC261 (chemical inhibitor of CK1epsilon), AZD6482 (chemical inhibitor of PIK3CB/p110β), or both IC261 and AZD6482. Cell viability was measured using the MTS viability assay. Cell viability for the treatment groups were as follows: AZD6482 (88.81%), IC261 (66.78%), and combination of AZD6482+IC261 (42.59%). Statistical analysis of drug synergy using the Bliss independence model yielded an Excess Over Bliss score greater than 0%, indicating a synergistic effect. To further elucidate the mechanism of GBM cell death, immunoblotting will also be performed to detect β-catenin activity after inhibition of CK1epsilon and PIK3CB/p110β. Overall, preliminary results show that co-inhibition of CK1epsilon and PIK3CB/p110β with chemical inhibitors yields synergistic GBM cell death.

Citation Format: Eileen Xu. Co-targeting CK1epsilon and PIK3CB/p110beta to treat glioblastoma [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 1081.
Abstract 1090: Dominant-negative TP53 variants confer radiation resistance in endometrial cancer
Authors: Petty Aaron , Durmaz Arda , Yard Brian , Scott Jacob , Vargas Roberto
Published: June 2023

Introduction: High-grade endometrial cancers (EC) belonging to the “serous-like” cluster are known to portend a worse clinical outcome. The direct contribution of commonly identified TP53 variants on radiotherapy (RT) response has not been demonstrated in EC.

Methods: To assess the impact of TP53 variants, allelic frequency, and p53/p21 signaling on radio-resistance in vitro, we utilized a high-throughput radiation assay and intron targeting CRISPR-Cas9 knockout approach in two low copy-number/TP53 wild-type EC cell lines (JHUEM1/JHUEM2). This approach facilitated TP53 cDNA complementation in a TP53-null background without significant impact from copy-number burden. The effect on radiation response was determined using high-throughput methodology and area under the curve (AUC) calculation along 5 dose-points. All experiments were carried out using 2 monoclonal isolates for each guide RNA (4 total replicates) and 2 non-targeting controls.

Results: Knockout (KO) of wild-type TP53 resulted in loss of downstream p21 signaling and increased radio-resistance, demonstrating the role of p53 signaling on RT response. Complementation with five common TP53 missense variants (Y220C, R273C, R273H, R248Q, R248W) into the KO cell lines led to increased p53 accumulation without an effect on p21 signaling or RT response. Complementation into the WT cell lines, mimicking tumors with low allelic frequency/heterozygous mutations, led to abrogation of p21 signaling and increased radio-resistance, establishing their gain-of-function/dominant-negative impact.

Conclusions: Our findings directly implicate TP53 status on radiotherapy response in EC, providing biologic rationale for the clinical observation that these patients may benefit from chemotherapy. Additionally, our findings demonstrate that dominant-negative variant alleles similarly impact RT response by abrogating p21 signaling.

Citation Format: Aaron Petty, Arda Durmaz, Brian Yard, Jacob Scott, Roberto Vargas. Dominant-negative TP53 variants confer radiation resistance in endometrial cancer [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 1090.
Abstract 1098: Combination of a DNA vaccine-induced immune checkpoint blockade and radiation therapy induces anti-tumor immunity
Authors: Lan Keng-Hsueh , Sheng Ying-Chun , Lan Keng-Li , Kim KyungMann , Kuo Sung-Hsin , Morris Zachary
Published: June 2023

Background: Immune checkpoint blockade (ICB) immunotherapy improves survival for many cancer patients, but those with immunologically ‘cold’ tumors do not derive benefit. Radiation therapy (RT) has been demonstrated to augment antitumor immunity in preclinical and clinical studies and may enhance response to ICB in immunologically cold tumors. We have developed DNA-based, cost-effective, and versatile ICB immunotherapies. Here, we test the use of these alone and in combination with RT as a novel treatment approach in syngeneic murine melanoma models.

Materials and methods: We constructed ICB DNA vaccines targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1), CTLA-4 Vax and PD-1 Vax, respectively. These were delivered to mice by intramuscular or intratumoral electroporation. The effects of combinations of ICB DNA vaccines and RT were monitored for generation of endogenous anti-CTLA-4 and anti-PD-1 antibodies, modification of tumor microenvironment (TME), and tumor response in mice bearing syngeneic B78 or B16 melanoma.

Results: Intramuscular vaccination with CTLA-4 Vax and PD-1 Vax induced endogenous anti-CTLA-4 and anti-PD-1 antibodies, respectively, and the titers increased with additional vaccinations. Vaccination with CTLA-4 Vax and PD-1 Vax alone or in combination (Dual Vax) did not inhibit the murine B16 melanoma model; however, the combination of CTLA-4 Vax and RT (CTLA-4 Vax + RT) led to enhanced infiltration of the TME with effector T cells. Dual Vax combined with RT enabled systemic anti-tumor immunity in mice bearing two B16 melanoma tumors in which only one was radiated. With intra-tumoral route of vaccination, the Dual Vax + RT treatment induced a trend toward systemic anti-tumor response in the immunologically cold B78 tumor model.

Conclusions: DNA vaccines that stimulate endogenous production of antibodies against immune checkpoints may serve as an alternative form of ICB. The combination of ICB DNA vaccine and RT enabled anti-tumor immunity and tumor response in preclinical models of melanoma.

Citation Format: Keng-Hsueh Lan, Ying-Chun Sheng, Keng-Li Lan, KyungMann Kim, Sung-Hsin Kuo, Zachary Morris. Combination of a DNA vaccine-induced immune checkpoint blockade and radiation therapy induces anti-tumor immunity [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 1098.
Abstract 1109: Effects of radiation therapy on the hardness of enamel and dentin
Authors: Kulchar Rachel , Eggmann Florin , Mina Celine , Szewczyk Steven , Yusuke Kakiuchi , Deng Jie , Mante Francis
Published: June 2023

Introduction: Radiation therapy is often used as the main or adjunctive treatment for cancer in the oral cavity. Unfortunately, prolonged exposure to radiation has adverse effects on tissues of the oral cavity, including a decrease in the hardness of dentin. Consequently, patients who receive radiation therapy are susceptible to tooth sensitivity and caries. Fluoride treatments have proven to be effective in restoring the hardness of dentin as it remineralizes the tooth. The aim of this study was to determine the optimal fluoride treatment for restoring the hardness of irradiated teeth.

Methods: 100 teeth were extracted, cleaned, and mounted in acrylic resin. The teeth were ground and polished to expose the dentin and enamel. The initial Knoop hardness of the teeth was measured and split equally among five groups and treated as follows: (1) sodium fluoride varnish (SF), (2) MI varnish (MI), (3) silver diamine fluoride and potassium iodide (SDFKI), (4) silver diamine fluoride (SDF), and (5) no treatment (NT). All groups were subjected to 2 grays of daily radiation treatment for 6 weeks. The hardness of the dentin was measured immediately following radiation. Afterwards, the 5 treatments were applied weekly for 6 weeks. Hardness was measured 1 week after each treatment. Kruskal-Wallis one way analysis of variance on ranks was used to compare the different groups.

Results: After 6 weeks of fluoride treatment, there was a significant difference (p = 0.013) between the hardness of the irradiated enamel, with Group 4 resulting in the largest median measurement (263.4). Similarly, 5 weeks of fluoride application resulted in a mean hardness of dentin that was 15.8%, 13.6%, 16.2%, and 19.4% higher than the control for groups 1, 2, 3, and 4, respectively. Again, Group 4 had the highest hardness measurement.

Conclusions: Radiation therapy decreases the hardness of enamel and dentin. SDF treatment resulted in the highest hardness for both irradiated dentin and enamel, suggesting that SDF is promising as a fluoride treatment for those undergoing radiation therapy for oral cancer.

Citation Format: Rachel Kulchar, Florin Eggmann, Celine Mina, Steven Szewczyk, Kakiuchi Yusuke, Jie Deng, Francis Mante. Effects of radiation therapy on the hardness of enamel and dentin [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 1109.
Abstract 1149: Universal redirection of chimeric antigen receptor T cells against solid tumors via tumor cell membrane-inserting CAR ligands
Authors: Zhang Angela
Published: June 2023

Chimeric antigen receptor (CAR) T cell therapy is effective in treating certain hematological malignancies, but its translation to solid tumors has been challenging. Selecting an effective target antigen is hampered by heterogeneous tumor antigen expression and target antigen expression in healthy tissues. We describe a strategy to promote CAR T-mediated destruction of any tumor via intratumoral administration of a membrane-inserting fluorescein isothiocyanate lipid amphiphile molecule (“amph-FITC”) recognizable by a FITC-specific CAR. Firstly, we show labeling of tumor cells with amph-FITC in vitro, mediating cytotoxicity by FITC CAR T cells in coculture. Then, we demonstrate efficient tagging of tumor cells in vivo upon intratumoral injection with minimal labeling of non-tumor tissues, driving FITC CAR T cell proliferation and accumulation in tumors. Subsequently, we determine that this strategy stimulates an anti-tumor response that facilitates tumor regression in several syngeneic and human xenograft mouse models bearing different tissues of origin. In syngeneic models, this strategy induced the infiltration of host T cells and elicited endogenous tumor-specific T cell priming, leading to protection against tumor rechallenge. These results demonstrate the capacity to treat tumors independent of antigen expression or tissue of origin, addressing a major bottleneck in adoptive T cell therapy.

Citation Format: Angela Zhang. Universal redirection of chimeric antigen receptor T cells against solid tumors via tumor cell membrane-inserting CAR ligands [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 1149.
Abstract 124: Autocrine signaling extends PD-L1 expression in NSCLC following an active immune response
Authors: Bursell Taylor M. , Prabhakaran Sandhya , Luddy Kimberly , Pineriro Julian , Bravo Rafael , West Jeffrey , Robertson-Tessi Mark , Beg Aner , Gray Jhanelle , Antonia Scott , Gatenby Robert , Anderson Alexander
Published: June 2023

Checkpoint inhibitors disrupting the PD-1/PD-L1 axis are used in multiple cancer subtypes. However, not all patients respond, and predictive biomarkers are needed to better stratify patients. PD-L1, the most studied biomarker, has given mixed results. The complexity of the immune response and plastic nature of PD-L1 expression on tumor and immune cells contributes to the heterogeneity of success. Not all malignant epithelial cells express PD-L1: some express it only when the correct signal is present, while others have constitutive expression. Additionally, the PD-L1 protein has multiple functions outside immune regulation, making its dynamics difficult to predict. In this study, we investigate these complex PD-L1 dynamics through a unique combination of in vitro studies and mathematical modeling simulations. IFN-γ, a pleotropic cytokine released by activated immune cells, induces PD-L1 expression in some tumor cells. Chronic IFN-γ results in long-term PD-L1 expression. However, relaxation dynamics following removal of IFN-γ remains unexplored. We show that PD-L1 relaxation depends on autocrine signaling, demonstrated by multiple in vitro assays seeded with varying population densities. Following 48h IFN-γ treatment, sub-confluent tumor cell populations demonstrated increased duration of PD-L1 expression, linking cell density to PD-L1 expression. Conditioned-media from A549 cells previously treated with IFN-γ induced PD-L1 on IFN-γ naïve tumor cell populations, indicative of autocrine signaling not previously identified. To reinforce our in vitro findings, we develop a hybrid agent-based model (ABM) to study PD-L1 dynamics. Tumor cells have variable PD-L1 expression and IFN-γ is modeled via reaction-diffusion. IFN-γ triggers tumor cells to secrete a diffusible factor that promotes PD-L1 expression. Initial fits of the ABM capture in vitro data dynamics for different conditions. In this ongoing project, we plan to identify the underlying mechanism responsible for extended PD-L1 expression in NSCLC cells, including investigation into specific molecular pathways. Identifying the cause for this phenomenon could help clinicians improve targeted therapy and introduce a potential avenue to enhance treatment in patients responsive to checkpoint inhibitors.

Citation Format: Taylor M. Bursell, Sandhya Prabhakaran, Kimberly Luddy, Julian Pineriro, Rafael Bravo, Jeffrey West, Mark Robertson-Tessi, Aner Beg, Jhanelle Gray, Scott Antonia, Robert Gatenby, Alexander Anderson. Autocrine signaling extends PD-L1 expression in NSCLC following an active immune response [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 124.
Abstract 1304: Multiomic approaches to illuminate molecular drivers of breast cancer metastasis to the liver
Authors: Silberberg Gilad , Mosesson Yaron , Khoury Haia , Ren Xuan , Gilardi Mara , Hanson Art , Zipeto Marianna , Ritchie Michael
Published: June 2023

The lack of knowledge around the mechanisms underlying metastatic progression is a major hurdle in achieving a durable response in the treatment of metastatic breast cancer (BC). Accordingly, effective therapies are not yet available, and the treatment of metastatic BC remains an unmet critical medical need. Circulating BC cancer cells can colonize the lungs, bone, brain, and liver generating metastatic lesions, which lead to poor outcomes. Liver metastases account for 30% of metastatic BC cases, therefore causing the greatest therapeutic challenge. The first line of therapy for BC liver metastasis is typically an invasive surgical resection, which unfortunately does not always resolve the metastatic lesion and requires further treatment. Unfortunately, there is currently no therapeutic standard of care (SOC) for BC liver metastasis, and therapy is selected based on the molecular profiling of primary tumor and metastasis biopsies. The scarcity of reliable and biologically relevant human experimental models, to provide a deep understanding of the molecular interactions underlying metastasis, is warranted. In this study, we exploit multiomic interrogation of breast cancer PDX models established from primary lesions, and metastasis of the liver, to uncover the molecular mechanisms underlying BC cells liver colonization. The results highlight global molecular differences between models derived from primary BC tumors and BC lesions collected from the liver. The analysis also reveals several genes at the DNA, RNA, and protein expression/activity level aiding in the adaptation of BC cell colonization in the liver. These novel findings provide insight into novel mechanisms of BC liver metastasis and highlight several targets suitable for future therapeutic intervention.

Citation Format: Gilad Silberberg, Yaron Mosesson, Haia Khoury, Xuan Ren, Mara Gilardi, Art Hanson, Marianna Zipeto, Michael Ritchie. Multiomic approaches to illuminate molecular drivers of breast cancer metastasis to the liver [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 1304.
Abstract 1328: Building a 3D co-culture model for metastatic pancreatic ductal cancer using Curiochips microphysiological system
Authors: Kim Sumin , Choi Yeongmin , Baek Jihye , Garg Bharti , Pencik Jan , Lowy Andrew M. , Tiriac Herve , Yoo Sanghee
Published: June 2023

Despite the use of multi-agent conventional chemotherapy regimens, metastatic pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid tumors with a 5-year survival of 9%. PDAC is characterized by a complex tumor microenvironment with multilayered interplay between neoplastic and stromal cells and the natural extracellular matrix (ECM). To date, models that recapitulate the complexity of these features are only partially reproduced ex vivo and lack the capacity to recreate PDAC tumor microenvironment physiology, fluid flow and the ECM architecture. To address these issues, we developed Curiochips MPS platform for metastatic PDAC on-a-chip. To replicate an accurate PDAC complex tumor microenvironment, we investigated human pancreatic cancer cell lines with/without SMAD4 mutation as a test model. SMAD4 is among the most frequently altered genes in PDAC and its mutation accelerates pancreatic cancer cell migration. To tailor cell-ECM interactions and recreate natural biochemical environment of tumors, we examined various ECM conditions. ECM substitutes such as type I collagen and fibrin gel offer mechanical properties to closely mimic the tumor ECM. We accessed the effect of ECM condition on the pancreatic stellate cells (PSC) activation and pancreatic cancer cell migration using PANC-1 (SMAD4-WT) and BxP3 (SMAD4-null) cell lines. Notably, type I collagen induced more PSC activation than fibrin gel. Interestingly BxP3 spheroids migrated toward to the endothelial compartment compared to PANC-1. Angiogenesis of endothelial cells was more prominent in co-culture with BxP3 than PANC-1. Furthermore, we are building the metastatic model using PDAC patient derived organoids and co-culture with primary PSC in different types of ECM. Preliminary analysis showed functional responses such as 3D organoid migration and aggregation, PSC activation and migration controlled by specific properties of EMC. Our data highlight the importance of the ECM composition on PDAC migration, PSC activation and angiogenesis in the context of genetic heterogeneity and presence/absence oncogenic mutation. The 3D co-culture platform, Curiochips offers suitable and tailored solution to investigate tumor-stroma interaction and potentially can be used as a platform for drug discovery and precision oncology to target PDAC desmoplastic tumor microenvironment.

Citation Format: Sumin Kim, Yeongmin Choi, Jihye Baek, Bharti Garg, Jan Pencik, Andrew M. Lowy, Herve Tiriac, Sanghee Yoo. Building a 3D co-culture model for metastatic pancreatic ductal cancer using Curiochips microphysiological 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 1328.
Abstract 1331: A novel approach to treating hormonal breast cancer using clinical database and 3D ex vivo model
Authors: Song Chaeun (Christine) , Lee SeungBaek
Published: June 2023

Type 2 diabetes (T2D) female patients have a higher risk of being diagnosed and have worse survival for breast cancer compared to non-diabetic females. Although the relationship between these two female diseases has been reported, specific functional studies on which subtypes of breast cancer are affected and which genes are regulated by T2D are little known. Here, I found that Forkhead Box A1 (FOXA1) and Metformin, anti-diabetic medication for T2D, affect hormonal positive (HR+) breast cancer tumor cell growth and metastasis. 14 diabetes-related genes highly expressed in three HR+ breast cancer cell lines but not other breast cancer subtypes using a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4,032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Specifically, the high expression of FOXA1 correlated to a worse ER+/PR+ breast cancer patient survival rate. Consistent with this, the loss of FOXA1 inhibited the tumor proliferation and invasion of MCF-7 and T47D HR+ breast cancer cell lines using in vitro. Metformin (1,1-dimethylbiguanide hydrochloride) conspicuously inhibits the tumor cell growth in MCF-7 human hormonal breast cancer cells. Metformin or FOXA1 deletion enhanced Tamoxifen-mediated tumor growth inhibition in HR+ breast cancer cell lines through the ex vivo three-dimensional (3D) organoid model. Therefore, HR+ breast cancer is closely related to T2D, and metformin and FOXA1 inhibition might be an optimal new treatment for patients with HR+ breast cancer when combined with tamoxifen, a hormone therapy.

Citation Format: Chaeun (Christine) Song, SeungBaek Lee. A novel approach to treating hormonal breast cancer using clinical database and 3D ex vivo model [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 1331.
Abstract 1333: A novel and highly efficient biomimetic capture approach for the isolation and characterization of circulating metastatic cancer cell clusters from lung cancer patients
Authors: Kouhmareh Kourosh , Martin Erika , Finlay Darren , Bhadada Anukriti , Downey Francisco , Allen Jeff A. , Teriete Peter
Published: June 2023

Capture and isolation of circulating metastatic cancer cell clusters (MCCC) is the essential first step to identify novel therapeutic targets focused on this important route of metastasis. We developed a unique biomimetic capture approach that allows selective isolation of these deadly clusters from the whole blood of lung cancer patients. Utilizing a microfluidic platform we developed a versatile smart-coating that combines biomimicry and immuno-capture for a highly efficient and selective isolation of viable MCCCs. Here we show the capture and characterization of multiple MCCCs from non-small cell lung cancer (NSCLC) patients. Table 1 shows the count of clusters detected in NSCLC patients based on a stringent criterion confirming their identification. The MCCCs were detected in every patient tested but none were detected in normal blood controls from donors of similar age. Isolated MCCC where characterized by immunofluorescence and submitted for genomic analyses.

Metastasis remains one of the leading causes of cancer related deaths worldwide. Insights into how the tumor propagates to pre-metastatic sites is necessary to develop focused therapeutic approaches. Circulating metastatic cancer cell clusters (MCCCs) have been established as a primary entity causing distal metastases. Significant advances have been made linking cluster integrity and viability to increased metastatic potential highlighting the unmet need for cluster focused therapies.

Our novel approach allows the rapid and easy capture of MCCCs paving the way for the discovery of novel or unique targets that eventually will bring new anti-metastatic therapies to the clinic.

Table 1 Patient Age/Sex Staging/Metastasis #MCCC INMC-044.1 82 M IVB/bone 2 INMC-044.2 53 F IV/bone 1 INMC-044.3 59 F IV/bone, brain 2 INMC-044.4 65 M IV/thoracic cav., lung 1 INMC-044.5 67 M IIIa/none 3 Normal Blood 54 F N/A 0 Normal Blood 68 M N/A 0

Citation Format: Kourosh Kouhmareh, Erika Martin, Darren Finlay, Anukriti Bhadada, Francisco Downey, Jeff A. Allen, Peter Teriete. A novel and highly efficient biomimetic capture approach for the isolation and characterization of circulating metastatic cancer cell clusters from lung cancer patients [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 1333.
Abstract 134: Lymph node metastases are seeded via two distinct ways in phylogenetic study of gastric cancer
Authors: Cheng Pei-Chi , Hung Wei-Ting , Jeng Yung-Ming , Lai I-Rue
Published: June 2023

Backgrounds: Gastric cancer (GC) ranked 5th and 8th on the list of cancer related deaths worldwide and in Taiwan, respectively. Due to its high frequency of lymph node spread, lymph node dissection has become a standard procedure in surgical treatment. A randomized trial showed that patients who underwent D2 lymphadenectomy had a better 5-year survival outcome than ones who had D1 dissection in advanced gastric cancer, implying the D2 lymph node might serve as an outpost before tumor cells spread to distant organs. This clinical observation raises a possibility that the regional lymphatic spread could be under strict selection but not a passive process.

Materials and Methods: To understand the evolutionary relationship between primary tumors, perigastric lymph nodes, and second tier of lymph nodes in the extra-perigastric area, we reconstruct their phylogeny using genetic variants in hypermutable DNA regions where the mutation rate is 102~104-fold than unique sequence. We have assembled a cohort of 10 gastric cancer patients, including intestinal-, diffuse- and mixed type GC. For each case, we collected all workable lymph node metastases and intensely sampled primary tumors. On average, we have over fifteen samples per case on the phylogenetic tree.

Results: Preliminary data of the first two patients show high heterogeneity within primary tumors as well as between different lesions of lymph nodes or peritoneal metastases in gastric cancer. Interestingly, in stark contrast to all other lymph node metastases which intermingle with primary tumors, a clade consisting of one proximal and one distal lymph node with a bootstrap value above 90% is observed in each phylogeny, and it is worth noting that samples on these clades are from intestinal type tumor.

Conclusion: Our results indicate that most tumor cells arrive both regional and distal lymph nodes passively via lymphatic drainage in GC while a selective process also exists which coincides with clinical observation. Whether the existence of tumor cells under a relatively stricter selection process would lead to different clinical outcomes is under investigation.

Citation Format: Pei-Chi Cheng, Wei-Ting Hung, Yung-Ming Jeng, I-Rue Lai. Lymph node metastases are seeded via two distinct ways in phylogenetic study of gastric cancer [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 134.
Abstract 1378: Proguanil inhibits breast cancer in vitro and in vivo through mitochondrial dysfunction
Authors: Curcic Marina , Gupta Nehal , Srivastava Sanjay K.
Published: June 2023

Breast cancer remains the second leading cause of cancer-related death among women in the U.S. New treatments for this aggressive disease are thus urgently needed. Repurposing FDA-approved non-cancer drugs for cancer treatment is an alternative that saves time and lowers the costs needed for drug development. In this study, we investigated the effects of proguanil, an anti-malarial drug, in breast cancer cells. Proguanil exhibited a significant cytotoxic effect on various breast cancer cell lines including patient derived cell lines through induction of apoptosis. Our results indicated that proguanil treatment caused a 3-fold increased production of ROS compared with control and reduced the mitochondrial membrane potential, mitochondrial respiration rate, and ATP production. Our studies also revealed the phosphorylation of H2AX, a marker for DNA damage. Proguanil treatment further increased the expression of apoptotic markers Bax, cleaved PARP, cleaved-caspase 9, and down-regulated anti-apoptotic Bcl-2 and survivin in breast cancer cells. Oral administration of 20mg/kg of proguanil significantly inhibited the tumor growth by 55% in mice model. Western blot analyses of tumors from proguanil-treated group showed increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 compared to control. Taken together, our results demonstrate the anti-cancer effect of proguanil by targeting mitochondria, and can be considered for clinical investigation against breast cancer.

Citation Format: Marina Curcic, Nehal Gupta, Sanjay K. Srivastava. Proguanil inhibits breast cancer in vitro and in vivo through mitochondrial dysfunction [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 1378.
Abstract 1380: Blocking autophagy ameliorates the severity of ConA induced autoimmune hepatitis in mice
Authors: Wang Juan , Qian Cheng , Yangmeng Chuanzhi , Fang Li , Yan Ruiqing
Published: June 2023

Autoimmune hepatitis (AIH) recognized as a typical inflammation-triggered liver disease, which usually begins as acute hepatitis and ultimately develops to fibrosis, liver damage, loss of function of liver. It largely leads to the disease-related mortality and morbidity. However, the mechanism AIH remains unclear and the novel therapeutic reagents and methodology are urgently needed. In the present study, we established the ConA induced autoimmune hepatitis model in-house and evaluate autophagy and other immune signaling pathway on the participation of AIH. Our results bring the direction for the future direction of novel therapeutic reagents discovery.

Citation Format: Juan Wang, Cheng Qian, Chuanzhi Yangmeng, Li Fang, Ruiqing Yan. Blocking autophagy ameliorates the severity of ConA induced autoimmune hepatitis in mice [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 1380.
Abstract 1413: Chromosome arm aneuploidies as genetic vulnerabilities of triple-negative breast cancer
Authors: Dandage Rohan , Schwartz Michael , Karam Lynn , Pacis Alain , Hart Traver , Bourque Guillaume , Park Morag , Kuzmin Elena
Published: June 2023

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. It has no approved targeted therapies due to the lack of the expression of key biomarkers, namely Estrogen and Progesterone receptors, and HER2 amplification. As a result, TNBC has the worst prognosis compared to other breast cancer subtypes. We previously showed that chromosome 4p (chr4p) loss is recurrent, correlates with poor prognosis, is an early event in tumor evolution, and confers a proliferative advantage. Here, we propose to leverage chr4p loss as a genetic vulnerability of TNBC by identifying its genetic interactions (GIs) with genes whose inactivation leads to synthetic lethality i.e. loss of viability of chr4p copy loss cells, but not of the chr4p copy neutral cells, or suppression i.e., positive GIs. We first classified breast cancer cell lines with TNBC enriched molecular subtype called basal-like, as chr4p copy loss (9) and chr4p copy neutral (7), using copy number data from CCLE. Associated with chr4p copy loss, the differential expression analysis carried out using CCLE data revealed transcriptomic changes that distinctly cluster the chr4p copy loss and chr4p copy neutral cell lines. We then used the publicly available CRISPR-based genome-wide gene inactivation data from the DepMap project and quantified chr4p loss-associated GIs using multiple scoring methods such as drugZ and MAGeCK. In total, we identified ~200 negative and ~70 positive statistically significant GIs involving genes annotated to biological processes such as translation, metabolism, and others. We have prioritized a subset of them for subsequent experimental validation using CRISPR-Cas9-based gene editing in TNBC cancer cell line models. Alongside, using the publicly available drug sensitivity data obtained from the PRISM project, we identified compounds that impair cell growth in a chr4p loss-specific manner, the strongest of which targeted redox balance. Collectively, the set of GIs, the compound sensitivities, and the computational methods we have generated are unique resources for developing precision oncology therapeutic strategies for TNBC, as well as for other cancers harboring chr4p loss.

Citation Format: Rohan Dandage, Michael Schwartz, Lynn Karam, Alain Pacis, Traver Hart, Guillaume Bourque, Morag Park, 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 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1413.
Abstract 1475: FOXO transcription factors regulate WNT pathway gene expression in GBM
Authors: Keniry Megan , Pintor Shania , Lopez Alma , Flores David
Published: June 2023

Basal-like breast cancer (BBC) and Glioblastoma Multiforme (GBM) are aggressive cancers associated with poor prognosis. BBC and GBM express stem gene expression signatures which are in part driven by FOXO transcription factors. To gain further insight into the impact of FOXO1 in BBC, we treated BT549 cells with the FOXO1 inhibitor AS1842856 and performed RNA Seq. Gene Set Enrichment Analysis (GSEA) with RNA Seq. data indicated that a set of WNT target genes including LEF1 and AXIN2 were robustly induced after 48-hours of AS1842856 treatment. These same genes were also induced in GBM cell lines U87MG, LN18, LN229, A172, and DBTRG upon AS1842856 treatment. RNAi targeting of FOXO1 led to reduced LEF1 gene expression in BT549 and U87MG cells at 18-hour and 24-hour timepoints respectively. CRISPR Cas9-mediated FOXO1 disruption led to reduced expression of canonical WNT target gene LEF1 in U87MG cells.

Citation Format: Megan Keniry, Shania Pintor, Alma Lopez, David Flores. FOXO transcription factors regulate WNT pathway gene expression in GBM [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 1475.