bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1488: The FOXA2 contributes to tumor proliferation and invasion via HGF mediated ERK signaling pathway in human gastric cancer
Authors: Jung Jiyoon , Koh Sungae , Lee Kyunghee 
Published: April 2023

Abstract
Background: FOXA1 and FOXA2, members of the forkhead transcription factor family, are critical for epithelial differentiation in many endoderm-derived organs and important regulators in body homeostasis. It has been shown that FOXA2 plays an important role in tumorigenesis and carcinogenesis in glioma, breast cancer, hepatoma, and others. However, FOXA2 has not yet been elucidated on the tumorigenesis, proliferation, and invasion of human gastric cancer, and needs to be researched and discovered. In this study, the HGF-mediated association of FOXA2, extracellular signal-regulated protein kinase (ERK), and matrix metalloproteinase 9 (MMP9) and cancer cell proliferation and invasion were investigated in two types of human gastric cancer cell lines.
Methods: In this study, cell culture, cDNA microarray analysis, western blotting, Real-time Polymerase chain reaction, Zymography, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, FOXA2 knock-down with short hairpin RNA (shRNA), chromatin immunoprecipitation assay, Standard two chamber invasion assay.
Results: First, we confirmed that the expression level of FOXA2 was up-regulated by HGF (hepatocyte growth factor) in human gastric cancer cells. To identify the associated pathway of HGF-induced FOXA2 about ERK, MMP9 expression, the cells were treated with PI3K (Phosphoinositide 3-kinase) inhibitor (LY294002) and then analyzed by Western blotting. The role of FOXA2 associated with MMP9 and ERK was determined by knockdown cell of FOXA2. FOXA2-sh RNA cells showed a decreased level of MMP9 and ERK. HGF-mediated cell proliferation and invasion were decreased in FOXA2 knockdown cell.
Conclusions: These results suggest that FOXA2 plays an important role in cell proliferation and metastasis in hepatocellular carcinoma, and FOXA2 may be a novel target for the prevention of progression and treatment of human gastric cancer.
Citation Format: Jiyoon Jung, Sungae Koh, Kyunghee Lee. The FOXA2 contributes to tumor proliferation and invasion via HGF mediated ERK signaling pathway in human 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 1488.
Abstract 1512: Evolution of large copy number variants in breast cancer through genetic network rewiring
Authors: Kuzmin Elena , Monlong Jean , Bourgey Mathieu , Lesluyes Tom , Barker Toby , Morin Genevieve , Zou Dongmei , Schwartz Michael , Yang Yang , Pacis Alain , Martinez Constanza , Kuasne Hellen , Fortier Anne-Marie , Li Rui , Kleinman Claudia , Huang Sidong , van Loo Peter , Ragoussis Jiannis , Bourque Guillaume , Park Morag 
Published: April 2023

Abstract
Large chromosomal alterations are common in cancer and often show preferential gain or loss across many cancer types indicating their selective advantage. Triple negative breast cancer (TNBC) exhibits complex mutational spectrum without common oncogenic drivers yet displays consistent loss of large chromosomal regions. Here, we characterize selection pressures that maintain a recurrently deleted region of chromosome 4p in TNBC. We used bulk WGS phylogenetic analysis of TNCB PT/PDX panel to show that chr4p deletion is an early event in tumor evolution. We used scRNAseq gene expression and inferred copy number analysis to show that chr4p loss is associated with a proliferative state. This finding was confirmed by a combination of RNA in situ hybridization and immunofluorescence. We then tested the dosage sensitivity of genes residing within this region by individual and dual overexpression in TNBC PDX-derived cell lines and control normal cell line by assessing their effect on cell proliferation. The overexpression of genes within chr4p elicited a strong cell proliferation defect in cancer but not normal cell line models. We also characterized an unknown gene within chr4p region as a novel member of the STRIPAK complex. Genome-wide pooled ORFeome library screens identified a global pattern of background-specific dosage sensitive regions. Our study shows that large chromosomal deletions are maintained due to evolutionary early genetic network rewiring rendering multiple genes within such regions to be dosage sensitive. Ultimately, this work enhances our understanding of genetic events that modulate TNBC.
Citation Format: Elena Kuzmin, Jean Monlong, Mathieu Bourgey, Tom Lesluyes, Toby Barker, Genevieve Morin, Dongmei Zou, Michael Schwartz, Yang Yang, Alain Pacis, Constanza Martinez, Hellen Kuasne, Anne-Marie Fortier, Rui Li, Claudia Kleinman, Sidong Huang, Peter van Loo, Jiannis Ragoussis, Guillaume Bourque, Morag Park. Evolution of large copy number variants in breast cancer through genetic network rewiring [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 1512.
Abstract 1513: A multi-sample study reveals the evolution and heterogeneity in high-grade serous ovarian cancer
Authors: Wong Siao-Han , Doberstein Kai , Marmé Frederik , Brors Benedikt 
Published: April 2023

Abstract
Ovarian cancer is a heterogeneous disease and high-grade serous carcinoma (HGSC) accounts for 70% of them. The pathogenesis of HGSC had remained obscure until the identification of its tubal origin; however, the carcinogenesis process remains largely underexplored. Meanwhile, targeted therapy using poly(ADP-ribose) polymerase (PARP) inhibitors have revolutionized the treatment of HGSCs and emphasizes the importance of patient stratification. Nonetheless, current clinical trials use different assays and a consensus approach for patient stratification is still lacking.
In this study, whole genome sequencing technique was used to profile tumor-normal sample pairs, including some related tumors collected from different anatomical sites. This yields a multi-sample cohort comprising 55 pre-treatment samples from 33 HGSC patients and is suitable for addressing questions about molecular stratification and tumor pathogenesis.
We first recapitulated two reported HGSC subgroups (H-HRD and H-FBI) in our cohort. Comprehensive analyses were conducted on genomic scars ranging from mutations, indels, structural variants and copy numbers. Our data suggests that the genomic subgroups are characterized by different extent and onset timing of homologous recombination repair defect (HRD) as well as CCNE1 activation. Of note, H-HRD group showed higher levels of copy number-based HRD score, which often serves as a surrogate biomarker for PARP inhibitor treatment response.
On the other hand, tumor evolutionary trajectory was reconstructed based on in silico methods capable of inferring relative timing of genetic alterations. This highlights an early bifurcation of carcinogenesis paths in this HGSC dichotomy, despite a common scenario of a very early TP53 mutation, an often early whole genome duplication and a chromosomal instability phenotype seen eventually.
Overall, these findings corroborate the concept of tumor-intrinsic genomic phenotypes by providing mechanistic underpinnings from the aspect of tumor evolution. This provides the rationale for studying HGSC disease biology in different contexts and formulating questions about subtype-specific pathogenesis and vulnerabilities. Translationally, it also holds the promise for better identifying the patient subset that might benefit from PARP inhibitor treatment.
Citation Format: Siao-Han Wong, Kai Doberstein, Frederik Marmé, Benedikt Brors. A multi-sample study reveals the evolution and heterogeneity in high-grade serous ovarian 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 1513.
Abstract 1547: The urokinase plasminogen activator receptor-associated protein (uPARAP) is an attractive target for the development of antibody-drug conjugates (ADCs) for treatment of mesenchymal malignancies
Authors: Barkholt Pernille , Wozniak Agnieszka , Wang Chao-Chi , Lee Che-Jui , De Kock Lore , Engelholm Lars H. , Lynch Carmel , Mumberg Dominik , Schöffski Patrick 
Published: April 2023

Abstract
Background: Soft tissue sarcoma (STS) is a complex family of rare malignancies with high unmet medical need. uPARAP is an endocytic receptor expressed at low levels on selected mesenchymal cell types, which internalizes fragments of collagen and transfers them to the lysosome for degradation. Besides its physiological role, uPARAP is considered a critical modulator of the tumor microenvironment. Here, for the first time, we explored the molecular epidemiology of uPARAP in sarcoma tissue to validate this receptor as target for the development of ADCs in this indication.
Methods: uPARAP expression was assessed in STS-specific tissue microarrays by immunohistochemistry in tissue samples from more than three hundred individual donors. Stainings were assessed by histopathologic scoring and grouped into high, medium and low expressing subgroups.
Results: uPARAP was found to be strongly over-expressed in a high percentage of cases of common STS, with variations in terms of incidence and level of expression between histological subtypes. High uPARAP expression was found in fibro- (86% of cases), synovial (84%), dedifferentiated lipo- (68%), pleomorphic lipo- (65%), myxofibro- (59%), leiomyo- (49%), and myxoid liposarcoma (24%). Work is ongoing in additional sarcoma subtypes.
Conclusions: Based on protein expression uPARAP is an attractive emerging therapeutic target for the development of uPARAP-binding ADCs in a broad range of mesenchymal malignancies. In addition, expression of uPARAP in STS may serve as a potential marker for patient selection in early clinical studies with uPARAP-targeting ADCs.
Citation Format: Pernille Barkholt, Agnieszka Wozniak, Chao-Chi Wang, Che-Jui Lee, Lore De Kock, Lars H. Engelholm, Carmel Lynch, Dominik Mumberg, Patrick Schöffski. The urokinase plasminogen activator receptor-associated protein (uPARAP) is an attractive target for the development of antibody-drug conjugates (ADCs) for treatment of mesenchymal malignancies [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 1547.
Abstract 1570: Novel Myc-dependent compound DL78 selectively induces mitotic catastrophe and cell death in high grade serous ovarian cancer
Authors: Teitel Jessica , Cusato Michele , Farah Margaret , Gandhi Agharnan , Lee Pil , White Andrew , Takyi-Williams John , Wen Bo , Da Rocha Andre Monterio , DiFeo Analisa 
Published: April 2023

Abstract
While the rates of new cases and deaths for high grade serous ovarian cancer (HGSC) have declined steadily in the past decade, HGSC remains the fifth leading cause of cancer death in women. As many patients succumb to chemoresistance, there is a need to uncover novel targeted drugs. One way to do so is by drug repurposing. A computational screen, DrugPredict, led to the discovery that amiodarone, an antiarrhythmic, is a potent apoptosis-inducer and Myc-degrader in numerous patient-derived ovarian cancer cell lines. In search of a more selective, but less toxic compound, structure-activity relationship was applied to identify DL78. Due to its structural differences, DL78 is considered to be independent of amiodarone. DL78 lacks hERG activity, retains Myc regulation, and gains selective anticancer properties. This compound produces significant cell death selectively in patient-derived HGSC cells, including isogenic cisplatin-resistant lines, but does not harm non-transformed fallopian tube cells. Cancer cells treated with DL78 arrest prior to anaphase and showcase microtubule abnormalities and upregulation of mitotic regulators. The prolonged arrest leads to loss of Myc, mitotic catastrophe, and apoptosis selectively in the HGSC cells, while fallopian tube cells can cycle normally. DL78’s activity is confirmed to be dependent on Myc expression because targeted inhibition of Myc decreases its potency and prevents the DL78-induced cell cycle arrest. Finally, pharmacokinetic analysis shows that DL78 saturates the tumor following intraperitoneal injection, yet drug concentrations in the blood and liver present at normal levels. Overall, these phenotypes do not show with amiodarone treatment, suggesting that structurally different DL78 performs through a different mechanism. Further classification of this tumor-selective compound may reveal targeted ovarian cancer vulnerabilities.
Citation Format: Jessica Teitel, Michele Cusato, Margaret Farah, Agharnan Gandhi, Pil Lee, Andrew White, John Takyi-Williams, Bo Wen, Andre Monterio Da Rocha, Analisa DiFeo. Novel Myc-dependent compound DL78 selectively induces mitotic catastrophe and cell death in high grade serous ovarian 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 1570.
Abstract 1594: SMARCA2 (BRM) degraders promotes differentiation and inhibit proliferation in AML models
Authors: Agarwal Anjana , Osinubi Olusola Peace , Vykuntam Komali , Fultang Norman , Bhagwat Neha , Heiser Diane , Vaddi Kris , Ito Koichi , Scherle Peggy 
Published: April 2023

Abstract
Dysregulated cellular differentiation is a major pathological feature of myeloid malignancies such as acute myeloid leukemia (AML). Targeting cellular differentiation programs has emerged as a novel therapeutic approach to treat patients with AML. Advantages of such differentiation therapy may include fewer systemic side-effects as well as opportunities to target leukemic stem cells (LSCs) and a broader range of clonal populations, likely resulting in lower frequencies of resistance and relapse in AML patients. The success of ATRA and decitabine in subsets of AML patients has proven that inducing differentiation can play a critical role in long-term durable responses. More agents targeting epigenetic regulators have been increasingly studied as differentiation inducers, including LSD1, DNMT1, Menin, and BET inhibitors. Recently, targeting SWI/SNF chromatin remodeling complexes has also been shown to regulate key leukemic gene expression signatures and induce AML differentiation. Small molecule inhibitors as well as gene knockdown for ATP-dependent SWI/SNF subunits SMARCA2 (BRM) and SMARCA4 (BRG1) are associated with re-direction of oncogenic transcriptional regulation to drive cellular differentiation and apoptosis in AML models. We have previously described the activity of highly potent, bispecific SMARCA2 degraders that efficiently promote SMARCA2 protein degradation in preclinical models. In the present study, we investigated the effects of our SMARCA2 selective degraders in AML models. Treatment with SMARCA2 degraders significantly inhibits AML cell line proliferation in vitro with IC50 ranging from 10 to 50 nM. In the SMARCA2 degrader treated cells, expression of PU.1 (SPI1), a key transcription factor in myeloid leukemias, was downregulated. In an in vivo OCI-AML3 xenograft model, treatment with a SMARCA2 selective degrader showed moderate tumor growth inhibition accompanied by robust increases in monocytic maturation markers CD11b and CD14. Further analyses of SMARCA2 degrader effects on global transcriptome and AML immunophenotypes as well as combination effects with other therapies are currently in progress. These findings highlight the potential of SMARCA2 degraders to target AML differentiation blocks and to improve the effectiveness of other therapeutic agents such as decitabine and venetoclax in AML patients.
Citation Format: Anjana Agarwal, Olusola Peace Osinubi, Komali Vykuntam, Norman Fultang, Neha Bhagwat, Diane Heiser, Kris Vaddi, Koichi Ito, Peggy Scherle. SMARCA2 (BRM) degraders promotes differentiation and inhibit proliferation in AML models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1594.
Abstract 1603: The effect of dickkopf-1 (DKK-1) on prostate cancer growth and bone metastasis using the canine osteoblastic Probasco cell line
Authors: Yuan Shiyu , Hoggard Nathan K. , Kantake Noriko , Hildreth Blake E. , Rosol Thomas J. 
Published: April 2023

Abstract
Osteoblastic bone metastasis is the predominant phenotype observed in advanced prostate cancer and is associated with high patient mortality and morbidity. WNT signaling is necessary for both bone formation and tumor progression. Dickkopf-1 (DKK-1), a secretory antagonist of the canonical WNT/β-catenin signaling pathway, plays a complex role in bone tumors since it can either promote or decrease tumor occurrence and metastasis. The present study explored the molecular role of DKK-1 in prostate tumor progression, metastasis, and tumor-bone interactions using the osteoblastic canine prostate cancer cell line, Probasco. Previously, we found that DKK-1 can inhibit bone mineralization of mouse calvaria by Probasco conditioned medium (CM). Now we stably expressed DKK-1 in Probasco cells (Probasco-DKK-1), which were injected into the tibias or left ventricle of athymic mice. Bone metastases were monitored by bioluminesent imaging, microCT, and histopathology. Our results showed that Probasco-DKK-1 bone metastases had increased tumor growth, increased osteoclastic bone resorption, and decreased intramedullary woven bone formation in vivo. In vitro, DKK-1 had an autocrine effect on Probasco cells, which altered the cell morphology, increased cell proliferation, and induced EMT. Mechanistically, DKK-1 had little effect on the canonical WNT/β-catenin signaling while dramatically down-regulated the non-canonical WNT/JNK signaling, which inhibited caspase-dependent apoptosis in Probasco-DKK-1 cells. To investigate the effect of Probasco-DKK-1 on bone cells, primary osteoblasts and osteoclasts were treated by CM collected from cancer cells. We found that DKK-1 did not inhibit the mineralization of osteoblasts nor stimulate the activity of osteoclasts directly, but the expression of RNAKL was significantly higher in Probasco-DKK-1 CM-treated osteoblasts. Therefore, the Probasco-DKK-1 cells enhanced the activity of osteoclasts indirectly via the regulation of osteoblasts, which induced bone resorption. In conclusion, we showed that DKK-1 promoted prostate tumor growth by stimulating cell proliferation and inhibiting apoptosis in a canonical WNT-independent manner and attenuated the osteoblastic activity of prostate cancer. These findings provide new insights into the molecular mechanisms of DKK-1 in tumor progression.
Citation Format: Shiyu Yuan, Nathan K. Hoggard, Noriko Kantake, Blake E. Hildreth, Thomas J. Rosol. The effect of dickkopf-1 (DKK-1) on prostate cancer growth and bone metastasis using the canine osteoblastic Probasco cell line [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 1603.
Abstract 1618: A highly selective and potent TLR8 agonist ZG0895 in preclinical studies of anti-tumor activities
Authors: Cui Dawei , Liu Ruifeng , Yang Huanyi , Zhu Bing , Sheng Zelin , Lv Binhua 
Published: April 2023

Abstract
Toll-like receptor 8 (TLR8) recognizes ssRNA fragments from pathogens and initiate both innate and adaptive immune responses. TLR8 activation can reverse Treg and myeloid-derived suppressor cells (MDSC) mediated immune suppression by tumors that lead to a restore of immune response to inhibit tumor growth. ZG0895 is a potent and novel TLR agonist that shows a highly selective activation of TLR8 and has a more than 300-fold potency over TLR7 in EC50 values. The agonist screening results further confirmed that ZG0895 without activation of TLR isoforms like TLR2, 4 or 9 in cells. In pharmacokinetics and pharmacodynamics, ZG0895 has a preferable ADME and PK profile and can activate immune system via subcutaneous (s.c.) administration. For in vivo anti-tumor efficacy studies, ZG0895 at 1~30 mg/kg exhibited significant dose-dependent inhibition of tumor growth in immunocompetent myeloid-sufficient murine models with CT26, EMT6 or HH subcutaneous xenografts. Furthermore, ZG0895 administration resulted in a complete tumor regression by ZG0895 at high dose via s.c. injection. Mechanism studies of ZG0895 in ex vivo human PBMC assay showed a strong induction of TLR8 related cytokines. In vivo study in tumor-bearing mouse demonstrated that pro-inflammatory cytokines, such as TNFα, IL12p40, IL6 and IL10, were quickly released after ZG0895 treatment but soon returned to normal that can avoid continuous activation of systemic immunity and reduce the risk of cytokine release storm. Consistently, in vivo cynomolgus monkey study by consecutive treatments with ZG0895 (day 30) resulted in a significant increase of immune system cells including intermediate monocytes, non-classic monocytes, cDCs and NK cells, along with notable decrease of classical monocytes but unchanged pDCs, suggesting a possible reversion of tumor-initiated MDSC via TLR8 activation. All these changes were back to normal after period of recovery (day 57), indicated the immune effect of ZG0895 was restrained. These preclinical results support that ZG0895 as a highly TLR8-selective agonist inhibits tumor growth via the activation of TLR8 eliciting immune responses but under a better safety than other conventional TLR8 agonists, and it is worth to be further explored as an anti-cancer drug candidate.
Citation Format: Dawei Cui, Ruifeng Liu, Huanyi Yang, Bing Zhu, Zelin Sheng, Binhua Lv. A highly selective and potent TLR8 agonist ZG0895 in preclinical studies of anti-tumor activities [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 1618.