bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4589: Synergistic effects of EZH1/2 dual inhibition and cisplatin on lung cancer cell lines with loss of SMARCA4 and SMARCA2
Authors: Lee Jeongjae , Keam Bhumsuk , Kim Soyeon , Youk Jeonghwan , Kim Miso , Kim Tae Min , Kim Dong-Wan , Seog Heo Dae 
Published: March 2024

Abstract
Purpose: SMARCA4 mutations are observed in approximately 10% of non-small cell lung cancer (NSCLC) cases and are implicated in various biological functions. Lung cancers harboring these mutations are associated with poor prognosis and often exhibit resistance to conventional chemotherapies, highlighting the urgent need for innovative therapeutic strategies. We evaluated the efficacy of a novel EZH1/2 dual inhibitor, HM97662, and its synergistic potential with cisplatin in SMARCA4-deficient lung cancer cell lines.
Experimental Design: CCLE datasets were employed to identify cell lines harboring truncated mutations in the SMARCA4 gene. Immunoblotting was conducted to verify the inactivation of SMARCA4 and to check for the expression of SMARCA2. We assessed cellular viability and colony-forming capabilities of lung cancer cell lines
(NCI-H1975, PC9, A549, HCC15, NCI-H522, NCI-H1581, NCI-H1048, NCI-H841) to determine the cytotoxic effects of an EZH1/2 dual inhibitor as well as cisplatin, both as single agents and in combination.
Results: Immunoblotting showed distinct lung cancer cell lines characterized by three profiles: proficient SMARCA4 expression, absent SMARCA4 but present SMARCA2 expression, and concurrent loss of both SMARCA4 and SMARCA2. After 14 days of treatment with the EZH1/2 dual inhibitor HM97662, there was a significant reduction in cell proliferation, particularly in the both SMARCA4- and SMARCA2-loss cell lines. Furthermore, colony-forming assays demonstrated a significant decrease in colony-forming ability upon HM97662 treatment, an effect exclusive to the both SMARCA4 and SMARCA2 loss cell lines. Pre-treatment with 1 µM of HM97662 for 7 days potentiated the cytotoxicity of cisplatin compared to untreated controls in the SMARCA4/2 loss cell lines, as indicated by a lower IC50 value.
Conclusion: The novel EZH1/2 dual inhibitor, HM97662, exhibits antitumor activity and a synergistic effect with cisplatin in lung cancer cell lines with concomitant loss of SMARCA4 and SMARCA2. These findings suggest the potential utility of EZH1/2 dual inhibition as a targeted therapeutic approach in lung cancers characterized by the dual loss of SMARCA4/2.
Citation Format: Jeongjae Lee, Bhumsuk Keam, Soyeon Kim, Jeonghwan Youk, Miso Kim, Tae Min Kim, Dong-Wan Kim, Heo Dae Seog. Synergistic effects of EZH1/2 dual inhibition and cisplatin on lung cancer cell lines with loss of SMARCA4 and SMARCA2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4589.
Abstract 4610: Dual inhibition of CDK4/6 and IL-6 pathways as a novel therapeutic approach for triple-negative breast cancer cells
Authors: Caroland Kailey , Shi Changyou , Lo Hui-Wen , Lin Jiayuh 
Published: March 2024

Abstract
Triplenegative breast cancer (TNBC) is highly aggressive and associated with poor clinical outcomes. TNBC stands as a major cause of death among breast cancer patients and offers only a few therapeutic options. Abemaciclib, a cyclin dependent kinase 4/6 (CDK4/6) inhibitor, has received FDA approval for use in hormone receptor-positive, HER2-negative, and metastatic breast cancers. However, acquired resistance to CDK4/6 inhibitors in treating TNBC is becoming an increasing concern. Our recent results indicated that CDK4/6 inhibitors can induce IL-6 levels in TNBC cells as a potential resistance mechanism by augment IL-6 signaling axis, and that targeting IL-6 signaling can sensitize TNBC cells to CDK4/6 inhibitor therapy. In this study, combination of Abemaciclib with an IL-6/GP130 inhibitor (bazedoxifene) was tested in TNBC cells. We examined the effect of the combination on cell viability, cell migration, and invasion of human and mouse TNBC cell lines. Our data demonstrated that the bazedoxifene and abemaciclib combination treatment synergistically inhibited TNBC cell viability, cell migration, and invasion in vitro. These results support dual inhibition of CDK4/6 and IL-6 as a novel therapeutic approach for TNBC.
Citation Format: Kailey Caroland, Changyou Shi, Hui-Wen Lo, Jiayuh Lin. Dual inhibition of CDK4/6 and IL-6 pathways as a novel therapeutic approach for triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4610.
Abstract 4648: Metabolic vulnerabilities of drug-resistant melanoma with therapeutic potential
Authors: Yu Yanlin , Huang Lei , Chen Weiping , Merlino Glenn 
Published: March 2024

Abstract
Melanoma has been at the center of revolutions in both targeted BRAF therapy and immune therapy. However, the resistance to current therapeutic drugs has been a formidable obstacle to continuing benefit to patients. Overcoming resistance and new therapeutic agents and strategies are the primary goals of current cancer research. We currently found that metabolic pathways altered significantly in BRAFi-resistant melanoma. We hypothesized that BRAFi-resistant melanoma rewires its metabolic routes to reach its needs in energy and biosynthetic precursors, both essential for escaping the BRAFi attack. We found that five amino acids transporters and metabolic enzymes (ASNS, slc7a11, slc7a5, slc3a2, slc4a7) were the significant increase in resistant melanoma. Knockdown by shRNA or knockout by crispr/cas9 of these amino acids transporters or/and metabolic enzymes enhanced the sensitivity of BRAFi resistant melanoma to BRAFi. In contrast, overexpression of these amino acid transporters or/and metabolic enzymes promoted the ability of resistance of BRAFi in parent melanoma cells. Moreover, the inhibition of these amino acid transporters and metabolic enzymes by small molecular inhibitors significantly attenuated the resistance of the BRAFi-resistant melanoma whereas less affected the parent melanoma. Notably, we confirmed that blocking these amino acid transporters and metabolic enzymes by shRNA and/or small molecular inhibitors could rescue the sensitivity of resistant melanoma cells and inhibit resistant-melanoma cell growth in the preclinical mouse model in vivo. Importantly, we found that overexpression of slc7a11, slc7a5 and slc3a2 correlated with worse survival in melanoma in SK-TCGA data. Our findings uncovered the mechanism of how metabolic reprogramming fueled melanoma cell growth and proliferation for escaping drug attacks and offered a rational strategy to guide clinical treatment. The identified novel molecular proteins represented a promising therapeutic target for BRAF mutant melanoma patients with resistance to current therapy.
Citation Format: Yanlin Yu, Lei Huang, Weiping Chen, Glenn Merlino. Metabolic vulnerabilities of drug-resistant melanoma with therapeutic potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4648.
Abstract 4655: Targeting FAK improves the tumor penetration of antibody-drug conjugates to strengthen the anti-cancer responses
Authors: Zhang Baoyuan , Zhang Zhixiang , Gao Jiaming , Lu Shiqiang , Pang Ran , Li Dongfang , Huang Xun , Qin Natasha , Liu Leo , Wang Zaiqi 
Published: March 2024

Abstract
Antibody-drug conjugates (ADCs) such as HER2 ADC Enhertu and TROP2 ADC Trodelvy have been proved to be the promising therapeutic agents in portion of cancer diseases. However, there are still numerous patients refractory to the therapy, indicating that the efficacy of ADCs may need to be further optimized. Here, we report that the excessive cancer-associated fibroblasts (CAFs) can serve as a fibrotic barrier, to the detriment of anti-tumor effects from ADCs by alleviating their tissue penetration. Mechanistically, the cancer cells can transform the normal fibrotic cells into CAFs which are featured by the hyperactivated focal adhesion kinase (FAK) signaling. The fast-growing CAFs would decrease the tumor uptake of the big molecules, conferring drug resistance of ADCs to the cancer cells. Targeting FAK with a small molecule inhibitor IN10018 is capable to reduce CAFs associated tumor barrier, elevating the tissue penetration of different types of ADCs regardless their respective targets. The combination regimen comprising IN10018 and the ADCs targeting either HER2 or TROP2 outperformed each monotherapy with respect to antitumor outcomes in different animal experiments. The preclinical evidence for the dual regimen of IN10018 and ADCs warrants a further validation in clinical settings.
Citation Format: Baoyuan Zhang, Zhixiang Zhang, Jiaming Gao, Shiqiang Lu, Ran Pang, Dongfang Li, Xun Huang, Natasha Qin, Leo Liu, Zaiqi Wang. Targeting FAK improves the tumor penetration of antibody-drug conjugates to strengthen the anti-cancer responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4655.
Abstract 4673: Genome-scale metabolic models identify gene targets that enhance drug response of drug-resistant breast cancer cells
Authors: Jung Hae Deok , Lim JinA , Ryu Han Suk , Kim Yoosik , Kim Hyun Uk 
Published: March 2024

Abstract
Adaptive drug resistance poses a significant therapeutic challenge in treatment of breast cancer patients. Metabolic reprogramming in cancer cells is one of the major mechanisms associated with drug resistance. In this study, we aim to identify gene targets that enhance the drug response of drug-resistant breast cancer cells through downregulation. We hypothesized that metabolic perturbation in drug-resistant breast cancer cells could revert their metabolic features to those of drug-sensitive cells. To predict such gene targets, we used a computational model known as a genome-scale metabolic model (GEM). A GEM simulates the entire metabolic reaction fluxes of a cell under varying genetic and/or environmental conditions. We specifically targeted two engineered MCF7 breast cancer cell lines: one resistant to doxorubicin and the other to paclitaxel. First, we generated proteome data from drug-sensitive and drug-resistant MCF7 cell lines, and used them to construct the cell-specific GEMs. Subsequently, single-gene knockout simulation was conducted using these cell-specific GEMs. The initial list of the gene knockout targets was subjected to pathway analysis involving proteome and metabolome data to finalize the gene targets. The final gene targets were expected to lead to metabolic features similar to those of drug-sensitive MCF7 upon the downregulation. In vitro experiments using inhibitors were conducted to validate these predicted gene targets. This study provides a computational approach that can also be applied to other types of drug-resistant cancer cells.
Citation Format: Hae Deok Jung, JinA Lim, Han Suk Ryu, Yoosik Kim, Hyun Uk Kim. Genome-scale metabolic models identify gene targets that enhance drug response of drug-resistant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4673.
Abstract 4686: Identification of ART3 as a novel synthetic lethal partner of the BRCA1 mutation in breast cancer
Authors: Neiger Hannah , Pei Xinyu , Nguyen Anh , Wang Wenjia , Siegler Emily L. , Zhou James , Lau Kristie , Tan Alexandra , Shi Yihui 
Published: March 2024

Abstract
Breast cancer (BC), the most prevalent malignancy in women, ranks fourth in cancer mortality as of 2022. Mutations in the BRCA genes significantly elevate BC risk and are associated with markedly reduced survival compared to non-carriers. These genes are crucial in homologous recombination, a mechanism essential for error-free DNA repair. Despite advancements, treatment options for BRCA mutation-driven cancers remain limited. Synthetic lethality (SL) has emerged as a promising strategy, with poly(ADP-ribose) polymerase inhibitors (PARPi) being the first developed drugs based on this principle. However, PARPi's effectiveness is limited, as nearly 40% of BRCA-mutated BCs are unresponsive, and resistance often develops in initial responders. Therefore, novel mutation-specific targeted therapies are urgently needed. In this study, we employed the novel computational method 'Mining Synthetic Lethals (MiSL)' to analyze TCGA pan-cancer primary tumor data, identifying ART3 as a potential SL partner of the BRCA1 germline mutation. Our approach focused on the intersection of genetic interactions and cancer vulnerabilities, providing a unique insight into SL relationships. siRNA-mediated silencing of ART3 in BRCA1-mutated cells consistently led to decreased cell viability, apoptosis induction, and G2/M cell cycle arrest. Following stable transfection with an inducible ART3 shRNA construct, we confirmed significant reduction in cell viability in BRCA1-deficient cells through colony formation assays. RNA sequencing of ART3 knockdown cells revealed transcriptional changes in genes involved in cell cycle progression, apoptosis, and growth and proliferation pathways compared with control cells. Immunofluorescent staining revealed increased DNA damage foci with decreased DNA repair in ART3 knockdown BRCA1-deficient cells. In conclusion, our study identifies ART3 as a novel SL partner of the BRCA1 mutation in BC. This discovery paves the way for developing new therapeutic strategies for BRCA1-mutated breast cancers and novel chemoprevention approaches for individuals carrying germline BRCA1 mutations. Future research will focus on further elucidating the molecular mechanisms underlying this SL interaction and exploring its therapeutic potential in clinical settings.
Citation Format: Hannah Neiger, Xinyu Pei, Anh Nguyen, Wenjia Wang, Emily L. Siegler, James Zhou, Kristie Lau, Alexandra Tan, Yihui Shi. Identification of ART3 as a novel synthetic lethal partner of the BRCA1 mutation in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4686.
Abstract 4692: A novel ceramide synthase 2 agonist and its implication in triple-negative breast cancer therapy
Authors: Alatawi Hissah , Koo Nayeong , Mahmud Iqbal , Nair Haritha , Singh Amandeep , Garrett Timothy J. , Sharma Arun K. , Hong Sukwon , Narayan Satya 
Published: March 2024

Abstract
Based on the biological/molecular markers, breast cancer can be classified into five subgroups: Luminal A (ER+/PR+/HER2-), Luminal B (ER+/PR-/HER2- or ER+/PR+/HER2+, triple-positive), ER-/PR-/HER2+, and ER-/PR-/HER2- (triple-negative). Significant progress has been made in treating hormone-responsive and HER2-expressing breast cancer. However, the targeted therapies are limited for triple-negative breast cancer (TNBC) due to lack of well-defined druggable targets. Additionally, all breast cancer subtypes can quickly develop resistance to current treatments. Thus, there is an urgent need for therapeutic strategies targeting pathways common to all subtypes, irrespective of receptor status. In this effort, we have synthesized a novel biisoquinoline-derivative, DH20931 (US Patent ID: US9914733B2) that induces cytotoxicity in breast cancer cells, including TNBC cells. The spatial molecular modeling and enzymatic assays show that DH20931 interacts with and stimulates ceramide synthase 2 (CerS2) activity, reduces the growth of hormone-responsive, HER2-expressing, and TNBC cells in monolayer and 3D spheroid culture models. DH20931 treatment increases the level of very long chain fatty acid (VLCFA) containing ceramides, induces lipotoxic endoplasmic reticulum (ER) stress, and ATF4/CHOP/PUMA pathway of apoptosis. Based on Swiss-ADME analysis, DH20931 possess all the properties of a druggable molecule and obeys the Lipinski-rule-of-five. Thus, DH20931 can be developed as a novel targeted therapeutic agent independent of ER, PR and HER2 status that potentially may reduce the morbidity and mortality for women with breast cancer.
Citation Format: Hissah Alatawi, Nayeong Koo, Iqbal Mahmud, Haritha Nair, Amandeep Singh, Timothy J. Garrett, Arun K. Sharma, Sukwon Hong, Satya Narayan. A novel ceramide synthase 2 agonist and its implication in triple-negative breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4692.
Abstract 4697: Surface localization of enolase-1 (ENO-1) as an attractive theranostic target in docetaxel-resistant neuroendocrine-like prostate cancer cells
Authors: Torres Krystal Rubi Santiago , Casiano Carlos A. , Almaguel Frankis , Duran Alfonso , Whitley Kristen 
Published: March 2024

Abstract
Prostate cancer (PCa) is American men's second most common cancer. Although taxane-based chemotherapy is the last line of defense for Metastatic Castration Resistant Prostate Cancer (mCRPC), it invariably fails due to chemoresistance. The protein-specific membrane antigen (PSMA) has been an effective target for the imaging and therapy of mCRPC. Although PSMA radioligand therapy (PSMA-RLT) is a theranostics option for men with advanced PCa, about 30% have a limited response due to neuroendocrine-like PCa (NEPC), which lacks PSMA expression. Enolase (ENO) is a promising theranostic alternative due to its cell surface localization in many human tumors. We observed that chemosensitive PCa cell lines expressing NEPC markers express both ENO-1 and ENO-2; however, docetaxel-resistant NEPC-like cells only express ENO-1 and have a metabolic vulnerability due to the loss of ENO-2. We hypothesize that ENO-1 is expressed on the surface of NEPC-like cell lines and can be targeted with small molecule inhibitors (SMIs) that could potentially be used as theranostics agents. Additionally, we have observed changes in the expression and localization of ENO-1 in NEPC-like cell lines under different glucose concentrations. Our data show that under high glucose conditions, found on metabolically active metastatic tumors, ENO-1 is highly expressed on the cell surface, making it a promising candidate target for theranostics. However, low glucose conditions inhibit the activity of the c-MYC oncogene resulting in ENO-1 downregulation and upregulation of MBP1, the small splice variant of ENO1 that blocks the transcriptional activity of c-MYC. Our efforts to confirm ENO-1 surface expression on NEPC-like cell lines entailed using confocal microscopy, cell fractionation analysis followed by Western blotting, and Flow cytometric cell surface staining. We also evaluated the cytotoxicity of SMIs designed to target ENO-1 in chemoresistant NEPC-like cell lines using MTT viability assays, clonogenic assays, and Hoffman Modulation microscopy imaging. Our long-term goal is to identify an alternative treatment for patients with NEPC by establishing ENO-1 as a novel theranostics target.
Citation Format: Krystal Rubi Santiago Torres, Carlos A. Casiano, Frankis Almaguel, Alfonso Duran, Kristen Whitley. Surface localization of enolase-1 (ENO-1) as an attractive theranostic target in docetaxel-resistant neuroendocrine-like prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4697.
Abstract 4705: Repetitive membrane potential oscillations enhance metformin's antiproliferative effect in glioblastoma stem cells
Authors: Verduci Ivan , Cannavale Gaetano , Rey Guido , Cianci Francesca , Fantin Alessandro , Mazzanti Michele 
Published: March 2024

Abstract
Glioblastoma (GB) is the most common and lethal brain tumor and there is a general agreement that GB stem cells (GSCs) are primarily responsible for its high aggressiveness and recurrence. It was recently reported that GSCs are enriched in the transmembrane form of CLIC1 protein (tmCLIC1) and its inhibition was shown to impair tumor growth both in vitro and in vivo. IAA94 hampers tmCLIC1 function but could not be used in clinics. However, tmCLIC1 is also sensitive to metformin, the most used drug to treat type-2 diabetes. Metformin has been demonstrated to have the same effect as IAA94 in in vitro experiments, resulting in an antitumoral action on cancer cells. Moreover, GB orthotopic mouse model treated with metformin shows a 50% survival compared to control animals, even if metformin concentration in the mice brain resulted in the nanomolar range. In this scenario, the main aim of this work is to enhance the effect of metformin able to reach the brain, improving its antitumoral activity in GB. The interaction between metformin and tmCLIC1 occurs only when this protein is in its open state. TmCLIC1 has the peculiarity of being a voltage-dependent ion channel that opens at depolarized voltages. Thus, our strategy is to apply electromagnetic field (EMF) stimulation to induce repetitive membrane depolarization, increasing metformin-tmCLIC1 binding. Our results show that EMF stimulation induces the close-to-open transitions of tmCLIC1, resulting in a 10-fold decrease of the operative concentration of Metformin. This was verified initially in vitro with GSC culture and spheroids model and afterward confirmed also in an in vivo model. The project’s long-term goal is to combine transcranial stimulation and metformin administration in patients as an adjuvant therapy able to target cells that are resistant to chemotherapy and drive tumor relapse.
Citation Format: Ivan Verduci, Gaetano Cannavale, Guido Rey, Francesca Cianci, Alessandro Fantin, Michele Mazzanti. Repetitive membrane potential oscillations enhance metformin's antiproliferative effect in glioblastoma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4705.