bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4527: TNG348 is synergistic with PARP inhibitors in tumor models with elevated replication stress
Authors: Simoneau Antoine , Wu Hsin-Jung , Pratt Charlotte , Comer Grace , Liu Shangtao , Meier Samuel , Khendu Tenzing , Choi Ashley , Zhang Hongxiang , Shen Binzhang , Whittington Douglas , Sudsakorn Sirimas , Zhang Wenhai , Yu Yi , Chen Yingnan , Haines Brian , Crystal Adam , Andersen Jannik N. , Maxwell John , Throner Scott 
Published: March 2024

Abstract
Defective maintenance of genomic integrity is a hallmark of cancer cells that can result from oncogene-induced replication stress and by loss of DNA repair mechanisms. DNA repair deficiencies and elevated replication stress present targetable vulnerabilities for cancer treatment. Notably, BRCA1/2 mutant and homologous recombination deficient (HRD) tumors cannot repair double-strand breaks by homologous recombination and rely on alternative pathways of DNA repair. PARP inhibitors (PARPi), which are a standard of care in many BRCA1/2 mutant tumors, cause synthetic lethality with BRCA1/2 mutation by inhibiting the DNA base excision repair pathway. Despite the clinical benefit of PARPi, they are not effective in every HRD tumor and the acquisition of PARPi resistance limits long-term response. TNG348, a selective allosteric inhibitor of the deubiquitinating enzyme USP1, was specifically designed to target HRD vulnerabilities through an alternative mechanism. We previously showed that the anti-tumor activity of USP1 inhibition results from disruption of the translesion synthesis DNA damage tolerance pathway, a mechanism of action that is functionally distinct from base excision repair targeted by PARPi. Our preclinical studies show that TNG348 is active in HRD models and strongly synergizes with PARP inhibitors to drive strong anti-tumor responses. We have identified replication stress as a predictive biomarker of TNG348 response using cell line profiling and genome-wide CRISPR screens. For example, overexpression of oncogenes known to induce replication stress sensitized to the TNG348 and PARPi combination both in vitro and in vivo. These data indicate that cancer-specific elevated DNA replication stress could contribute to tumor sensitivity to TNG348 and provide additional patient stratification strategies and opportunities for indication expansion.
Citation Format: Antoine Simoneau, Hsin-Jung Wu, Charlotte Pratt, Grace Comer, Shangtao Liu, Samuel Meier, Tenzing Khendu, Ashley Choi, Hongxiang Zhang, Binzhang Shen, Douglas Whittington, Sirimas Sudsakorn, Wenhai Zhang, Yi Yu, Yingnan Chen, Brian Haines, Adam Crystal, Jannik N. Andersen, John Maxwell, Scott Throner. TNG348 is synergistic with PARP inhibitors in tumor models with elevated replication stress [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 4527.
Abstract 4614: Inhibition of NEK2 promotes chemosensitivity and reduces primary effusion lymphoma burden
Authors: White Maria C. , Wong Jason P. , Damania Blossom 
Published: March 2024

Abstract
Non-Hodgkin lymphoma (NHL) is a common cancer in both men and women, and represents a significant cancer burden worldwide. Primary effusion lymphoma (PEL) is a subtype of NHL infected with Kaposi sarcoma-associated herpesvirus (KSHV). PEL is an aggressive and lethal cancer with no current standard of care, owing largely to its propensity to develop resistance to current chemotherapeutic regimens. Here, we report a reliance of PEL on the mitotic kinase, NEK2, for survival. Genetic and pharmacologic targeting of NEK2 resulted in caspase 3-mediated apoptotic cell death of PEL. Furthermore, inhibition of NEK2 significantly prolonged survival and reduced tumor burden in a PEL mouse model. We also report that the ABC transporter proteins, MDR1 and MRP, are most active in PEL and that NEK2 inhibition of PEL reduced the expression and activity of these ABC transporter proteins, which are known to mediate drug resistance in cancer. Additionally, NEK2 inhibition sensitized both viral and non-viral NHL to other chemotherapeutic agents such as rapamycin, resulting in enhanced cancer cell death. Overall, these data offer insight into the mechanisms underlying PEL survival and drug resistance, and suggest that NEK2 is a viable therapeutic target for PEL.
Citation Format: Maria C. White, Jason P. Wong, Blossom Damania. Inhibition of NEK2 promotes chemosensitivity and reduces primary effusion lymphoma burden [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 4614.
Abstract 4629: QClampTM Plex VEXAS syndrome UBA1 mutation detection assay: A noval XNA based assay to simultaneously detect eight UBA1 somatic mutations associated with VEXAS syndrome
Authors: Ma Yunqing 
Published: March 2024

Abstract
VEXAS syndrome (acronym for Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is a monogenic disease discovered in December 2020. It is an adult-onset systemic inflammatory disorder genetically characterized by somatic mutation of the UBA1 gene which encodes the ubiquitin like modifier activating enzyme 1. VEXAS patients have overlapping rheumatologic and hematologic manifestations, including increased risk for myelodysplastic syndrome (MDS). It is critically important to diagnose VEXAS syndrome, but UBA1 mutation test is still not commercially available. The three most frequent mutations of UBA1 gene are p.M41T(122T&gt;C), p.M41V (c.121A&gt;G), and p.M41L (c.121A&gt;C) in codon 41 of exon 3. Other mutations including splice site mutations at exon 3 (c.118-2A&gt;C, c.118-1G&gt;C and c.118- 9_118-2del), p.S56F (c.167C&gt;T) in codon 56 of exon 3, and p.S621C (c.1861A&gt;T) in codon 621 of exon 16 have been reported. Based on XNA technology, we developed a QClampTM Plex platform to detect all the eight mutations in a single reaction with Luminex system. XNA technology enriches mutant target sequence in a PCR reaction by using synthetic DNA analog XNA (xenonucleic acid) to block wild type DNA. With spiking synthetic mutant DNA in GM24385 cell line DNA, we determined that this assay can detect mutations with a detection limit of variant allele frequency (VAF) for M41T at 0.1%, M41V at 0.1%, M41L at 0.25%, c.118-2A&gt;C at 1%, c.118-1G&gt;C at 1%, c.118- 9_118-2del at 1%, S56F at 0.25% and S621C at 1%, respectively, and specificity of 100% for all mutations. We tested saved DNA samples extracted from whole blood previously collected from suspected VEXAS patients and tested at the National Cancer Institute by Sanger sequencing, including 13 positive and 20 negative samples. Our assay detected all corresponding UBA1 mutations in the 13 positive patient samples, and did not detect UBA1 mutation in 18 of the 20 negative patient samples. Two of the 20 negative samples were also tested positive for UBA1 M41T and M41L on our assay, respectively, due to its significantly higher sensitivity than the Sanger sequencing platform, which has a detection limit of 15-20% VAF.
Citation Format: Yunqing Ma. QClampTM Plex VEXAS syndrome UBA1 mutation detection assay: A noval XNA based assay to simultaneously detect eight UBA1 somatic mutations associated with VEXAS syndrome [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 4629.
Abstract 4687: Primary study on the anticancer role of BAM15 in lung cancer cells
Authors: Zhang Mei-yin , Wang Yue-Ning , Zhou Yu-Feng , Wang Shuo-Cheng , Mai Shi-Juan , Wang Hui-Yun 
Published: March 2024

Abstract
Background: Lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for about 80-85% of all lung cancer cases. BAM15, a mitochondrial uncoupler, is a potential therapeutic agent for many diseases, including obesity, diabetes, nonalcoholic fatty liver disease, Sepsis and cancers. However, there is no report on the anti-tumor role of BAM15 in NSCLC.
Methods: To investigate the direct anti-cancer effects of BAM15 in NSCLC, we examined its inhibitory role on cell proliferation of NSCLC cells using the Cell Counting Kit-8(CCK8), colony forming assays and EdU staining assays. The impact of BAM15 on the cell cycle and cell apoptosis of NSCLC cells was analyzed by flow cytometric. A xenotransplanted NSCLC model in mice were used to test the anticancer role of BAM15.
Result: Using the CCK8 assay, we found that the inhibitory role of BAM15 on the proliferation and colony formation of NSCLC cells is dose-dependent. The half maximal inhibitory concentration (IC50) values for cell proliferation were 2.71, 4.74, and 9.50 μM for A549, PC9, and H1299 NSCLC cells, respectively. The EdU staining assay demonstrated that BAM15 treatment significantly inhibited DNA synthesis in NSCLC cells. Flow cytometric analysis revealed that BAM15 arrested cell cycle at G2 phase in NSCLC cells and caused a striking increase in the percentage of apoptotic cells in NSCLC cells. The xenotransplanted NSCLC experiment indicated that BAM15 could significantly suppressed the growth of NSCLC tumors compared with the control tumors.
Conclusions: Our study demonstrates that BAM15 significantly inhibits cell proliferation and promotes apoptosis in NSCLC cells, indicating that BAM15 is a potential therapeutic candidate for the treatment of NSCLC.
Citation Format: Mei-yin Zhang, Yue-Ning Wang, Yu-Feng Zhou, Shuo-Cheng Wang, Shi-Juan Mai, Hui-Yun Wang. Primary study on the anticancer role of BAM15 in lung 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 4687.
Abstract 4704: Biochemical and cell-based assay platforms for development of RAF inhibitors against human cancers
Authors: Wu Jianghong , Wan Yong , Liang Shuguang , Gallagher Peter , Liang Li , Loch Christian , Ma Haiching 
Published: March 2024

Abstract
The RAF protein kinases are key intermediates in cellular signal transduction, functioning as direct effectors of the RAS GTPases and as the initiating kinases in the ERK cascade. In human cancer, RAF activity is frequently dysregulated due to mutations in the RAF family members (ARAF, BRAF, and CRAF) or to alterations in upstream RAF regulators, including RAS and receptor tyrosine kinases. The first and second generations of RAF inhibitors have yielded dramatic responses in malignant melanomas containing BRAF mutations; however, their overall usefulness has been limited by both intrinsic and acquired drug resistance. In addition, cancers with hyperactive RAS exhibit intrinsic resistance to these drugs. In particular, issues related to the dimerization of the RAF kinases can impact the efficacy of these compounds and are a primary cause of drug resistance. We have established biochemical HotSpotTM kinase assay, NanoBRETTM and NanoBITTM cell assay platforms for High Through Screening of kinase inhibitors. Here, we demonstrate that the 3rd generation of pan-RAF inhibitors LY3009120, LXH254, and Belvarafenib inhibit ARAF, BRAF, CRAF, BRAF(V600E), and CRAF(R391W) kinase activity in biochemical HotSpotTM assay. Our NanoBRETTM target engagement and NanoBITTM cellular assay data show that LY3009120, LXH254, and Belvarafenib bind to KRAS(G12C) primed BRAF and CRAF, and block BRAF and CRAF dimerization. Furthermore, our results show these inhibitors can block the downstream ERK phosphorylation in cellular HTRF assay and induce caspase-3/7 activation in Western blot assay in the triple negative breast cancer MDA-MB-231 cells. Taken together, our results indicate the biochemical HotSpotTM kinase activity assay, and NanoBRETTM target engagement and NanoBITTM cellular assays can serve as great platforms to facilitate RAF drug discovery against human cancers.
Citation Format: Jianghong Wu, Yong Wan, Shuguang Liang, Peter Gallagher, Li Liang, Christian Loch, Haiching Ma. Biochemical and cell-based assay platforms for development of RAF inhibitors against human cancers [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 4704.
Abstract 4716: First-in-class peroxiredoxin 3 (PRX3) inhibitor RSO-021 triggers mesenchymal-to-epithelial transition in mesothelioma
Authors: Messier Terri , Gibson Victoria , Seward David J. , Baitei Essa Y. , Jordan Peter Wells , Poile Charlotte , Dzialo Joanna , Bzura Aleksandra , Kutywayo Kudzayi , Nakas Apostolos , Naumov George N. , Fennell Dean A. , Cunniff Brian 
Published: March 2024

Abstract
Mesothelioma, a lethal cancer associated with asbestos exposure, lacks effective drug therapy particularly in the relapsed treatment setting. Epithelial-to-mesenchymal transition (EMT) confers an aggressive sarcomatoid phenotype capable of invasion, metastasis, and drug resistance. Pharmacological targeting of EMT could favorably alter the progression and treatment of mesothelioma. We identified a geospatial transcriptomic gradient between adjacent epithelioid and sarcomatoid regions in patient-derived biphasic mesotheliomas involving hypoxia tolerance, TGF-β, mitochondrial oxidative phosphorylation, and EMT. Mesothelioma cells rely on buffering of mitochondrial oxidative stress through the expression and activity of mitochondrial peroxiredoxin 3 (PRX3), which is covalently inactivated by the first-in-class inhibitor RSO-021, now under investigation in the phase 1/2 MITOPE clinical trial (NCT05278975). To better understand the pharmacodynamics of RSO-021, transcriptomic profiles of drug sensitive and resistant biphasic mesothelioma cell lines were generated. Differential analysis revealed that RSO-021 induced up-regulation of ROS response and apoptosis signaling, while down-regulating TGF-β and EMT markers, WNT signaling, and TEAD target genes. Additionally, we observed altered expression of the mesothelioma specific EMT genes Col5A2, mesothelin and VISTA. Resistance to RSO-021 conferred significant proliferative defects and was reversible upon RSO-021 removal, however the down-regulation of EMT genes was conserved, suggesting an irreversible mesenchymal-to-epithelial transition. In summary PRX3 is a clinically actionable drug target, inhibition of which correlates with EMT modulation. This activity suggests a mechanism to alter mesothelioma progression and prevent the emergence of the most aggressive mesothelioma phenotype.
Citation Format: Terri Messier, Victoria Gibson, David J. Seward, Essa Y. Baitei, Peter Wells Jordan, Charlotte Poile, Joanna Dzialo, Aleksandra Bzura, Kudzayi Kutywayo, Apostolos Nakas, George N. Naumov, Dean A. Fennell, Brian Cunniff. First-in-class peroxiredoxin 3 (PRX3) inhibitor RSO-021 triggers mesenchymal-to-epithelial transition in mesothelioma [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 4716.
Abstract 4741: Targeting sorafenib-resistant HCCs by protein X-armed T cell immunotherapy
Authors: Ngo Mai-Huong Thi , Chen Michael , Lan Pei-Chi , Chuang Kuo-Hsiang , Huang Yen-Hua 
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer globally, ranking fourth according to the World Health Organization's GLOBOCAN database. Sorafenib and lenvatinib are single-drug therapies used for advanced HCC, but only around 30% of patients benefit from them, and drug resistance typically develops within a few months. Our previous study has demonstrated the specific IL-6-IGF-1R-YAP signaling in regulating the stemness expressions, tumor metastasis, and drug-resistance of the sorafenib resistant HCC (2015 Clinical Cancer Res, 2019 J Exp Clinical Cancer Research, 2021 Cancers, 2023 Cancers). In advance our previous study, this study aims to develop a novel immune therapeutic strategy for sorafenib-resistant HCC treatment. We found, when compared to peri-tumor tissues, the immunohistochemical staining showed a high co-expression of both protein X and PD-L1 in liver tumor tissues (6.25%, n=32 versus 28.125%, n = 64, respectively). To further confirm this observation, we used in vitro cell line models with sorafenib-naïve HCCs (HepG2215_N, Hep3B_N, Huh7_N, and PLC5_N) and sorafenib-resistant HCCs (HepG2215_R, Hep3B_R, Huh7_R, and PLC5_R) in this study. As PD-L1 on tumor cells can dampen T cell cytotoxicity, we generated CD3/protein X bispecific antibodies, which can bind to both CD3 and protein X, and coupled them to T cells (Arm-T cells) and normal T cells (N-T cells). We tested their cytotoxic effects on sorafenib-resistant HCCs using the sorafenib-resistant HepG2215_R cells, co-cultured with Arm-T cells and N-T cells for 24 hours. Our results showed that Arm-T cells exhibited a significantly stronger cytotoxic effect on sorafenib-resistant HepG2215_R cells, with several notable findings: (1) The binding time of Arm-T cells to HepG2215_R cells was significantly longer than that of N-T cells (248.9 ± 146.6 minutes, n=23 versus 28.3 ± 13.49 minutes, n=24); (2) The cytotoxicity of Arm-T cells was significantly higher than that of N-T cells (29.7 ± 2.3% versus 13.6 ± 3.3%); and (3) The secreted levels of INFγ and TNFα by Arm-T cells were significantly higher than those of N-T cells (138.1 ± 7.2 ng/ml and 34.6 ± 0.7 ng/ml versus 31.4 ± 2.5 ng/ml and 3.6 ± 1.1 ng/ml, respectively). These findings were also consistent when using Hep3B-R cells (data not shown). To summarize, our study shows that Arm-T cells possess strong cytotoxic abilities against sorafenib-resistant HCC. These findings have implications for developing effective immuno-therapeutic strategies for patients with sorafenib-resistant HCCs.
Citation Format: Mai-Huong Thi Ngo, Michael Chen, Pei-Chi Lan, Kuo-Hsiang Chuang, Yen-Hua Huang. Targeting sorafenib-resistant HCCs by protein X-armed T cell immunotherapy [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 4741.
Abstract 4742: Targeting the RNA-binding protein LARP1 overcomes therapeutic resistance in ovarian cancer
Authors: Elsayed Abdelrahman M. , Amero Paola , Bayraktar Emine , Sood Anil K. , Lopez-Berestein Gabriel , Rodriguez-Aguayo Cristian 
Published: March 2024

Abstract
La-related protein 1 (LARP1) is an RNA-binding protein that plays a pivotal role in regulating mRNA on a post-transcriptional level. Overexpression of LARP1 has been detected in multiple cancers substantiating the critical role of LARP1 as a driver for cancer progression. This study aims to investigate the downstream target pathways regulated by LARP1 and to determine the impact of LARP1 targeting on the resistance to cisplatin and olaparib therapy in ovarian cancer (OC). Analysis of The Cancer Genome Atlas OC dataset, reverse phase protein array, in vitro functional and mechanistic experiments, and a xenograft OC mouse model using OVCAR8 cell line were executed. Our results revealed that overexpression of LARP1 is negatively correlated with progression-free survival in OC patients. Furthermore, LARP1 knockdown using two independent small interfering RNAs (siRNAs) suppressed cell growth, invasion, and migration, and ameliorated cisplatin resistance in vitro. Mechanistic analyses identified AXL as a target of LARP1 and this finding was further supported clinically in which co-overexpression of LARP1 and AXL is associated with poor prognosis in OC. Furthermore, LARP1 knockdown resulted in reduced phosphorylation of mTOR, AKT, and SRC with no significant effect on FAK. In vivo, administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) nanoparticles loaded with LARP1-siRNA suppressed tumor growth and improved the response to cisplatin and olaparib in a xenograft OC mouse model. In conclusion, LARP1 acts as an oncogenic RNA-binding protein in OC, and targeting LARP1 may represent an innovative therapeutic approach for ameliorating resistance to chemotherapy and targeted therapy in OC.
Keywords: RNA-binding proteins; cisplatin resistance; olaparib resistance; chemotherapy resistance; LARP1; ovarian cancer.
Citation Format: Abdelrahman M. Elsayed, Paola Amero, Emine Bayraktar, Anil K. Sood, Gabriel Lopez-Berestein, Cristian Rodriguez-Aguayo. Targeting the RNA-binding protein LARP1 overcomes therapeutic resistance in ovarian 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 4742.
Abstract 4754: Targeted inhibition of the HNF1A/SHH axis by triptolide overcomes paclitaxel resistance in non-small cell lung cancer
Authors: Li Peichao , Li ngbing , Yang Lingxiao , Liu Lei , Zhao Xiaogang 
Published: March 2024

Abstract
Paclitaxel resistance is commonly associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and there are no promising pharmacological treatments for paclitaxel resistance. Here, we constructed human NSCLC-derived paclitaxel-resistant cell lines as an effective tool to explore the mechanisms of chemoresistance. We discovered that triptolide, a monomer compound extracted from Tripterygium wilfordii Hook F, was able to reverse paclitaxel resistance by reducing ABCB1 expression in vivo and in vitro. Through high-throughput sequencing, we found that the SHH-initiated Hedgehog signaling pathway played an important role in this process. More importantly, triptolide could directly target HNF1A, a transcription factor of SHH, and inhibited HNF1A/SHH expression, ensuing in attenuation of Hedgehog signaling. Clinically, we found a positive correlation between HNF1A and SHH expression in both NSCLC tumor tissue microarrays and cancer network databases. These findings illuminated a novel molecular mechanism through which triptolide effectively targets and inhibits HNF1A, thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1. This finding indicated the potential clinical application of triptolide and provided promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance.
Citation Format: Peichao Li, ngbing Li, Lingxiao Yang, Lei Liu, Xiaogang Zhao. Targeted inhibition of the HNF1A/SHH axis by triptolide overcomes paclitaxel resistance in non-small cell lung 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 4754.