Статті в журналах: "Schlafen-11"

1

Razzak, Mina. "Schlafen 11 naturally blocks HIV." Nature Reviews Urology 9, no. 11 (October 9, 2012): 605. http://dx.doi.org/10.1038/nrurol.2012.188.

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2

Bednarikova, Marketa, Jitka Hausnerova, Lucie Ehrlichova, Kvetoslava Matulova, Eliska Gazarkova, Lubos Minar, and Vit Weinberger. "Can Schlafen 11 Help to Stratify Ovarian Cancer Patients Treated with DNA-Damaging Agents?" Cancers 14, no. 10 (May 10, 2022): 2353. http://dx.doi.org/10.3390/cancers14102353.

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Platinum-based chemotherapy has been the cornerstone of systemic treatment in ovarian cancer. Since no validated molecular predictive markers have been identified yet, the response to platinum-based chemotherapy has been evaluated clinically, based on platinum-free interval. The new promising marker Schlafen 11 seems to correlate with sensitivity or resistance to DNA-damaging agents, including platinum compounds or PARP inhibitors in various types of cancer. We provide background information about the function of Schlafen 11, its evaluation in tumor tissue, and its prevalence in ovarian cancer. We discuss the current evidence of the correlation of Schlafen 11 expression in ovarian cancer with treatment outcomes and the potential use of Schlafen 11 as the key predictive and prognostic marker that could help to better stratify ovarian cancer patients treated with platinum-based chemotherapy or PARP inhibitors. We also provide perspectives on future directions in the research on this promising marker.

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3

Tian, Li, Santai Song, Xiaojing Liu, Yan Wang, Xiaoguang Xu, Yi Hu, and Jianming Xu. "Schlafen-11 sensitizes colorectal carcinoma cells to irinotecan." Anti-Cancer Drugs 25, no. 10 (November 2014): 1175–81. http://dx.doi.org/10.1097/cad.0000000000000151.

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4

Jitobaom, Kunlakanya, Thanyaporn Sirihongthong, Chompunuch Boonarkart, Supinya Phakaratsakul, Ornpreya Suptawiwat, and Prasert Auewarakul. "Human Schlafen 11 inhibits influenza A virus production." Virus Research 334 (September 2023): 199162. http://dx.doi.org/10.1016/j.virusres.2023.199162.

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5

Li, Manqing, Elaine Kao, Hilary Sandig, Sebastien Landry, Matthew D. Weitzman, and Michael David. "SS5-8 Inhibition of retroviral replication by human Schlafen 11." Cytokine 52, no. 1-2 (October 2010): 45. http://dx.doi.org/10.1016/j.cyto.2010.07.433.

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6

Zhou, Jing, Mei-Ying Zhang, Ai-Ai Gao, Cheng Zhu, Tao He, James G. Herman, and Ming-Zhou Guo. "Epigenetic silencing schlafen-11 sensitizes esophageal cancer to ATM inhibitor." World Journal of Gastrointestinal Oncology 16, no. 5 (May 15, 2024): 2060–73. http://dx.doi.org/10.4251/wjgo.v16.i5.2060.

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BACKGROUND Targeting DNA damage response (DDR) pathway is a cutting-edge strategy. It has been reported that Schlafen-11 (SLFN11) contributes to increase chemosensitivity by participating in DDR. However, the detailed mechanism is unclear. AIM To investigate the role of SLFN11 in DDR and the application of synthetic lethal in esophageal cancer with SLFN11 defects. METHODS To reach the purpose, eight esophageal squamous carcinoma cell lines, 142 esophageal dysplasia (ED) and 1007 primary esophageal squamous cell carcinoma (ESCC) samples and various techniques were utilized, including methylation-specific polymerase chain reaction, CRISPR/Cas9 technique, Western blot, colony formation assay, and xenograft mouse model. RESULTS Methylation of SLFN11 was exhibited in 9.15% of (13/142) ED and 25.62% of primary (258/1007) ESCC cases, and its expression was regulated by promoter region methylation. SLFN11 methylation was significantly associated with tumor differentiation and tumor size (both P < 0.05). However, no significant associations were observed between promoter region methylation and age, gender, smoking, alcohol consumption, TNM stage, or lymph node metastasis. Utilizing DNA damaged model induced by low dose cisplatin, SLFN11 was found to activate non-homologous end-joining and ATR/CHK1 signaling pathways, while inhibiting the ATM/CHK2 signaling pathway. Epigenetic silencing of SLFN11 was found to sensitize the ESCC cells to ATM inhibitor (AZD0156), both in vitro and in vivo . CONCLUSION SLFN11 is frequently methylated in human ESCC. Methylation of SLFN11 is sensitive marker of ATM inhibitor in ESCC.

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7

Jo, Ukhyun, Yasuhisa Murai, Naoko Takebe, Anish Thomas, and Yves Pommier. "Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11." Cancers 13, no. 18 (September 14, 2021): 4601. http://dx.doi.org/10.3390/cancers13184601.

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Precision medicine aims to implement strategies based on the molecular features of tumors and optimized drug delivery to improve cancer diagnosis and treatment. DNA replication is a logical approach because it can be targeted by a broad range of anticancer drugs that are both clinically approved and in development. These drugs increase deleterious replication stress (RepStress); however, how to selectively target and identify the tumors with specific molecular characteristics are unmet clinical needs. Here, we provide background information on the molecular processes of DNA replication and its checkpoints, and discuss how to target replication, checkpoint, and repair pathways with ATR inhibitors and exploit Schlafen 11 (SLFN11) as a predictive biomarker.

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8

Borrego, Andre Raymundo, Christian Corona-Ayala, Julienne Christa Salvador, Federico Christa Valdez, and Manuel Llano. "Gene Expression Regulation of the Type I Interferon‐Induced Protein Schlafen 11." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.00603.

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9

Li, Manqing, Elaine Kao, Xia Gao, Hilary Sandig, Kirsten Limmer, Mariana Pavon-Eternod, Thomas E. Jones, et al. "Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11." Nature 491, no. 7422 (September 23, 2012): 125–28. http://dx.doi.org/10.1038/nature11433.

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10

Buettner, Reinhard. "Awakening of SCHLAFEN 11 by immunohistochemistry: a new biomarker predicting response to chemotherapy." Virchows Archiv 478, no. 3 (February 10, 2021): 567–68. http://dx.doi.org/10.1007/s00428-021-03051-3.

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11

Taniyama, Daiki, Naoya Sakamoto, Tsuyoshi Takashima, Masahiko Takeda, Quoc Thang Pham, Shoichi Ukai, Ryota Maruyama, et al. "Prognostic impact of Schlafen 11 in bladder cancer patients treated with platinum‐based chemotherapy." Cancer Science 113, no. 2 (December 7, 2021): 784–95. http://dx.doi.org/10.1111/cas.15207.

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12

Inno, Alessandro, Anna Stagno, and Stefania Gori. "Schlafen-11 (SLFN11): a step forward towards personalized medicine in small-cell lung cancer?" Translational Lung Cancer Research 7, S4 (December 2018): S341—S345. http://dx.doi.org/10.21037/tlcr.2018.11.06.

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13

Malone, Dane, Rea M. Lardelli, Manqing Li, and Michael David. "Dephosphorylation activates the interferon-stimulated Schlafen family member 11 in the DNA damage response." Journal of Biological Chemistry 294, no. 40 (August 8, 2019): 14674–85. http://dx.doi.org/10.1074/jbc.ra118.006588.

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14

Zoppoli, G., M. Regairaz, E. Leo, W. C. Reinhold, S. Varma, A. Ballestrero, J. H. Doroshow, and Y. Pommier. "Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA-damaging agents." Proceedings of the National Academy of Sciences 109, no. 37 (August 27, 2012): 15030–35. http://dx.doi.org/10.1073/pnas.1205943109.

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15

Yamamura, T., K. C. Hatanaka, K. Harada, Y. Kawamoto, R. Watanabe, T. Nakamura, S. Yuki, T. Mitsuhashi, Y. Hatanaka, and Y. Komatsu. "1712P Usefulness of schlafen-11 expression level in cstage II/III esophageal squamous cell carcinoma." Annals of Oncology 33 (September 2022): S1322. http://dx.doi.org/10.1016/j.annonc.2022.07.1790.

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16

Isnaldi, Edoardo, Domenico Ferraioli, Lorenzo Ferrando, Sylvain Brohée, Fabio Ferrando, Piero Fregatti, Davide Bedognetti, Alberto Ballestrero, and Gabriele Zoppoli. "Schlafen-11 expression is associated with immune signatures and basal-like phenotype in breast cancer." Breast Cancer Research and Treatment 177, no. 2 (June 20, 2019): 335–43. http://dx.doi.org/10.1007/s10549-019-05313-w.

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17

Murai, Junko, Anish Thomas, Markku Miettinen, and Yves Pommier. "Schlafen 11 (SLFN11), a restriction factor for replicative stress induced by DNA-targeting anti-cancer therapies." Pharmacology & Therapeutics 201 (September 2019): 94–102. http://dx.doi.org/10.1016/j.pharmthera.2019.05.009.

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18

Bell, Timothy A., Elena de la Casa-Esperón, Heather E. Doherty, Folami Ideraabdullah, Kuikwon Kim, Yunfei Wang, Leslie A. Lange, et al. "The Paternal Gene of the DDK Syndrome Maps to the Schlafen Gene Cluster on Mouse Chromosome 11." Genetics 172, no. 1 (September 19, 2005): 411–23. http://dx.doi.org/10.1534/genetics.105.047118.

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19

Lin, Yue-Zhi, Liu-Ke Sun, Dan-Tong Zhu, Zhe Hu, Xue-Feng Wang, Cheng Du, Yu-Hong Wang, Xiao-Jun Wang, and Jian-Hua Zhou. "Equine schlafen 11 restricts the production of equine infectious anemia virus via a codon usage-dependent mechanism." Virology 495 (August 2016): 112–21. http://dx.doi.org/10.1016/j.virol.2016.04.024.

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20

Isnaldi, Edoardo, Domenico Ferraioli, Lorenzo Ferrando, Sylvain Brohée, Fabio Ferrando, Piero Fregatti, Davide Bedognetti, Alberto Ballestrero, and Gabriele Zoppoli. "Correction to: Schlafen-11 expression is associated with immune signatures and basal-like phenotype in breast cancer." Breast Cancer Research and Treatment 177, no. 3 (July 12, 2019): 773. http://dx.doi.org/10.1007/s10549-019-05348-z.

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21

Marzi, Laetitia, Ludmila Szabova, Melanie Gordon, Zoe Weaver Ohler, Shyam K. Sharan, Michael L. Beshiri, Moudjib Etemadi, Junko Murai, Kathleen Kelly, and Yves Pommier. "The Indenoisoquinoline TOP1 Inhibitors Selectively Target Homologous Recombination-Deficient and Schlafen 11-Positive Cancer Cells and Synergize with Olaparib." Clinical Cancer Research 25, no. 20 (August 13, 2019): 6206–16. http://dx.doi.org/10.1158/1078-0432.ccr-19-0419.

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22

Miladinov, Marko, Jovana Rosic, Katarina Eric, Azra Guzonjic, Jelenko Jelenkovic, Natasa Bogavac-Stanojevic, Ivan Dimitrijevic, Jelena Kotur-Stevuljevic, and Goran Barisic. "Analysis of the Prognostic Potential of Schlafen 11, Programmed Death Ligand 1, and Redox Status in Colorectal Cancer Patients." International Journal of Molecular Sciences 24, no. 20 (October 11, 2023): 15083. http://dx.doi.org/10.3390/ijms242015083.

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The Schlafen 11 (SLFN11) protein has recently emerged as pivotal in DNA damage conditions, with predictive potential for tumor response to cytotoxic chemotherapies. Recent discoveries also showed that the programmed death ligand 1 (PD-L1) protein can be found on malignant cells, providing an immune evasion mechanism exploited by different tumors. Additionally, excessive generation of free radicals, redox imbalance, and consequential DNA damage can affect intestinal cell homeostasis and lead to neoplastic transformation. Therefore, our study aimed to investigate the significance of SLFN11 and PD-L1 proteins and redox status parameters as prognostic biomarkers in CRC patients. This study included a total of 155 CRC patients. SLFN11 and PD-L1 serum levels were measured with ELISA and evaluated based on redox status parameters, sociodemographic and clinical characteristics, and survival. The following redox status parameters were investigated: spectrophotometrically measured superoxide dismutase (SOD), sulfhydryl (SH) groups, advanced oxidation protein products (AOPP), malondialdehyde (MDA), pro-oxidant–antioxidant balance (PAB), and superoxide anion (O2•–). The prooxidative score, antioxidative score, and OXY-SCORE were also calculated. The results showed significantly shorter survival in patients with higher OXY-SCOREs and higher levels of serum SLFN11, while only histopathology-analysis-related factors showed significant prognostic value. OXY-SCORE and SLFN11 levels may harbor prognostic potential in CRC patients.

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23

Tang, Sai-Wen, Anish Thomas, Junko Murai, Jane B. Trepel, Susan E. Bates, Vinodh N. Rajapakse, and Yves Pommier. "Overcoming Resistance to DNA-Targeted Agents by Epigenetic Activation of Schlafen 11 (SLFN11) Expression with Class I Histone Deacetylase Inhibitors." Clinical Cancer Research 24, no. 8 (February 1, 2018): 1944–53. http://dx.doi.org/10.1158/1078-0432.ccr-17-0443.

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24

Scher, Howard I., Luisa Fernandez, Kate Cunningham, Natalie Elphick, Ethan Barnett, Jerry Lee, Cole Gilbertson, et al. "Schlafen 11 (SLFN11), a putative predictive biomarker of platinum/PARPi response, is frequently detected on circulating tumor cells (CTCs) in advanced prostate cancer." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e17039-e17039. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e17039.

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e17039 Background: Schlafen 11 (SLFN11) is a DNA repair protein (DNA/RNA helicase homology) that is recruited to stressed replication forks and leads to cell death. Recent ph II trial data in Extensive Stage Small-Cell Lung Cancer (ES-SCLC) [Byers et al. JCO 2018 PMID: 29906251] and a retrospective analysis of Circulating Tumor Cells (CTCs) and tumor tissue in patients (Pts) with advanced prostate cancer [Conteduca et al. Mol Cancer Therapeutics 2020 PMID: 32127465] suggested that SLFN11 expression predicts sensitivity to DNA damage targeting agents. In both contexts, metastatic tumor biopsies may not provide adequate material for profiling. We assessed the frequency of SLFN11 expression in CTCs isolated from blood in men with progressing metastatic Castration Resistant Prostate Cancer (mCRPC) and related expression to Homologous Recombination Repair (HRR) alterations identified in metastatic tumor biopsies profiled by MSK-IMPACT. Methods: 95 patients with progressing mCRPC about to start a new systemic therapy who had undergone pre-treatment metastatic tumor profiling by MSK-IMPACT and a matched blood draw for CTC profiling were selected. Blood was sent overnight to Epic Sciences and processed onto glass pathology slides and bio-banked until analysis. Detected CTCs (cytokeratin (CK) positive and leukocyte (CD45) negative) were analyzed for SLFN11 protein expression by immunofluorescence and correlated to Homologous Recombination Repair (HRR) alterations in metastatic biopsy from the bone, lymph node, or visceral metastases (15 PROFOUND genes). A mean of 1.2 mL of blood was analyzed per patient. Results: CTCs with SLFN11 expression (DAPI+, CK+, CD45-, SLFN11+) were detected in 28.4% (27/95) of the patient sample analyzed. SLFN11 signal was found to overlap with the nuclear DAPI signal. Individual CTC expression of SLFN11 in a sample was heterogeneous and ranged from a minimum of 2.9% to 100%. Seven of 10 (70%) of patients with a BRCA1/2 or ATM alteration had a least one SLFN11 expressing CTC. In contrast, in patients with other HRR alterations, only 20% (1/5) had CTCs with SLFN11. Sequencing of single CTCs is ongoing. Conclusions: SLFN11 expression is detected with high frequency in CTCs in men with progressing mCRPC. In whom CTCs are detected, the majority of patients with BRCA1/2 or ATM altered tumors also had SLFN11 expressing CTCs. The results support the prospective evaluation of CTC SLFN11 expression as a predictive biomarker for PARPi or platinum agents.

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25

Pommier, Y., S. W. Bilke, F. Sousa, M. Yamade, J. Murai, V. Rajapakse, L. Helman, and P. Meltzer. "252 The DNA damage response gene Schlafen 11 (SLFN11) is a transcriptional target of ETS transcription factors in Ewing's sarcoma and other cancers." European Journal of Cancer 50 (November 2014): 84. http://dx.doi.org/10.1016/s0959-8049(14)70378-8.

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26

Jo, Ukhyun, Yasuhisa Murai, Sirisha Chakka, Lu Chen, Ken Cheng, Junko Murai, Liton Kumar Saha, Lisa M. Miller Jenkins, and Yves Pommier. "SLFN11 promotes CDT1 degradation by CUL4 in response to replicative DNA damage, while its absence leads to synthetic lethality with ATR/CHK1 inhibitors." Proceedings of the National Academy of Sciences 118, no. 6 (February 3, 2021): e2015654118. http://dx.doi.org/10.1073/pnas.2015654118.

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Schlafen-11 (SLFN11) inactivation in ∼50% of cancer cells confers broad chemoresistance. To identify therapeutic targets and underlying molecular mechanisms for overcoming chemoresistance, we performed an unbiased genome-wide RNAi screen in SLFN11-WT and -knockout (KO) cells. We found that inactivation of Ataxia Telangiectasia- and Rad3-related (ATR), CHK1, BRCA2, and RPA1 overcome chemoresistance to camptothecin (CPT) in SLFN11-KO cells. Accordingly, we validate that clinical inhibitors of ATR (M4344 and M6620) and CHK1 (SRA737) resensitize SLFN11-KO cells to topotecan, indotecan, etoposide, cisplatin, and talazoparib. We uncover that ATR inhibition significantly increases mitotic defects along with increased CDT1 phosphorylation, which destabilizes kinetochore-microtubule attachments in SLFN11-KO cells. We also reveal a chemoresistance mechanism by which CDT1 degradation is retarded, eventually inducing replication reactivation under DNA damage in SLFN11-KO cells. In contrast, in SLFN11-expressing cells, SLFN11 promotes the degradation of CDT1 in response to CPT by binding to DDB1 of CUL4CDT2 E3 ubiquitin ligase associated with replication forks. We show that the C terminus and ATPase domain of SLFN11 are required for DDB1 binding and CDT1 degradation. Furthermore, we identify a therapy-relevant ATPase mutant (E669K) of the SLFN11 gene in human TCGA and show that the mutant contributes to chemoresistance and retarded CDT1 degradation. Taken together, our study reveals new chemotherapeutic insights on how targeting the ATR pathway overcomes chemoresistance of SLFN11-deficient cancers. It also demonstrates that SLFN11 irreversibly arrests replication by degrading CDT1 through the DDB1–CUL4CDT2 ubiquitin ligase.

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Nakata, Satoshi, Manabu Natsumeda, Junko Murai, Masayasu Okada, and Yukihiko Fujii. "SPDR-4 SLFN11 RENDERS MEDULLOBLASTOMA SENSITIVE TO DNA DAMAGE CHEMOTHERAPIES." Neuro-Oncology Advances 4, Supplement_3 (December 1, 2022): iii3. http://dx.doi.org/10.1093/noajnl/vdac167.008.

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Abstract Background Intensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma. Methods SLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo. Results High SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells. Conclusions High SLFN11 expression renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma through enhancing response to cisplatin.

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Natsumeda, Manabu, Satoshi Nakata, Junko Murai, Takahashi Haruhiko, Masayasu Okada, Jun Watanabe, Yoshihiro Tsukamoto, et al. "EXTH-46. SCHLAFEN11 IS A POWERFUL BIOMARKER OF CHEMOSENSITIVITY IN MEDULLOBLASTOMAS." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v235. http://dx.doi.org/10.1093/neuonc/noad179.0899.

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Abstract Non-biased and biased screening for prognostic factors in medulloblastomas showed that Schlafen family member 11 (SLFN11) is a powerful prognostic marker. SLFN11 is a putative DNA/RNA helicase, whose expression improves response to DNA damaging agents in some cancers, but its role in medulloblastoma has not been reported. SLFN11 protein and mRNA level were found to be expressed exclusively in WNT-activated and a proportion of SHH-activated medulloblastoma. WNT pathway activation did not acutely induce SLFN11, rather, its expression correlated with a specific hypomethylation site on the SLFN11 promoter. Genetic introduction of SLFN11 into medulloblastoma cell lines with no baseline expression dramatically increased their response to the DNA damaging agents cisplatin and SN-38 in vitro. Intracranial xenograft studies also showed markedly increased sensitivity to cisplatin after induced SLFN11 overexpression in medulloblastoma cells. In addition, CRISPR-mediated deletion of SLFN11 in a medulloblastoma cell line with high baseline expression reduced the response to chemotherapy. SLFN11 could also be upregulated pharmacologically by the histone deacetylase-inhibitor RG2833, supporting the importance of epigenetic control. Importantly, markedly increased sensitivity to cisplatin and SN-38 was seen in initially SLFN11-negative medulloblastoma cells also treated with RG2833, suggesting an approach by which more aggressive medulloblastoma subtypes might be targeted. Our findings suggest a novel mechanism for the increased chemosensitivity of some medulloblastoma subtypes linked to a specific biomarker, as well as a novel combinatorial chemotherapeutic strategy for the treatment of more aggressive medulloblastoma subtypes (Groups 3 and 4) lacking SLFN11.

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Toivanen, Kirsi, Luna De Sutter, Agnieszka Wozniak, Tom Böhling, Patrick Schöffski, and Harri Sihto. "Abstract A030: Treatment with sustained-release anagrelide reduces tumor volume and has antiproliferative effects in a patient-derived GIST xenograft mouse model." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): A030. http://dx.doi.org/10.1158/1535-7163.targ-23-a030.

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Abstract Anagrelide is a phosphodiesterase 3A inhibitor that is used to treat essential thrombocythemia. The drug stabilizes the interaction of PDE3A and Schlafen 12 (SLFN12), resulting in complex stabilization, activation of SLFN12 RNase activity and cytotoxic effects in cancer cells. Gastrointestinal stromal tumors (GIST) exhibit high levels of PDE3A expression compared to other cancers or healthy tissue. Orally administered anagrelide has shown antitumor effects in patient-derived GIST xenograft (PDX) mouse models. In this study, we investigated the efficacy of subcutaneously administered, sustained-release anagrelide in UZLX-GIST2B, a PDX mouse model characterized by a KIT mutation in exon 9 and typical dose-dependent imatinib sensitivity. We assessed changes in tumor volume and evaluated histological drug responses including hyalinization, fibrosis, myxoid generation, and tumor necrosis. Anagrelide was administered either orally (2.5 mg/kg, twice a day) or subcutaneously (35 mg/kg and 70 mg/kg, every fourth day) for a duration of 11 days. Treatments with both 35 mg/kg and 70 mg/kg doses resulted in a significant reduction in average tumor volume compared to untreated control mice (both doses 25% vs.129%, P < 0.001) or mice treated with oral anagrelide (25% vs. 61%, P =0 .08, P < 0.05, respectively). The histological response in tumor tissue was positively correlated with dose level, and tumors treated with the highest dose exhibited grade 3 to 4 responses in all cases. These results suggest that sustained-release anagrelide holds promise as a therapeutic option for the treatment of GIST. Further preclinical studies are warranted to investigate the pharmacokinetics and toxicity of this treatment approach. Citation Format: Kirsi Toivanen, Luna De Sutter, Agnieszka Wozniak, Tom Böhling, Patrick Schöffski, Harri Sihto. Treatment with sustained-release anagrelide reduces tumor volume and has antiproliferative effects in a patient-derived GIST xenograft mouse model [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A030.

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Weidema, Marije E., Ingrid M. E. Desar, Melissa H. S. Hillebrandt-Roeffen, Anke E. M. van Erp, Mikio Masuzawa, J. W. R. Meyer, M. C. H. Hogenes, Uta E. Flucke, Winette T. A. van der Graaf, and Yvonne M. H. Versleijen-Jonkers. "PARP inhibition in UV-associated angiosarcoma preclinical models." Journal of Cancer Research and Clinical Oncology 147, no. 9 (June 3, 2021): 2579–90. http://dx.doi.org/10.1007/s00432-021-03678-4.

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Abstract Purpose Angiosarcoma (AS) is a rare vasoformative sarcoma, with poor overall survival and a high need for novel treatment options. Clinically, AS consists of different subtypes, including AS related to previous UV exposure (UV AS) which could indicate susceptibility to DNA damage repair inhibition. We, therefore, investigated the presence of biomarkers PARP1 (poly(ADP-ribose)polymerase-1) and Schlafen-11 (SLFN11) in UV AS. Based on experiences in other sarcomas, we examined (combination) treatment of PARP inhibitor (PARPi) olaparib and temozolomide (TMZ) in UV AS cell lines. Methods Previously collected UV AS (n = 47) and non-UV AS (n = 96) patient samples and two UV AS cell lines (MO-LAS and AS-M) were immunohistochemically assessed for PARP1 and SLFN11 expression. Both cell lines were treated with single agents PARPi olaparib and TMZ, and the combination treatment. Next, cell viability and treatment synergy were analyzed. In addition, effects on apoptosis and DNA damage were examined. Results In 46/47 UV AS samples (98%), PARP1 expression was present. SLFN11 was expressed in 80% (37/46) of cases. Olaparib and TMZ combination treatment was synergistic in both cell lines, with significantly increased apoptosis compared to single agent treatment. Furthermore, a significant increase in DNA damage marker γH2AX was present in both cell lines after combination therapy. Conclusion We showed combination treatment of olaparib with TMZ was synergistic in UV AS cell lines. Expression of PARP1 and SLFN11 was present in the majority of UV AS tumor samples. Together, these results suggest combination treatment of olaparib and TMZ is a potential novel AS subtype-specific treatment option for UV AS patients.

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Coussy, Florence, Rania El-Botty, Sophie Château-Joubert, Ahmed Dahmani, Elodie Montaudon, Sophie Leboucher, Ludivine Morisset, et al. "BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers." Science Translational Medicine 12, no. 531 (February 19, 2020): eaax2625. http://dx.doi.org/10.1126/scitranslmed.aax2625.

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Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors.

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Nakata, Satoshi, Aki NAKATA, Hideaki Yashima, Takuya Araki, Junko Murai, Sumihito Nobusawa, Masayasu Okada, Manabu Natsumeda, and Masahiko Tosaka. "10199-SPDR-2 PERSONALIZED SYNTHETIC LETHALITY INDUCED BY TARGETING ATR-CHK1 IN MEDULLOBLASTOMAS IDENTIFIED BY IMPLEMENTATION OF SLFN11 IMMUNOHISTOCHEMISTRY." Neuro-Oncology Advances 5, Supplement_5 (December 1, 2023): v19. http://dx.doi.org/10.1093/noajnl/vdad141.077.

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Abstract Survival in medulloblastoma varies widely between molecular subgroups, and risk-adapted treatment stratification is necessary. Schlafen family member 11 (SLFN11) defines sensitivity to DNA-damaging therapies in a variety of cancers and may be useful in stratifying medulloblastomas. We previously showed that SLFN11 immunohistochemistry identifies poor-prognosis groups that lack expression; however, the additional treatment for these groups has not been fully elucidated. The serine/threonine kinase ATR (ataxia telangiectasia and Rad3-related) binds to single-stranded DNA upon DNA damage competing with SLFN11 and leads to cell cycle arrest and DNA repair process via Chk1 phosphorylation. Although therapeutic effects of ATR/Chk1 inhibitors on SLFN11-deficient cell lines have been reported in other carcinomas, little is known on brain tumors. In the present study, we investigated the effect of ATR/Chk1 inhibition on SLFN11-negative medulloblastomas. ATR knockdown was introduced to the medulloblastoma cell line DAOY and the isogenic SLFN11-knockout line DYB9, and only DYB9 showed increased sensitivity to cisplatin (Prestoblue assay, p < 0.05, t-test). The ATR inhibitor ceralasertib and the Chk1 inhibitor prexasertib also increased cisplatin and camptothecin sensitivity in DYB9 and SLFN11-low Group 3 medulloblastoma D425. Furthermore, combination therapy with cisplatin and prexasertib inhibited the growth of D425 cerebellar tumors (Akaluc IVIS imaging, p < 0.05, t-test) and prolonged survival of the mice (p < 0.05, Log-rank). Combination therapy with irradiation is currently under investigation. Evaluation of SLFN11 expression in medulloblastoma may lead to new treatment strategies, such as reduced radiation dose for the SLFN11-high groups and the combination therapy with ATR/Chk1 inhibitors for the low-expressing groups.

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Simić, Ivana, Azra Guzonjić, Jelena Kotur Stevuljević, Vesna Ćeriman Krstić, Natalija Samardžić, Katarina Savić Vujović, and Dragana Jovanović. "Correlation of Systemic Inflammation Parameters and Serum SLFN11 in Small Cell Lung Cancer—A Prospective Pilot Study." Biomedicines 12, no. 5 (April 29, 2024): 976. http://dx.doi.org/10.3390/biomedicines12050976.

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Background and objectives: The objective of this research was to analyze the correlation of the neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), soluble programmed cell death ligand 1 (sPD-L1), and Schlafen 11 (SLFN11) with the response to first-line chemotherapy in a cohort of small cell lung cancer (SCLC) patients, and to determine their potential as predictive serum biomarkers. Materials and Methods: A total of 60 SCLC patients were included. Blood samples were taken to determine CRP, sPD-L1, and SLFN11 levels. The first sampling was performed before the start of chemotherapy, the second after two cycles, and the third after four cycles of chemotherapy. Results: The patients who died earlier during the study had NLR and SLFN11 concentrations significantly higher compared to the survivor group. In the group of survivors, after two cycles of chemotherapy, the NLR ratio decreased significantly (p < 0.01), but after four cycles, the NLR ratio increased (p < 0.05). Their serum SLFN11 concentration increased significantly (p < 0.001) after two cycles of chemotherapy, but after four cycles, the level of SLFN11 fell significantly (p < 0.01). CRP, NLR, and SLFN11 were significant predictors of patient survival according to Kaplan–Meier analysis. The combination of inflammatory parameters and SLFN11 with a cutoff value above the 75th percentile of the predicted probability was associated with significantly lower overall survival in SCLC patients (average survival of 3.6 months vs. 4.8 months). Conclusion: The combination of inflammatory markers and the levels of two specific proteins (sPD-L1, SLFN11) could potentially serve as a non-invasive biomarker for predicting responses to DNA-damaging therapeutic agents in SCLC.

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Rathkey, Daniel, Manakamana Khanal, Junko Murai, Jingli Zhang, Manjistha Sengupta, Qun Jiang, Betsy Morrow, et al. "Sensitivity of Mesothelioma Cells to PARP Inhibitors Is Not Dependent on BAP1 but Is Enhanced by Temozolomide in Cells With High-Schlafen 11 and Low-O6-methylguanine-DNA Methyltransferase Expression." Journal of Thoracic Oncology 15, no. 5 (May 2020): 843–59. http://dx.doi.org/10.1016/j.jtho.2020.01.012.

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Conteduca, Vincenza, Loredana Puca, Sheng-Yu Ku, Judy Hess, Megan Kearney, Luisa Fernandez, Rohan Bareja, et al. "SLFN11 expression (exp) in castration-resistant prostate cancer (CRPC) patients (pts) to predict response to platinum-based chemotherapy (PLT)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 5065. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.5065.

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5065 Background: Schlafen family member 11 (SLFN11) sensitizes tumor cells to DNA-damaging agents and has been investigated as a potential predictive biomarker of response to PLT and PARP inhibitors, especially in small cell lung cancer (Lok, CCR 2017; Pietanza, JCO 2018). We aimed to explore the predictive/prognostic role of SLFN11 in PLT-treated CRPC. Methods: We assessed tumor exp of SLFN11 in PLT-treated, metastatic CRPC pts by RNAseq (N=27) and/or CTCs (N=20) (via the Epic Sciences platform). In addition, tumor morphology for neuroendocrine (NE) features and genomic status of select genes (ie, AR, TP53, RB1, BRCA2, BRCA1, ATM) by whole exome sequencing were evaluated. Statistical comparisons used Cox regression analysis and Kaplan Meier method for the association with overall/radiographic progression free survival (OS/rPFS). A dose response curve with PLT was performed in patient-derived organoids using Cell Title Glo according to the manufacturer’s protocol. Results: 41 CRPC (including 20 CRPC-NE) treated with PLT monotherapy (N=3) or PLT combination therapy (N=38) between August 2013 and December 2017 were evaluated. Median age was 67.1 years (range 51-91). Median number of prior therapies was 2 (range 1-7). A longer median rPFS was observed in all SLFN11+ pts treated with PLT (regardless of histology, RB1, TP53, PTEN, or DNA repair status) compared to SLFN11- [5.2 vs 2.3 months, HR 3.5, 95%CI 1.6-7.7, P<0.0001]. No association was reported for OS. On multivariable analysis (Table), SLFN11 was an independent factor associated with rPFS. Organoids derived from patient tumors expressing SLFN11 showed sensitivity to PLT in vitro. Conclusions: SLFN11 exp identifies both CRPC and CRPC-NE pts with a better response to PLT. Patient-derived organoids expressing SLFN11 confirmed increased sensitivity to PLT. Larger prospective evaluation of therapy decisions based on SLFN11 exp is now required. [Table: see text]

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Mellado-Lagarde, Marcia, Sara Michele Federico, Christopher Tinkle, Anang Shelat, and Elizabeth Stewart. "PARP inhibitor combination therapy in desmoplastic small round cell tumors." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e23212-e23212. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23212.

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e23212 Background: Desmoplastic small round cell tumor (DSRCT) is a rare but pernicious mesenchymal neoplasm that expresses the EWS-WT1 gene fusion transcript. It has similar histopathology to Ewing sarcoma (EWS). In previous work, we showed that addition of Poly (ADP-ribose) polymerase 1 and 2 inhibitors (PARPi) to the existing standard of care (SOC) therapy of irinotecan (IRN) and temozolomide (TMZ) was remarkably successful at treating mouse models of EWS, resulting in > 80% complete response compared to 100% mortality with SOC alone. EWS has high levels of the protein Schlafen-11 (SLFN11), a putative biomarker for defective DNA damage repair. The goal of this study is to determine whether DSCRT also expresses SLFN11, and whether high levels of the protein sensitize the tumor to PARPi as single-agent or in combination with other drugs and ionizing radiation. Methods: SLFN11 mRNA and protein levels were assessed by immunohistochemistry, quantitative PCR, Western blot, and immunofluorescence microscopy. Viability of the DSRCT cell line, JN-DSCRT-1, was measured using CellTiterGlo and the colony forming assay. Ionizing radiation (IR) was delivered using an orthovoltage irradiator calibrated to deliver graded doses of 0-16 Gy. Results: We found that SLFN11 was detected at high levels in several DSRCT patient tumor samples, and we confirmed that SLFN11 transcript and protein levels in JN-DSCRT-1were comparable to EWS cell lines. JN-DSCRT-1 demonstrated sensitivity to PARPi as single-agent or in combination with either the topoisomerase I inhibitor irinotecan or ionizing radiation comparable to EWS cell lines. To supplement our in vitro studies and to utilize more accurate models of the clinical disease, we developed orthotopic patient derived xenograft models (O-PDX) from three patients with DSCRT. Preliminary findings suggest that these O-PDX models maintain SLFN11 expression and recapitulate important aspects of DSRCT biology, including widespread dissemination of tumor in the abdominal cavity and characteristic cellular phenotype. Preclinical in vivo efficacy studies with PARPi combinations are in progress. Conclusions: Our work suggests that DSCRT expresses the SLFN11 biomarker and is sensitive to PARPi combination therapy.

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Toivanen, Kirsi L. J., Astrid Murumägi, Mariliina A. Arjama, Nanna J. Merikoski, Sami I. Salmikangas, Olli P. Kallioniemi, Tom O. Böhling, and Harri J. Sihto. "Abstract B028: Phosphodiesterase 3A modulators sensitize tumor cells to Bcl-2/Bcl-xL inhibitors." Molecular Cancer Therapeutics 22, no. 12_Supplement (December 1, 2023): B028. http://dx.doi.org/10.1158/1535-7163.targ-23-b028.

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Abstract Phosphodiesterase 3A (PDE3A) modulators are promising anticancer agents for tumors that coexpress PDE3A and Schlafen 12 (SLFN12), including sarcomas. The cytotoxic effect of these modulators is based on their ability to form a complex between PDE3A and SLFN12, and correlates with the expression levels of the two proteins. In cases where the two proteins are only moderately expressed, PDE3A modulator efficacy may remain poor and additional therapeutic options are needed. In this study, we investigated the combinatorial effects of a PDE3A modulator, anagrelide, with 526 other oncological compounds in two PDE3A and SLFN12 expressing liposarcoma cell lines (SA4 and GOT3). Both cell lines were responsive to PDE3A modulators, as expected. Interestingly, we found synergy with seven different drug classes that can be grouped based on their protein and protein family targets: Bcl-2l/Bcl-xL, HDAC, integrin α2 (ITGA2), mTOR, NEDD-activating enzyme E1 regulatory subunit proteins, and PAK. Additional detailed drug combination synergy studies in PDE3A modulator –sensitive liposarcoma, gastrointestinal stromal tumor, melanoma, and astrocytoma cell lines indicated a sensitizing effect of PDE3A modulators to Bcl-2/Bcl-xL inhibitors. These cell lines, excluding GOT3, showed no response to Bcl-2/Bcl-xL inhibitors otherwise. Furthermore, we discovered that the sensitization effect depends on the coexpression of PDE3A and SLFN12, and that cotreatment resulted in stronger activation of programmed cell death. Our findings suggest additional combinatorial opportunities between PDE3A modulators and inhibitors of key cancer pathways that could be explored for their therapeutic value. Citation Format: Kirsi L. J. Toivanen, Astrid Murumägi, Mariliina A. Arjama, Nanna J. Merikoski, Sami I. Salmikangas, Olli P. Kallioniemi, Tom O. Böhling, Harri J. Sihto. Phosphodiesterase 3A modulators sensitize tumor cells to Bcl-2/Bcl-xL inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B028.

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Shelat, Anang, Christopher Tinkle, Elizabeth Stewart, Sara Michele Federico, Brandon Bianski, and Marcia Mellado-Lagarde. "A biomarker-guided approach to combining PARP inhibitors with radiotherapy in pediatric solid tumors." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 10556. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.10556.

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10556 Background: Ewing sarcoma (EWS) expresses high levels of Schlafen-11 (SLFN11). SLFN11 disrupts checkpoint maintenance and may serve as a biomarker to assess sensitivity to Poly (ADP-ribose) polymerase 1 and 2 inhibitors (PARPi). The goal of this study is to evaluate SLFN11 protein expression in a panel of pediatric solid tumors and correlate levels of protein with sensitivity to PARP inhibition combined with ionizing radiation (IR), a component of therapy for many pediatric solid tumors and a potent inducer of DNA damage. Methods: SLFN11 mRNA and protein levels were assessed by quantitative RT-PCR, and immunohistochemistry, Western blot, and immunofluorescence microscopy, respectively. PARPi included: talazoparib (TAL), niraparib (NIR), veliparib (VEL), and olaparib (OLA). Approximately 30 minutes after addition of systemic therapy, graded doses of radiation were delivered and viability across a panel of pediatric solid tumor cell lines was measured using the ATP-based Cell TiterGlo assay and confirmed with the colony formation assay. Results: We found that SLFN11 mRNA and protein is expressed at high levels in EWS, and SLFN11 is also variably present in a subset of other pediatric solid tumor lines, including desmoplastic small round cell tumor, osteosarcoma, and rhabdomyosarcoma. In all tumor cells with detectable SLFN11 expression, viability was reduced by greater than 90% when exposed to 2Gy IR and 1-10nM TAL, whereas cells with undetectable levels of SLFN11 were 5-10 times less sensitive. Intriguingly, variation in the potentiation between specific PARPi and IR correlated with the ability to form drug-induced PARP-DNA adducts, with the strong PARP trapper TAL showing ~10-fold higher potency compared to the moderate trapper NIR, and ~300-fold more potency relative to the weak trapper VEL. Consistent with our PARPi findings, the toposiomerase 1 inhibitor irinotecan, which also forms DNA adducts, potentiated with IR similarly to TAL at concentrations < 10nM in tumor cells expressing detectable levels of SLFN11. Conclusions: SLFN11 is present in select pediatric solid tumors and may induce a DNA repair defect that is best exploited by combining low-doses of TAL and irinotecan with IR.

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Ingham, Matthew, Jacob B. Allred, Katherine Gano, Suzanne George, Steven Attia, Melissa Amber Burgess, Sosipatros Alexandros Boikos, et al. "NCI protocol 10250: A phase II study of temozolomide and olaparib for the treatment of advanced uterine leiomyosarcoma." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS11570. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps11570.

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TPS11570 Background: Soft tissue sarcoma (STS) is a heterogenous malignancy of mesenchymal origin and includes more than 50 biologically distinct subtypes. Leiomyosarcoma (LMS), a neoplasm of smooth muscle origin, represents up to 20% of STS. The uterus is the most common site of origin in women. Advanced uterine LMS (uLMS) is initially treated with gemcitabine + docetaxel or anthracycline-based chemotherapy but overall survival remains < 24 mos. Besides recurrent alterations in RB1, TP53 and ATRX, insight into cancer biology of uLMS remains limited. Recently, whole exome and transcriptomic sequencing studies suggest uLMS harbors characteristic defects in the homologous recombination (HR) DNA repair pathway and thus features of BRCAness. HR-deficient cancers are unable to efficiently repair double-stranded DNA breaks and appear sensitive to treatment with poly ADP-ribose polymerase (PARP) inhibitors. In preclinical studies, the combination of temozolomide (T), an alkylating agent, and olaparib (O), a PARP inhibitor, was synergistic and markedly suppressed proliferation of uLMS models. A recent phase II study in small cell lung cancer defined the RP2D for T + O where the chief toxicity was myelosuppression. Methods: NCI Protocol #10250 is a single-arm, open-label, multi-center phase II clinical trial of T + O in patients with advanced uLMS. Eligible pts have ECOG PS ≤ 2, progression on ≥ 1 prior line of therapy and disease measurable by RECIST v1.1 and amenable to image-guided biopsy. Pts receive T 75 mg/m2 PO daily + O 200 mg PO BID on days 1-7 in 21-day cycles. The 1° endpoint is objective response rate (ORR). A one-stage binomial design is used to evaluate for an ORR ≤ 10% (null hypothesis) versus ≥ 35% (alternative hypothesis). The design calls for 22 patients. If 5/22 respond, the treatment is promising. This design yields 93% power and 1-sided type I error of 6%. 2° endpoints include progression free survival and safety. All pts undergo tumor biopsies pre-treatment and during cycle 2. Tissue is used for correlative analysis interrogating uLMS for features of BRCAness through (a) whole exome sequencing/RNAseq to evaluate for alterations in HR pathway component genes, (b) RAD51 foci formation by immunohistochemistry as a functional marker of HR pathway activity and (c) protein expression of Schlafen family member number 11 (SLFN11), an emerging biomarker for PARPi. Tumors are also evaluated for MGMT protein expression, a known determinant of sensitivity to T. The study opened to accrual 10/2019. Clinical trial information: NCT03880019.

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Zhao, Ming, Timothy P. DiPeri, Gabriela Raso, Yasmeen Q. Rizvi, Xiaofeng Zheng, Kurt Evans, Argun Akcakanat, et al. "Abstract 1791: Epigenetically upregulating TROP2 enhances therapeutic efficacy of TROP2 ADC sacitizumab govitecan." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1791. http://dx.doi.org/10.1158/1538-7445.am2022-1791.

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Abstract Purpose: TROP2 is overexpressed in many tumor types and is being actively pursued as a target. Sacituzumab govitecan (SG), a humanized anti-TROP2 antibody conjugated with SN-38, was approved for treatment of metastatic triple negative breast cancer, with the greatest efficacy in patients with medium or high TROP2 levels. We sought to enhance efficacy of TROP2-targeted therapies by pharmacological regulation of TROP2 expression. Methods: TROP2 levels were assessed by immunohistochemistry (IHC) in two sets of breast tumors: a set of surgical samples and a tissue microarray. TROP2 mRNA expression was assessed in surgical samples and breast cancer patient-derived xenografts (PDXs) with RNAseq and assessed in the TCGA. In cell lines, expression of TROP2, E-cadherin (E-cad), and Schlafen family member 11 (SLFN11) were assessed by immunoblotting and qPCR following drug treatment or cell line manipulation. Epithelial-mesenchymal transition was evaluated by cell migration, cell invasion, and anchorage-independent growth assays. Antitumor efficacy of drug combination was assessed by cell survival, cell colony formation, and apoptosis assays. Results: By IHC, TROP2 was expressed in only 40% of metaplastic breast cancers (MpBC), but nearly all non-MpBC tumors. TCGA database evaluation further showed higher TROP2 levels in non-MpBC tumors than metaplastic tumors. In breast cancer surgical specimens, breast cancer PDXs, and the TCGA, there was a strong correlation between TROP2 and E-cad expression. In vitro, we demonstrated that downregulating transcriptional factor zinc finger E-box binding homeobox 1 (ZEB1) led to mesenchymal-epithelial transition with upregulation of both E-cad and TROP2 expression in breast cancer cells, leading to increased sensitivity to SG treatment. Screening of epigenetic modulators identified DNA methyltransferase inhibitor decitabine as an enhancer of TROP2 and E-cad expression in PDX cell lines of metaplastic cancer origin and mesenchymal subtype breast cancer cell lines. Decitabine increased TROP2 expression by decreasing TROP2 promoter methylation. Decitabine was significantly synergistic with SG, and enhanced apoptosis. Similarly, overexpression of TROP2 (by plasmid) in cell lines enhanced activity of SG. Furthermore, decitabine increased expression of SLFN11, a putative biomarker of SN38 sensitivity, and was synergistic with SG in TROP2 expressing, SLFN11 low breast cancer cell lines. Conclusion: TROP2 is expressed in most breast cancers, but is expressed less frequently in MpBC, an aggressive subtype unresponsive to traditional therapies. Epigenetic modulator decitabine upregulates TROP2 and SLFN11 expression and enhances antitumor efficacy of SG. Combinatorial treatment of TROP2 ADCs with epigenetic modulators of TROP2 represent a novel therapeutic strategy for tumors with low TROP2 or SLFN11 expression. Citation Format: Ming Zhao, Timothy P. DiPeri, Gabriela Raso, Yasmeen Q. Rizvi, Xiaofeng Zheng, Kurt Evans, Argun Akcakanat, Fei Yang, Debu Tripathy, Ecaterina Ileana Dumbrava, Senthil Damodaran, Funda Meric-Bernstam. Epigenetically upregulating TROP2 enhances therapeutic efficacy of TROP2 ADC sacitizumab govitecan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1791.

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Wang, Yinu, Xiaolei Situ, Horacio Cardenas, and Daniela Matei. "Abstract 5467: NTX301 targets platinum resistant ovarian cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5467. http://dx.doi.org/10.1158/1538-7445.am2022-5467.

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Abstract Background: The majority of patients with ovarian cancer (OC) experience tumor relapse and develop chemoresistant tumors, which are fatal. Epigenetic alterations, especially DNA methylation, result in silencing of tumor suppressor and differentiation-associated genes, confer chemoresistance and are linked to stemness. Although our and others’ previous studies demonstrated that hypomethylating agents (HMA) could re-sensitize OC cells to chemotherapy, translation to the clinic has been slow due the poor stability and bioavailability of existing HMAs. Novel agents are critically needed. Methods: NTX 301 is a novel, highly potent and orally bioavailable HMA, in early clinical development, provided by PinotBio. Here, we assessed its anti-tumor effects in OC models by using cell proliferation, stemness assays, and RNA sequencing and validation. Results: OC cells (SKOV3, IC50=5.089nM; OVCAR4, IC50=29.68nM; and OVCAR5 IC50=3.664nM) were highly sensitive to NTX301 (p<0.05) compared to immortalized fallopian tube epithelial cells (FT-190) (IC50=103.3nM). Treatment with NTX301 induced more significant downregulation of the DNA methyltransferases (DNMTs) 1-3 expression in SKOV3 and OVCAR5 cells compared with decitabine (p<0.05). Treatment with low dose NTX301 (100nM) reset the transcriptome of OC cells, inducing about 15,000 differentially expressed genes (DEGs) compared to DMSO (P<0.05). Gene Ontology Enrichment analysis classified upregulated DEGs enriched in biological processes related to cellular response to DNA damage stimulus, DNA repair, positive regulation of cell cycle process; down-regulated DEGs enriched in processes of regulation of alcohol, cholesterol, and fatty acid biosynthesis and regulation of cell migration. GO analysis indicated NTX301 down-regulated molecular functions related to aldehyde dehydrogenase (ALDH) and oxidoreductase activity, known features of cancer stem cells (CSCs). Indeed, treatment with low dose NTX301 (100nM, 4 days) reduced ALDH(+) cell population, inhibited their self-renewal ability, and repressed the stemness-related transcription factor, Sox2 (P<0.05). We next tested the effects NTX301 in cisplatin (CDDP) resistant OC cells, developed by repeated treatments with CDDP. Priming with NTX301 reduced the IC50 (~two-fold) to CDDP in OVCAR5_CDDP (5.43μM vs. 9.79μM) and OVCAR4_CDDP (2.19μM vs. 9.29μM) resistant cells (p<0.05). NTX301 with CDDP induced phospho-γH2AX and cleaved caspase 3. To discover the mechanisms by which NTX301 restored chemosensitivity, we measured its effects on Schlafen-11 (SLFN11), a DNA damage response regulator silenced through methylation. SLFN11 expression was repressed in CDDP resistant compared to parental cells (P<0.05) and treatment with NTX301 induced its re-expression (P<0.05). Conclusions: Our data indicate that NTX301 is a potent HMA which targets ovarian CSCs and re-sensitizes OC cells to chemotherapy, supporting its further development in OC. Citation Format: Yinu Wang, Xiaolei Situ, Horacio Cardenas, Daniela Matei. NTX301 targets platinum resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5467.

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Abdel Karim, Nagla Fawzy, Jieling Miao, Karen L. Reckamp, Carl Michael Gay, Lauren Averett Byers, Yingqi Zhao, Mary Weber Redman, et al. "SWOG S1929: Phase II randomized study of maintenance atezolizumab (A) versus atezolizumab + talazoparib (AT) in patients with SLFN11 positive extensive stage small cell lung cancer (ES-SCLC)." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 8504. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.8504.

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8504 Background: In unselected patients (pts) with extensive-stage small cell lung cancer (ES-SCLC), the addition of immune checkpoint inhibitors (ICI) to chemotherapy resulted in a modest improvement in OS. In a retrospective analysis of a study with veliparib (PARP inhibitor [PARPi]) and temozolomide in patients with SCLC, Schlafen-11 (SLFN11) predicted PFS and OS benefit for the addition of PARPi. We evaluated whether the addition of PARPi (talazoparib) to standard-of-care maintenance ICI (atezolizumab) following frontline chemoimmunotherapy improved outcomes in pts with SLFN11-positive ES-SCLC. Methods: Participants with ES-SCLC expressing SLFN11 (H-score ≥ 1, evaluated centrally at MDACC) were randomized to maintenance atezolizumab (A) versus atezolizumab plus talazoparib (AT) following frontline chemotherapy and A. Randomization was stratified by Zebrod PS (0-1 vs 2) and use of consolidation thoracic radiation. The primary endpoint was PFS, and secondary endpoints included ORR, OS, and toxicity. The primary analysis was done using a 1-sided 10% level stratified log-rank test. Target sample size was 94 pts. Results: From June 2020 to December 2022, 309 pts were screened, of which 204 of 259 (79%) with evaluable tissue were SLFN11 positive, and 106 were randomized (52 A, 54 AT). Median follow up time is 5 months. Median age was 67 (45-84); 51 (48%) were females; 94 (89%) were white,102 (96%) were PS 0-1, and 26 (25%) had radiation prior to randomization. With 80 PFS events reported, PFS was significantly improved with AT (hazard ratio [80% CI]: 0.70 [0.52-0.94]; p = 0.056). Median PFS was 2.8 months (80% CI 2.0-2.9) for A and 4.2 months (80% CI 2.8-4.7) for AT. OS was not different (hazard ratio [80% CI]: 1.17 [0.80-1.71]; p = 0.30). Median OS was 8.5 months (80 % CI 7.4-12.7) for A and 9.4 months (80% CI 8.1-14.2) for AT. ORR was 16% (5/32, 80% CI 8-27%) for A and 12% (4/34, 80% CI 5-22%) for AT. Grade 3 or greater treatment related non-hematological adverse events (AEs) occurred in 13% pts in A and 15% in AT. Hematological AEs occurred 4% in A compared to 50% pts in AT (Expected for T) (p < 0.001). There were no treatment related grade 5 events. One participant on AT experienced grade 3 febrile neutropenia. The majority of grade 3 AEs were due to anemia (2% in A and 37% in AT). Only three pts discontinued treatment due to toxicity (2 in A and 1 in AT). Conclusions: This study met its primary endpoint demonstrating that maintenance AT improved PFS in SLFN11-selected patients with ES-SCLC. Hematologic toxicity was increased with AT as expected, with majority being grade 3 anemia. This study demonstrates the feasibility of conducting biomarker selected trials in SCLC, paving the way for future evaluation of novel therapies in selected SCLC populations. Clinical trial information: NCT04334941 .

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Gupta, Aparna, Kedar S. Vaidya, Janneke J. T. M. Melis, Robert Hauptschein, Graham Brock, and Robin Humphreys. "Abstract 2145: High SLFN11 expression correlates with sensitivity to lurbinectedin in small cell lung cancer (SCLC) models." Cancer Research 83, no. 7_Supplement (April 4, 2023): 2145. http://dx.doi.org/10.1158/1538-7445.am2023-2145.

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Abstract Background: Lurbinectedin monotherapy received accelerated FDA approval for adults with metastatic SCLC with disease progression on or after platinum-based chemotherapy. Lurbinectedin binds to GC-rich areas of gene promoters, blocks RNA-polymerase-II and induces degradation via ubiquitin/proteasome machinery. DNA binding of lurbinectedin results in double stranded DNA breaks and DNA damage that leads to cellular apoptosis. Schlafen 11 (SLFN11), a putative DNA/RNA helicase irreversibly binds to DNA replication forks resulting in replication block and is a predictive biomarker of response to therapeutics that elicit DNA damage including cisplatin, topoisomerase I/II inhibitors and PARP inhibitors. Objective: Evaluate the role of SLFN11 expression in predicting response to lurbinectedin, a DNA damaging agent, in human SCLC cell lines and in vivo models. Methods: Cytotoxicity assays: SCLC cell lines DMS 53, DMS 114, NCI-H69, NCI-H82, NCI-H196, NCI-H209, NCI-H211, NCI-H446, NCI-H526, NCI-H841, NCI-H889, NCI-H1048, and SHP-77 were tested with lurbinectedin dose range from 100 nM to 0.01 nM. Cell viability was determined by measuring intracellular ATP to determine percent cellular viability and IC50 of lurbinectedin. SLFN11 expression of 13 SCLC cell lines were retrieved as RNAseq values from the DepMap database. RNAseq value >2 was assigned as SLFN11 high, values <2 assigned as low. Western blot analysis was used to confirm protein expression. The difference in 10log IC50 between SLFN11 high and low lines is determined using Mann-Whitney test. In vivo efficacy studies: High SLFN11 (NCI-H1048) and low SLFN11 (NCI-H889 and NCI-H69) SCLC cell lines were used for xenograft studies in BALB/c nude mice. Mice were randomly allocated to 4 groups (n=8) as tumors reached a volume of 100 - 150 mm3. Groups received either vehicle or lurbinectedin at doses of 0.06, 0.12 or 0.18 mg/kg IV, QWx 3 weeks. Immunohistochemistry was used to assess SLFN11 protein expression on xenograft tissue. Results and Conclusions: Cell viability assays in 13 SCLC models confirm high SLFN11 expressing cell lines are 4-fold more sensitive to lurbinectedin compared to low SLFN11 expressing cell lines (ΔpIC50 = 0.64; p = 0.0451). The in vivo efficacy data confirms that the SLFN11 high NCI-H1048 model is more responsive with 90% TGI compared to 35% observed in SLFN11 low models (NCI-H889 and NCI-H69) at the highest lurbinectedin dose (p-value = 0.006). Efficacy data confirms correlation to SLFN11 protein expression, consistent with the RNA level association. Both in vitro cytotoxicity and in vivo efficacy studies in SCLC models confirm that high SLFN11 expression predicts response to lurbinectedin. Cell viability studies demonstrate that a limited set of SLFN11 low expressing cell lines are sensitive to lurbinectedin, suggesting a role for other genes. Proteomics and genomics work is underway to define additional response biomarkers Citation Format: Aparna Gupta, Kedar S. Vaidya, Janneke J.T.M. Melis, Robert Hauptschein, Graham Brock, Robin Humphreys. High SLFN11 expression correlates with sensitivity to lurbinectedin in small cell lung cancer (SCLC) 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 2145.

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Yuca, Erkan, Kurt Evans, Argun Akcakanat, Gabriela Raso, Yasmeen Q. Rizvi, Fei Yang, Lauren Byers, Senthil Damodaran, Okajima Daisuke, and Funda Meric-Bernstam. "Abstract 1768: Anti-tumor activity and biomarker analysis for datopotamab deruxtecan in breast cancer PDX models." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1768. http://dx.doi.org/10.1158/1538-7445.am2022-1768.

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Abstract Background: Trophoblast cell surface antigen (TROP2), is expressed on many tumors including breast cancer, thus TROP2 antibody drug conjugates are being pursued as a therapeutic strategy. Datopotamab deruxtecan (Dato-DXd) is composed of a humanized anti-TROP2 IgG1 monoclonal antibody attached to a highly potent topoisomerase I inhibitor payload (an exatecan derivative DXd) via a stable tetrapeptide-based cleavable linker. Dato-DXd has shown promise in the treatment of TROP2 expressing lung and breast cancers. However, the role of TROP2 as a predictor of therapeutic sensitivity is yet to be elucidated. We sought to determine efficacy of Dato-DXd in breast cancer patient-derived xenografts (PDXs) as well as explore biomarkers of response and combinations with PARP inhibitors. Methods: Membrane expression of TROP2 was assessed in 31 breast cancer PDXs and matching patient tumors by immunohistochemistry (IHC). Schlafen family member 11 (SLFN11) nuclear expression was also assessed by IHC. The antitumor efficacy of two doses (1 and 10 mg/kg, q3wk, IV) of Dato-DXd and the isotype control-DXd (IgG-DXd) were tested against 9 breast cancer PDXs derived from residual tumors after neoadjuvant chemotherapy. The PDXs represented a range of TROP2 expression levels, including 3 TROP2 negative/low PDXs. The antitumor activity of Dato-DXd in combination with PARP inhibition (olaparib) was assessed in 3 PDXs with intermediate Dato-DXd activity. Tumor volumes were measured twice weekly; antitumor activity was assessed by treatment-to-control ratio (T/C) and event-free survival (EFS-2). T/C ratio was calculated as (Vt,21/Vt,0)/(Vc,21/Vc,0), where t = treatment, c = control (no treatment or IgG-DXd), and V = tumor volume (mm3). Stable disease (SD) and response (R) were based on day 21 (-30- to 20% and <-30%, respectively). An event was defined as tumor doubling. Results: TROP2 H-score in PDXs correlated with TROP2 expression in matched patients (r= 0.7264, p<0.0001), however expression was lower in PDXs (p= 0.04). Dato-DXd caused R/SD in 2 of 9 models at 1 mg/kg, and in 4 of 9 models at 10 mg/kg. All models that regressed with Dato-DXd expressed TROP2. TROP2 expression was associated with higher antitumor activity compared to IgG-DXd based on T/C ratio (r= -0.7448, p= 0.0213) and EFS-2 (r= 0.9318, p= 0.0068) at 10 mg/kg but not at 1 mg/kg. Three models with low TROP2 expression had >50% SLFN11 positivity in the nucleus by IHC; 2 of 3 had doubling of EFS-2 both by Dato-DXd and IgG-DXd. The combination of Dato-DXd and olaparib had improved activity over single agents in 2 of 3 models. Additional comparative predictive and pharmacodynamic biomarker studies will be presented. Conclusion: Dato-DXd is a promising therapy for breast cancer patients including those resistant to standard chemotherapy. Additional biomarkers may better integrate DXd sensitivity into patient selection. Citation Format: Erkan Yuca, Kurt Evans, Argun Akcakanat, Gabriela Raso, Yasmeen Q. Rizvi, Fei Yang, Lauren Byers, Senthil Damodaran, Okajima Daisuke, Funda Meric-Bernstam. Anti-tumor activity and biomarker analysis for datopotamab deruxtecan in breast cancer PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1768.

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Valdez, Federico, Julienne Salvador, Pedro M. Palermo, Jonathon E. Mohl, Kathryn A. Hanley, Douglas Watts, and Manuel Llano. "Schlafen 11 Restricts Flavivirus Replication." Journal of Virology 93, no. 15 (May 22, 2019). http://dx.doi.org/10.1128/jvi.00104-19.

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ABSTRACTSchlafen 11 (Slfn11) is an interferon-stimulated gene that controls the synthesis of proteins by regulating tRNA abundance. Likely through this mechanism, Slfn11 has previously been shown to impair human immunodeficiency virus type 1 (HIV-1) infection and the expression of codon-biased open reading frames. Because replication of positive-sense single-stranded RNA [(+)ssRNA] viruses requires the immediate translation of the incoming viral genome, whereas negative-sense single-stranded RNA [(−)ssRNA] viruses carry at infection an RNA replicase that makes multiple translation-competent copies of the incoming viral genome, we reasoned that (+)ssRNA viruses will be more sensitive to the effect of Slfn11 on protein synthesis than (−)ssRNA viruses. To evaluate this hypothesis, we tested the effects of Slfn11 on the replication of a panel of ssRNA viruses in the human glioblastoma cell line A172, which naturally expresses Slfn11. Depletion of Slfn11 significantly increased the replication of (+)ssRNA viruses from theFlavivirusgenus, including West Nile virus (WNV), dengue virus (DENV), and Zika virus (ZIKV), but had no significant effect on the replication of the (−)ssRNA viruses vesicular stomatitis virus (VSV) (Rhabdoviridaefamily) and Rift Valley fever virus (RVFV) (Phenuiviridaefamily). Quantification of the ratio of genome-containing viral particles to PFU indicated that Slfn11 impairs WNV infectivity. Intriguingly, Slfn11 prevented WNV-induced downregulation of a subset of tRNAs implicated in the translation of 11.8% of the viral polyprotein. Low-abundance tRNAs might promote optimal protein folding and enhance viral infectivity, as previously reported. In summary, this study demonstrates that Slfn11 restricts flavivirus replication by impairing viral infectivity.IMPORTANCEWe provide evidence that the cellular protein Schlafen 11 (Slfn11) impairs replication of flaviviruses, including West Nile virus (WNV), dengue virus (DENV), and Zika virus (ZIKV). However, replication of single-stranded negative RNA viruses was not affected. Specifically, Slfn11 decreases the infectivity of WNV potentially by preventing virus-induced modifications of the host tRNA repertoire that could lead to enhanced viral protein folding. Furthermore, we demonstrate that Slfn11 is not the limiting factor of this novel broad antiviral pathway.

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Murai, Junko, Michele Ceribelli, Haiqing Fu, Christophe E. Redon, Ukhyun Jo, Yasuhisa Murai, Mirit I. Aladjem, Craig J. Thomas, and Yves Pommier. "Schlafen 11 (SLFN11) kills cancer cells undergoing unscheduled re-replication." Molecular Cancer Therapeutics, May 22, 2023. http://dx.doi.org/10.1158/1535-7163.mct-22-0552.

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Abstract SLFN11 is an increasingly prominent predictive biomarker and a molecular sensor for a wide range of clinical drugs: topoisomerases, PARP and replication inhibitors, and platinum derivatives. To expand the spectrum of drugs and pathways targeting SLFN11, we ran a high-throughput screen (HTS) with 1,978 mechanistically-annotated, oncology-focused compounds in two isogenic pairs of SLFN11-proficient and -deficient cells (CCRF-CEM and K562). We identified 29 hit compounds that selectively kill SLFN11-proficient cells, including not only previously known DNA-targeting agents, but also the neddylation inhibitor Pevonedistat (MLN-4924) and the DNA polymerase alpha inhibitor AHPN/CD437, which both induced SLFN11 chromatin recruitment. By inactivating cullin-ring E3 ligases, Pevonedistat acts as an anticancer agent partly by inducing unscheduled re-replication through supra-physiological accumulation of CDT1, an essential factor for replication initiation. Unlike the known DNA-targeting agents and AHPN/CD437 that recruit SLFN11 onto chromatin in 4 hours, Pevonedistat recruited SLFN11 at late time points (24 hours). While Pevonedistat induced unscheduled re-replication in SLFN11-deficient cells after 24 hours, the re-replication was largely blocked in SLFN11-proficient cells. The positive correlation between sensitivity to Pevonedistat and SLFN11 expression was also observed in non-isogenic cancer cells in three independent cancer cell databases (NCI-60, CTRP: Cancer Therapeutics Response Portal and GDSC: Genomic of Drug Sensitivity in Cancer). The present study reveals that, in addition to sensing stressed replication, SLFN11 blocks unscheduled re-replication provoked by Pevonedistat, which augments the anti-cancer effect of Pevonedistat. It also suggests SLFN11 as a potential predictive biomarker for Pevonedistat in ongoing and future clinical trials.

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Takashima, Tsuyoshi, Daiki Taniyama, Naoya Sakamoto, Maika Yasumoto, Ryuichi Asai, Takuya Hattori, Ririno Honma, et al. "Schlafen 11 predicts response to platinum-based chemotherapy in gastric cancers." British Journal of Cancer, March 30, 2021. http://dx.doi.org/10.1038/s41416-021-01364-3.

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Fujiwara, Kohei, Masashi Maekawa, Yuki Iimori, Akane Ogawa, Takeshi Urano, Nobuaki Kono, Hiroyuki Takeda, Shigeki Higashiyama, Makoto Arita, and Junko Murai. "The Crucial Role of Single-Stranded DNA Binding in Enhancing Sensitivity to DNA-Damaging Agents for Schlafen 11 and Schlafen 13." iScience, November 2023, 108529. http://dx.doi.org/10.1016/j.isci.2023.108529.

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Watanabe, Sho, Ryu Nishimura, Tomoaki Shirasaki, Nobuhiro Katsukura, Shuji Hibiya, Susumu Kirimura, Mariko Negi, et al. "Schlafen 11 Is a Novel Target for Mucosal Regeneration in Ulcerative Colitis." Journal of Crohn's and Colitis, February 17, 2021. http://dx.doi.org/10.1093/ecco-jcc/jjab032.

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Abstract Background and Aims Ulcerative colitis [UC] is a chronic inflammatory disease of the colon with an intractable course. Although the goal of UC therapy is to achieve mucosal healing, the pathogenesis of mucosal injury caused by chronic inflammation remains unknown. We therefore aim to elucidate molecular mechanisms of mucosal injury by establishing in vitro and in vivo humanised UC-mimicking models. Methods An in vitro model using human colon organoids was established by 60 weeks of inflammatory stimulation. The key gene for mucosal injury caused by long-term inflammation was identified by microarray analysis. An in vivo model was established by xenotransplantation of organoids into mouse colonic mucosa. Results An in vitro model demonstrated that long-term inflammation induced irrecoverable changes in organoids: inflammatory response and apoptosis with oxidative stress and suppression of cell viability. This model also mimicked organoids derived from patients with UC at the gene expression and phenotype levels. Microarray analysis revealed Schlafen11 [SLFN11] was irreversibly induced by long-term inflammation. Consistently, SLFN11 was highly expressed in UC mucosa but absent in normal mucosa. The knockdown of SLFN11 [SLFN11-KD] suppressed apoptosis of intestinal epithelial cells [IECs] induced by inflammation. Moreover, SLFN11-KD improved the take rates of xenotransplantation and induced the regenerative changes of crypts observed in patients with UC in remission. Conclusions In vitro and in vivo UC-mimicking models were uniquely established using human colonic organoids. They revealed that SLFN11 is significant for mucosal injury in UC, and demonstrated its potential as a novel target for mucosal regeneration.

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Poets, Christian F., Ekkehart Paditz, Thomas Erler, Axel Hübler, Julia Jückstock, Mirja Quante, Jan Pauluschke-Fröhlich, et al. "Prävention des plötzlichen Säuglingstods (SIDS, „sudden infant death syndrome“, ICD 10: R95)." Monatsschrift Kinderheilkunde, March 8, 2023. http://dx.doi.org/10.1007/s00112-023-01724-8.

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ZusammenfassungDieser Beitrag fasst die Datenlage zu den wichtigsten Handlungsanweisungen für Eltern bezüglich der Gewährleistung einer sicheren Schlafumgebung für Säuglinge zusammen. Hierzu gehören folgende: 1. Legen Sie Ihr Kind zum Schlafen auf den Rücken; benutzen Sie dabei eine feste und waagerechte Unterlage. 2. Legen Sie Ihr Kind tagsüber, solange es wach ist und Sie es gut beobachten können, regelmäßig für kurze Zeit auch auf den Bauch. 3. Vermeiden Sie Überwärmung: Während der Nacht ist eine Raumtemperatur von 18 °C optimal, anstelle einer Bettdecke empfiehlt sich die Verwendung eines Baby-Schlafsacks in altersentsprechender Größe. 4. Falls Sie keinen Schlafsack verwenden möchten, achten Sie darauf, dass Ihr Kind nicht mit dem Kopf unter die Bettdecke rutschen kann, indem Sie es so ins Bett legen, dass es mit den Füßen am Fußende anstößt. 6. Verzichten Sie auf Kopfkissen, Fellunterlagen, „Nestchen“, gepolsterte Bettumrandungen und größere Kuscheltiere, mit denen sich Ihr Kind überdecken könnte. 7. Wickeln Sie Ihr Kind zum Schlafen nicht fest ein. 8. lassen Sie Ihr Kind bei sich im Zimmer, aber im eigenen Kinderbett schlafen. 9. Achten Sie auf eine rauchfreie Umgebung für Ihr Kind auch schon während der gesamten Schwangerschaft. 10. Stillen Sie im 1. Lebensjahr, möglichst mindestens 4 bis 6 Monate. 11. Bieten Sie Ihrem Kind zum Schlafengehen einen Schnuller an. 12. Diese Empfehlungen gelten auch für die Zeit unmittelbar nach Geburt: Sollte Ihr Kind auf Ihrem Körper liegen, achten Sie darauf, dass es stets freie Atemwege hat.

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