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BIOMARKER:

SLFN11 overexpression

i
Other names: SLFN11, Schlafen Family Member 11,SLFN8/9
Entrez ID:
Related biomarkers:
2ms
RAISE: Niraparib Added to Anti-PD-L1 Antibody Maintenance in SLFN11-positive, Extensive-disease SCLC (clinicaltrials.gov)
P2, N=44, Recruiting, ETOP IBCSG Partners Foundation | Not yet recruiting --> Recruiting
Enrollment open
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SLFN11 (Schlafen Family Member 11)
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SLFN11 expression • SLFN11 overexpression
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Zejula (niraparib)
2ms
RAISE: Niraparib Added to Anti-PD-L1 Antibody Maintenance in SLFN11-positive, Extensive-disease SCLC (clinicaltrials.gov)
P2, N=44, Not yet recruiting, ETOP IBCSG Partners Foundation | Initiation date: Dec 2023 --> Mar 2024
Trial initiation date
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SLFN11 (Schlafen Family Member 11)
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SLFN11 expression • SLFN11 overexpression
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Zejula (niraparib)
3ms
SLFN11 promotes clear cell renal cell carcinoma progression via the PI3K/AKT signaling pathway. (PubMed, Med Oncol)
Finally, we demonstrated that miR-183 may specifically target SLFN11, and miR-183 expression was correlated with predicted survival. SLFN11 may play a critical role in ccRCC progression and may serve as a novel prognostic biomarker in ccRCC.
Journal
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SLFN11 (Schlafen Family Member 11) • MIR183 (MicroRNA 183)
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SLFN11 overexpression
5ms
Schlafen11 is a powerful biomarker of chemosensitivity in medulloblastomas (SNO 2023)
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.
SLFN11 (Schlafen Family Member 11)
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SLFN11 expression • SLFN11 overexpression
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cisplatin • RG2833
10ms
RAISE: Niraparib Added to Anti-PD-L1 Antibody Maintenance in SLFN11-positive, Extensive-disease SCLC (clinicaltrials.gov)
P2, N=44, Not yet recruiting, ETOP IBCSG Partners Foundation | Initiation date: May 2023 --> Aug 2023
Trial initiation date
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SLFN11 (Schlafen Family Member 11)
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SLFN11 expression • SLFN11 overexpression
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Zejula (niraparib)
1year
Lurbinectedin shows potent activity in all four molecular subtypes of small cell lung cancer (SCLC) and POU2F3 and SLFN11 are biomarkers for a better response (AACR 2023)
The aim of this study was to analyze the activity of lurbinectedin in the different SCLC molecular subtypes and to investigate new biomarkers of response.Methods and Results - We have characterized a panel of 20 SCLC human cell lines based on the expression of ASCL1, NEUROD1, YAP1 and POU2F3, where lurbinectedin yielded a mean IC50 value of 6.52 nM, which is considerable greater than the activity exerted by topotecan, irinotecan, carboplatin, etoposide, olaparib, alisertib and navitoclax (IC50 100 µM-100 nM). Finally, SLFN11 expression was evaluated by IHC in FFPE tumor samples from SCLC patients participating in a multicenter phase II clinical trial in advanced solid tumors (NCT02454972), which allowed lurbinectedin accelerated approval in this indication by FDA. Patients with higher expression of SLFN11 had a slightly better overall survival (OS at 6 months: 68.4% (<15%, N=20) vs. 98.7% (≥15%, N=20) p=0.0261)), especially in the refractory/resistant subgroup (OS at 6 months: 33.3% (<15%, N=9) vs. 100.0% (≥15%, N=6) p<0.0001).Conclusions - Lurbinectedin is highly effective in all molecular subtypes of SCLC in vitro and in vivo, with IC50 values at least two logs more potent than for other antitumoral agents and its activity is even greater in tumors with high POU2F3 expression and/or high SLFN11 expression.
PARP Biomarker
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SLFN11 (Schlafen Family Member 11) • YAP1 (Yes associated protein 1) • POU2F3 (POU Class 2 Homeobox 3) • ASCL1 (Achaete-Scute Family BHLH Transcription Factor 1) • NEUROD1 (Neuronal Differentiation 1)
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SLFN11 expression • SLFN11 overexpression • POU2F3 expression • POU2F3 overexpression
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Lynparza (olaparib) • carboplatin • etoposide IV • irinotecan • navitoclax (ABT 263) • topotecan • Zepzelca (lurbinectedin) • alisertib (MLN8237)
1year
High SLFN11 expression correlates with sensitivity to lurbinectedin in small cell lung cancer (SCLC) models (AACR 2023)
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. 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 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.
PARP Biomarker
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SLFN11 (Schlafen Family Member 11)
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SLFN11 expression • SLFN11 overexpression • SLFN11 underexpression
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cisplatin • Zepzelca (lurbinectedin)
1year
New P2 trial
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SLFN11 (Schlafen Family Member 11)
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SLFN11 expression • SLFN11 overexpression
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Zejula (niraparib)
over1year
Epigenetic upregulation of Schlafen11 renders WNT- and SHH- activated medulloblastomas sensitive to cisplatin. (PubMed, Neuro Oncol)
High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin.
Journal
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SLFN11 (Schlafen Family Member 11)
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SLFN11 expression • SLFN11 overexpression
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cisplatin • RG2833
almost2years
Targeting genome integrity dysfunctions impedes metastatic potency in non-small-cell lung cancer circulating tumor cell-derived eXplants. (PubMed, JCI Insight)
GR-CDXL1 presented homologous recombination deficiency linked to biallelic BRCA2 mutation and FANCA deletion, unrepaired DNA lesions after mitosis, and olaparib sensitivity, despite resistance to chemotherapy...Centrosome clustering promoted targetable chromosomal instability in GR-CDXL3 cells. These CDX unravel DDR and genome integrity-related defects as a central mechanism underpinning metastatic potency of CTCs and provide rationale for their therapeutic targeting in metastatic NSCLC.
Journal • Circulating Tumor Cells • BRCA Biomarker • PARP Biomarker
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BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • SLFN11 (Schlafen Family Member 11) • FANCA (FA Complementation Group A) • CDX2 (Caudal Type Homeobox 2)
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BRCA2 mutation • HRD • SLFN11 expression • FANCA mutation • SLFN11 overexpression • FANCA deletion
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Lynparza (olaparib)
2years
Circulating tumor cell-derived explant models reveal DNA damage response-based therapeutic opportunities in non-small cell lung cancer (AACR 2022)
This study unravels distinct DDR profiles as a central mechanism underpinning CTC metastatic potency. Our CDX models provide a robust platform for ex vivo drug testing of DDR-targeted strategies to expand patient categories that may benefit from precision medicine in metastatic NSCLC.
Circulating Tumor Cells • BRCA Biomarker • PARP Biomarker
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BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • SLFN11 (Schlafen Family Member 11) • FANCA (FA Complementation Group A) • CDX2 (Caudal Type Homeobox 2)
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BRCA2 mutation • HRD • SLFN11 expression • FANCA mutation • SLFN11 overexpression • FANCA deletion
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Lynparza (olaparib)
over2years
Schlafen 11 expression in human acute leukemia cells with gain-of-function mutations in the interferon-JAK signaling pathway. (PubMed, iScience)
In these cells, the clinical JAK inhibitors cerdulatinib, ruxolitinib, and tofacitinib reduced SLFN11 expression, but IFN did not further induce SLFN11 despite phosphorylated STAT1...Accordingly, the AKT and ERK inhibitors MK-2206 and SCH77284 suppressed SLFN11 expression...Moreover, SLFN11 expression was inhibited by the ETS inhibitor TK216. Our study reveals that SLFN11 expression is regulated via the JAK, AKT and ERK, and ETS axis. Pharmacological suppression of SLFN11 warrants future studies.
Journal
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SLFN11 (Schlafen Family Member 11) • ETS1 (ETS Proto-Oncogene 1) • STAT1 (Signal Transducer And Activator Of Transcription 1)
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SLFN11 expression • SLFN11 overexpression
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Jakafi (ruxolitinib) • MK-2206 • ONCT-216 • tofacitinib
over2years
SLFN11 is widely expressed in pediatric sarcoma and induces variable sensitization to replicative stress caused by DNA damaging agents. (PubMed, Mol Cancer Ther)
Sensitivity to the PARP inhibitor talazoparib (TAL) and the topoisomerase I inhibitor irinotecan (IRN) was assessed in sarcoma cell lines, including SLFN11 knock-out and over-expression models, and a patient-derived orthotopic xenograft model (PDOX). Although SLFN11 appears to drive sensitivity to replicative stress in pediatric sarcomas, its potential to act as a biomarker may be limited to certain tumor backgrounds or contexts. Impaired apoptotic response may be one mechanism of resistance to DDA-induced replicative stress.
Clinical • Journal • PARP Biomarker
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BCL2L1 (BCL2-like 1) • SLFN11 (Schlafen Family Member 11)
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SLFN11 expression • SLFN11 overexpression
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Talzenna (talazoparib) • irinotecan