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SLFN11 Expression in Advanced Prostate Cancer and Response to Platinum-based Chemotherapy
Vincenza Conteduca1,2, Sheng-Yu Ku1, Loredana Puca3
1Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
Abstract:
Expression of the DNA/RNA helicase schlafen family member 11 (SLFN11) has been identified as a sensitizer of tumor cells to DNA-damaging agents including platinum chemotherapy. We assessed the impact of SLFN11 expression on response to platinum chemotherapy and outcomes in patients with metastatic castration-resistant prostate cancer (CRPC). Tumor expression of SLFN11 was assessed in 41 patients with CRPC treated with platinum chemotherapy by RNA sequencing (RNA-seq) of metastatic biopsy tissue (n = 27) and/or immunofluorescence in circulating tumor cells (CTC; n = 20). Cox regression and Kaplan-Meier methods were used to evaluate the association of SLFN11 expression with radiographic progression-free survival (rPFS) and overall survival (OS). Multivariate analysis included tumor histology (i.e., adenocarcinoma or neuroendocrine) and the presence or absence of DNA repair aberrations. Patient-derived organoids with SLFN11 expression and after knockout by CRISPR-Cas9 were treated with platinum and assessed for changes in dose response. Patients were treated with platinum combination (N = 38) or platinum monotherapy (N = 3). Median lines of prior therapy for CRPC was two. Median OS was 8.7 months. Overexpression of SLFN11 in metastatic tumors by RNA-seq was associated with longer rPFS compared with those without overexpression (6.9 vs. 2.8 months, HR = 3.72; 95% confidence interval (CI), 1.56-8.87; P < 0.001); similar results were observed for patients with SLFN11-positive versus SLFN11-negative CTCs (rPFS 6.0 vs. 2.2 months, HR = 4.02; 95% CI, 0.77-20.86; P = 0.002). A prostate-specific antigen (PSA) decline of ≥50% was observed in all patients with SLFN11 overexpression. No association was observed between SLFN11 expression and OS. On multivariable analysis, SLFN11 was an independent factor associated with rPFS on platinum therapy. Platinum response of organoids expressing SLFN11 was reduced after SLFN11 knockout. Our data suggest that SLFN11 expression might identify patients with CRPC with a better response to platinum chemotherapy independent of histology or other genomic alterations. Additional studies, also in the context of PARP inhibitors, are warranted.
Insights
Schlafen family member 11 (SLFN11) expression predicts better radiographic progression-free survival in metastatic castration-resistant prostate cancer (CRPC) patients treated with platinum chemotherapy. SLFN11 may identify patients with improved response to platinum agents.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Schlafen family member 11 (SLFN11) is a DNA/RNA helicase known to sensitize tumor cells to DNA-damaging agents.
- Platinum chemotherapy is a standard treatment for metastatic castration-resistant prostate cancer (CRPC).
- Identifying biomarkers to predict treatment response in CRPC is crucial for personalized therapy.
Purpose of the Study:
- To investigate the association between SLFN11 expression and response to platinum chemotherapy in CRPC patients.
- To evaluate SLFN11 as a predictive biomarker for radiographic progression-free survival (rPFS) and overall survival (OS) in CRPC.
- To assess the functional role of SLFN11 in platinum chemotherapy response using patient-derived organoids.
Main Methods:
- Tumor SLFN11 expression was analyzed by RNA sequencing in metastatic biopsies and by immunofluorescence in circulating tumor cells (CTCs) from 41 CRPC patients treated with platinum chemotherapy.
- Cox regression and Kaplan-Meier methods were used to assess the association of SLFN11 expression with rPFS and OS.
- Patient-derived organoids with and without SLFN11 expression (via CRISPR-Cas9 knockout) were treated with platinum agents to evaluate dose response.
Main Results:
- Overexpression of SLFN11 in metastatic tumors was significantly associated with longer rPFS (6.9 vs. 2.8 months) compared to tumors without SLFN11 overexpression.
- SLFN11 positivity in CTCs also correlated with improved rPFS (6.0 vs. 2.2 months).
- All patients with SLFN11 overexpression achieved a prostate-specific antigen (PSA) decline of ≥50%; however, no significant association was found between SLFN11 expression and OS. SLFN11 was an independent predictor of rPFS in multivariable analysis. Organoid experiments showed reduced platinum response after SLFN11 knockout.
Conclusions:
- SLFN11 expression is a promising predictive biomarker for enhanced response to platinum chemotherapy in patients with metastatic CRPC, independent of histology or DNA repair aberrations.
- SLFN11 may play a functional role in mediating sensitivity to platinum agents.
- Further studies, including those exploring combination therapies with PARP inhibitors, are warranted to validate these findings and optimize treatment strategies.
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