FASN for diffuse malignant peritoneal mesothelioma: a prognostic biomarker after CRS+HIPEC and a therapeutic target

Our plain-English summary of FASN for diffuse malignant peritoneal mesothelioma: a prognostic biomarker after CRS+HIPEC and a therapeutic target, by V. Doldi, C.M. Ciniselli, C. Aurelio, et al (Journal of Translational Medicine, 2026).

The study

• Authors: V. Doldi, C.M. Ciniselli, C. Aurelio, E. Favini, S.M. Veronese, F. Bozzi, S. Kusamura, D. Baratti, S. Martini, P. Verderio, M. Deraco, M. Folini, P. Gandellini, S. Pasquali, N. Zaffaroni
• Journal: Journal of Translational Medicine
• Published: 2026;24(1)
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and aggressive malignancy with limited therapeutic options and poor clinical outcomes. While metabolic reprogramming, including altered lipid metabolism, is a recognized hallmark of cancer, its contribution to DMPM progression and treatment response remains poorly understood.

Methods: Gene expression profiling was performed on tumor samples from 45 DMPM patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS+HIPEC), comparing patients who developed recurrence within 30 months (N = 13) to those with later relapse or no recurrence (N = 32). Candidate prognostic markers were validated by immunohistochemistry in a cohort of 80 DMPM patients treated with CRS+HIPEC. Associations with progression-free survival (PFS) and overall survival (OS) were assessed using univariate and multivariate Cox regression analyses. To evaluate therapeutic potential, selective (cerulenin, C75) and non-selective (orlistat) fatty acid synthase (FASN) inhibitors were tested in patient-derived DMPM cell lines. Effects on cell proliferation, cell cycle progression, and apoptosis were assessed. Combination treatments with selinexor (XPO1/CRM1 inhibitor) or IAG-933 (inhibitor of FASN-derived palmitoyl-CoA activity) were also evaluated.

Results: Fatty acid synthase (FASN) was significantly upregulated in tumors from patients with early recurrence. High FASN protein expression was associated with reduced PFS (HR = 1.93; p = 0.01) and OS (HR = 1.85; p = 0.02). Multivariate analysis confirmed FASN as an independent predictor of both PFS (HR = 2.24; p = 0.005) and OS (HR = 2.24; p = 0.014). In vitro, FASN inhibition significantly reduced DMPM cell growth, disrupted cell cycle progression, and induced apoptosis, with C75 showing the strongest effects. Combination treatment with FASN inhibitors and selinexor or IAG-933 resulted in enhanced growth inhibition and apoptosis compared with single-agent treatments.

Conclusions: FASN represents a novel independent prognostic biomarker in DMPM patients undergoing CRS+HIPEC and a promising therapeutic target. Given the limited treatment options for DMPM, combination strategies incorporating FASN inhibitors with selinexor or TEAD-pathway-targeting agents, supported by existing clinical trial data, may offer a rapidly translatable therapeutic approach.

© 2026. The Author(s).

In plain English

Researchers in Milan, Italy, studied an enzyme called fatty acid synthase (FASN) in diffuse malignant peritoneal mesothelioma (DMPM), a cancer of the abdominal lining. The study did not look at asbestos or other occupational or environmental exposures. The authors used stored tumor samples from patients treated between 1995 and 2013 with surgery plus heated abdominal chemotherapy (CRS+HIPEC). In 45 patients, FASN was among the genes most raised in those who relapsed within 30 months. In 80 patients, high FASN staining was associated with shorter progression-free survival (hazard ratio 1.93, 95% CI 1.144 to 3.249) and overall survival (1.854, 1.054 to 3.260). In the final adjusted models, these were 2.240 (1.243 to 4.039) and 2.246 (1.182 to 4.269). In the initial adjusted overall-survival model, FASN was not statistically significant. In two patient-derived cell lines, FASN-blocking drugs reduced cell growth. Combining cerulenin or C75 with selinexor, or C75 with IAG-933, increased this effect. The authors concluded that FASN is an independent prognostic marker and a potential treatment target. They noted that the patients came from a single institution and that the drug results come only from cell cultures.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective study of archived tumor samples from a single institution (gene expression profiling, then immunohistochemistry on tissue microarrays, with Cox survival analysis), combined with laboratory (in vitro) experiments on patient-derived cell lines
• Who was studied: Patients with diffuse malignant peritoneal mesothelioma treated with CRS+HIPEC at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, between October 1995 and February 2013. Frozen tumors from 45 patients were used for gene expression analysis (13 relapsed within 30 months; 32 relapsed later or did not relapse). Tumors from 80 patients were used for FASN immunohistochemistry. The laboratory work used two cell lines (MP-115 and SSL1) from two patients with epithelioid DMPM, compared with normal human mesothelial cells (MES-F).
• Exposure: The article does not address asbestos or any occupational or environmental exposure. The factor studied was the level of FASN in tumors: protein staining was scored 1 to 4, with scores 3 to 4 counted as high and 1 to 2 as low. In the cell experiments, cells were treated with the FASN inhibitors orlistat, cerulenin and C75. Cerulenin or C75 was also combined with selinexor, and C75 was combined with the TEAD inhibitor IAG-933.
• Main results:
  • In the 45-patient gene expression analysis, FASN was one of the most up-regulated genes in patients who relapsed within 30 months, compared with those who relapsed later or not at all (fold change 1.8829, p = 2.00E-05).
  • In the same 45 patients, a univariate Cox analysis of FASN gene expression and recurrence gave HR 2.83 (95% CI 1.67 to 4.8).
  • In the 80-patient immunohistochemistry cohort, 71% of tumors from patients who relapsed had high FASN staining. Among patients without recurrence, 70% of tumors had low FASN staining.
  • In univariate analysis of the 80 patients, high FASN staining (scores 3 to 4 vs 1 to 2) was associated with progression-free survival (HR 1.93, 95% CI 1.144 to 3.249 in the text, 1.144 to 3.259 in Table 4, p = 0.014). It was also associated with overall survival (HR 1.854, 95% CI 1.054 to 3.260, p = 0.032).
  • For progression-free survival, high FASN staining (3 to 4 vs 1 to 2) had HR 2.240 (95% CI 1.243 to 4.039, p = 0.005) in the final, backward-selected multivariate model. In the initial multivariate model it had HR 2.244 (1.144 to 4.404, p = 0.016).
  • For overall survival, high FASN staining had HR 2.246 (95% CI 1.182 to 4.269, p = 0.014) in the final, backward-selected multivariate model. In the initial multivariate model the HR was 1.893 (0.937 to 3.824, p = 0.069), which was not statistically significant.
  • FASN was significantly higher in the two DMPM cell lines than in normal mesothelial cells.
  • Combining cerulenin or C75 with selinexor increased cell growth inhibition in both cell lines compared with single drugs.
  • In MP-115 cells, apoptosis (TUNEL-positive cells) reached 60% with cerulenin plus selinexor and 87% with C75 plus selinexor. In SSL1 cells, single drugs did not cause appreciable apoptosis, and the combinations caused a modest amount (25.3% and 22.5%).
  • Combining C75 with IAG-933 enhanced cell growth inhibition compared with single drugs. The interaction was classified as additive to moderately synergistic.
• The authors' conclusion: The authors concluded that FASN is an independent prognostic biomarker for DMPM patients treated with CRS+HIPEC and a potential therapeutic target. They proposed further study of combining FASN inhibitors with selinexor or TEAD inhibitors.
• Limitations the authors state:
  • The patients came from a single institution. The authors stated that validation in an independent cohort, ideally from several centres, would strengthen the results.
  • The drug combination findings come only from cell cultures, and the authors stated that confirmation in living animals (in vivo) is needed.
  • The proposed mechanism behind the C75 plus IAG-933 effect requires further investigation.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Biomarker, HIPEC, Cytoreductive Surgery, Immunohistochemistry, Progression-Free Survival, Overall Survival, Apoptosis.

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• National Guidelines for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Peritoneal Malignancies: A Worldwide Systematic Review and Recommendations of Strength Analysis — M. Tonello, C. Cenzi, et al. (2025)

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