For one of the most difficult-to-treat abdominal cancers, identifying who will relapse early after aggressive combined treatment has been an unsolved clinical problem. A dual role for a metabolic enzyme — both forecasting outcomes and serving as a druggable target — could meaningfully shift how oncologists approach this disease, even if the patient numbers remain small.
Fatty acid synthase (FASN), a central enzyme in de novo lipid biosynthesis, emerged as significantly overexpressed in tumor tissue from diffuse malignant peritoneal mesothelioma (DMPM) patients who relapsed within 30 months of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS+HIPEC). Gene expression profiling across 45 patients identified FASN as a candidate marker, which was then validated by immunohistochemistry in an independent cohort of 80 patients. High FASN protein expression correlated with shorter progression-free and overall survival on both univariate and multivariate Cox regression — suggesting independence from established clinical variables. In patient-derived cell lines, FASN inhibitors including cerulenin, C75, and orlistat suppressed proliferation and induced apoptosis. Notably, combination strategies pairing FASN inhibition with selinexor (an XPO1/CRM1 nuclear export inhibitor) or IAG-933 (targeting palmitoyl-CoA activity downstream of FASN) showed additive or synergistic effects.
FASN upregulation in cancer has been documented across multiple tumor types for over two decades, yet translating this biology into clinical utility has proven elusive — most FASN inhibitors have struggled with tolerability or modest single-agent efficacy in vivo. What distinguishes this work is the application to an orphan disease where treatment options are essentially exhausted after CRS+HIPEC failure, and where even modest stratification of prognosis has real triage value. The cohort sizes — while reasonable for a rare malignancy — remain a fundamental limitation, and the therapeutic data are entirely preclinical. The combination with selinexor is mechanistically intriguing given that protein is involved in nuclear export of tumor suppressors, but clinical translation requires considerable additional validation. This is incremental-to-meaningful progress for a neglected cancer rather than a paradigm shift.