Sarcoma Gene Signature May Predict Who Benefits From Pazopanib

A gene called SERPINE1 rose sharply in tumor tissue after patients with advanced soft tissue sarcoma (STS) were treated with pazopanib (Votrient; Novartis), according to an exploratory study published in Therapeutic Advances in Medical Oncology.¹ The increase showed up earliest in the sarcoma cell lines most sensitive to the drug, which raises the possibility that a marker long associated with poor cancer outcomes could double as a real-time signal of treatment response.

The findings, drawn from paired pre- and post-treatment biopsies and laboratory experiments in sarcoma cell lines, add SERPINE1 to a short list of candidate biomarkers for a disease that has struggled to find any.

Pazopanib is an oral tyrosine kinase inhibitor that targets a wide spectrum of receptors that are normally overexpressed in STS and associated with worse prognosis, metastatic disease, resistance to chemotherapy, and a higher histologic grade.

“Although pazopanib is active in some patients, there is a clinical need in terms of predictive biomarkers for this drug in STS,” the authors explained.

Why Does STS Need a Predictive Biomarker?

STS is a rare and heterogeneous group of cancers, and treatment options thin out considerably after first-line therapy. Second-line agents such as gemcitabine (Gemzar; Eli Lilly) combinations, eribulin (Halaven; Eisai), trabectedin (Yondelis; PharmaMar), and pazopanib produce response rates below 10%, with median progression-free survival (PFS) typically under 4 to 5 months.

Even the pivotal phase 3 PALETTE trial (NCT00753688), which established pazopanib's role in STS, failed to turn up a reliable predictive biomarker of response.² Beyond blocking angiogenesis, pazopanib has also been shown, in studies of renal cell carcinoma, to dial back immunosuppressive cell populations, such as myeloid-derived suppressor cells and regulatory T cells, while boosting T-cell and natural killer cell activity. While it is not established whether the same immune effect holds in STS, the results hint that immune-related markers might help forecast which patients benefit from pazopanib.

SERPINE1 Rose Fastest in Drug-Sensitive Cell Lines

Researchers collected paired tumor samples—taken at diagnosis at 6 Spanish hospitals and again after pazopanib treatment—from 11 patients with advanced STS, profiling them with a 549-gene immuno-oncology transcriptomic panel.¹ Because paired pre- and post-pazopanib specimens are exceedingly rare, the authors designed the analysis as exploratory and hypothesis-generating rather than confirmatory.

Of 38 genes that were differentially expressed between baseline and post-pazopanib samples, only 4 survived corrections for multiple comparisons. CD68, SERPINE1, C1QA, and CXCL8 were all upregulated after treatment. SERPINE1 encodes plasminogen activator inhibitor-1 (PAI-1), a regulator of fibrinolysis and angiogenic signaling, and showed the largest and most consistent change, with a 4.19-fold increase (FDR = 0.016). In a separate analysis of the Cancer Genome Atlas sarcoma database, SERPINE1 overexpression was significantly associated with worse PFS (P = .033) and disease-free survival (P = .004), though not overall survival.

In follow-up experiments using 4 sarcoma cell lines, SERPINE1 RNA and protein expression rose after pazopanib treatment. The increased expression appeared earlier in cell lines that were more sensitive to the drug and later, or not at all, in more resistant ones.

Where Does This Fit Among Emerging Sarcoma Biomarkers?

The search for predictive tools in STS has intensified as clinicians look to sequence a growing menu of second-line options more precisely. Traditional biomarkers such as PD-L1 expression, microsatellite instability, and tumor mutation burden have shown limited predictive value in sarcomas, prompting researchers to explore blood-based signals such as the neutrophil-to-lymphocyte ratio, which has separately been linked to better survival in patients with STS treated with pazopanib.³

SERPINE1 offers a different kind of signal because it is a change in tumor tissue triggered by treatment, not a blood count. But the goal is the same: match patients to therapies more likely to work and spare other patients weeks of toxicity without benefit.

Limitations and the Path Toward Validation

The authors were candid about the constraints of the work. Only 11 patients contributed paired samples, and the STS subtypes varied across the cohort. Patients also received pazopanib at different points in their treatment, meaning their tumors carried different amounts of prior treatment exposure at the time of biopsy. These factors limit statistical power and introduce potential confounding. The authors emphasized that SERPINE1's predictive value for pazopanib response, as distinct from its established prognostic role, remains an indirect, exploratory finding drawn from a small cohort.

The investigators suggested that testing whether SERPINE1 changes can be detected in liquid biopsies could offer a minimally invasive way to flag treatment responders within 24 to 72 hours of starting pazopanib. They also noted that the next logical step is to combine antiangiogenic agents like pazopanib with immune checkpoint inhibitors, which is already showing encouraging activity in early-phase sarcoma trials.

“Ultimately, large-scale, prospective validation in independent and uniformly treated patient cohorts is strictly required to definitively establish the predictive and clinical utility of SERPINE1, as well as the roles of other emerging candidates such as MMP9 and CXCL8, before any translational application can be considered,” they concluded.

References

1. Mondaza-Hernandez JL, Amian-Ruiz R, Cordero Varela JA, et al. Biomarkers of prognosis and pazopanib response in soft tissue sarcoma: an exploratory analysis. Ther Adv Med Oncol. 2026;18. doi:10.1177/17588359261474856
2. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879-1886. doi:10.1016/S0140-6736(12)60651-5
3. Kaltwasser J. Blood-based biomarkers could reshape soft tissue sarcoma therapy. AJMC^®. September 30, 2025. Accessed August 14, 2026. https://www.ajmc.com/view/blood-based-biomarkers-could-reshape-soft-tissue-sarcoma-therapy