Ultrasound-Assisted Radiopharmaceutical Investigation of GNL1-Mediated AKT-P53-P21 Axis Activation in Cervical Cancer Progression

Abstract

Background:

Cervical cancer is a leading cause of cancer death in women worldwide, and the outcomes for advanced or recurrent disease remain poor. Ultrasound-assisted delivery could increase intratumoral uptake of radiopharmaceuticals, but prospective clinical evidence and risk data are limited.

Methods:

In a single-center pilot (n = 30), patients with advanced cervical cancer underwent paired PET/CT sessions 60 min after identical intravenous radiopharmaceutical injections: control (no ultrasound) and ultrasound-assisted delivery using 1 MHz focused ultrasound (FUS) for 10 min with microbubble cavitation monitoring. Uptake (SUV_max) and tumor-to-background ratio (TBR) were compared within patient; response used RECIST 1.1, and adverse events (AEs) used CTCAE v5.0. Paired biopsies quantified GNL1, phospho-AKT, p53, and p21 (H-score).

Results:

Ultrasound increased median index-lesion SUV_max by ∼28% (p < 0.001) with improved TBR. The objective response rate was 26.7% and the disease control rate was 76.7%. Median progression-free survival was 8.5 months (95% confidence interval, 6.2–11.8) and the 12-month overall survival was 75% (median not reached). Most AEs were Grades 1–2; 20% were Grade ≥3, with no treatment-related deaths. Post-ultrasound biopsies showed decreased GNL1 and phospho-AKT with increased p53 and p21, and Δp21 correlated with uptake gain.

Conclusions:

Nonablative FUS can safely enhance radiopharmaceutical uptake in cervical cancer and is associated with biomarker shifts consistent with p53/p21 pathway activation.