Identification of alpha1-oleate as a potent regulator of adipokine-dependent metabolism, in bladder cancer tissue.

Abstract

Background: Metabolic dysfunctions are associated with increased cancer morbidity and rapid tumor progression. The alpha1-oleate complex has been used successfully to treat bladder cancer in a placebo-controlled Phase II study. Studies of the related BAMLET complexes recently identified effects on metabolism, suggesting additional functions of the "HAMLET family" of tumoricidal complexes.

Aims: To investigate if intravesical alpha1-oleate treatment affects metabolism in bladder cancer tissue.

Materials and methods: Samples were obtained from patients with NMIBC, enrolled in a placebo-controlled study of intravesical alpha1-oleate treatment [1]. Cells shed into the urine were harvested at each instillation and biopsies obtained at TURBT after six instillations of alpha1-oleate. The shed cells and biopsies were subjected to RNA sequencing and genome-wide transcriptomic analysis, and urine samples were analyzed using adipokine arrays.

Results: RNA sequencing detected significant inhibition of metabolic genes and networks in shed cells and tissue biopsies from alpha1-oleate treated patients, compared to the placebo group. Genes and gene networks regulating glucose and lipid synthesis were inhibited in alpha1-oleate treated patients, including ADIPOQ, which encodes the lipid- and glucose-regulating protein adiponectin and LEP, which encodes the metabolism and fat storage regulator Leptin. Leptin was further identified as an upstream regulator of the adiponectin response to alpha1-oleate and LEP and ADIPOQ networks showed strong interconnection in treated tissues. Analysis of shed tumor cells, suggested rapid kinetics of the metabolic response and urine levels of adiponectin and leptin were increased post-treatment, compared to pre-treatment samples and the shed tumor cells in urine contained adiponectin and leptin, as shown by immunohistochemistry.

Conclusions: The findings identify potent local effects of alpha1-oleate treatment on tumor metabolism, after intravesical instillation. The metabolic regulators adiponectin and leptin were affected in tumor tissue and cells containing adiponectin and leptin were shed into the urine, potentially depleting the tumor of cells with high adipokine levels. These potent effects suggest a new molecular approach for targeting and inhibiting key regulators of cancer metabolism in superficial tumors.

Trial registration: Doubleblinded Phase I/II clinical trial (EudraCT 201600426914 NCT03560479, Registration Date 20180521).