Tirzepatide as an innovative treatment strategy in a pre-clinical model of obesity-driven endometrial cancer

Abstract

Objective: Interventions that combat obesity and its associated metabolic perturbations may decrease incidence and improve outcomes of endometrial cancer (EC). Potential options for weight loss include pharmacotherapeutic interventions such as tirzepatide, a dual-acting glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptor agonist. Given this, we explored the anti-obesity and anti-tumorigenic effects of tirzepatide in our pre-clinical mouse model of endometrioid EC.

Methods: Starting at 4 weeks of age, Lkb1^fl/flp53^fl/fl mice were fed a low-fat diet vs a high-fat diet to generate a lean or obese phenotype. Nine weeks after induction of EC, obese and lean mice were randomized to receive tirzepatide for 4 weeks. Body and tumor weights, tumor transcriptomic and metabolomic profiles, and serum metabolic markers and chemokines were assessed.

Results: Both obese and lean mice began to lose body weight after 2 weeks of tirzepatide treatment, ultimately achieving a significant weight loss of 20.1 % in obese mice and 16.8 % in lean mice. Tirzepatide improved obesity-induced serum adiponectin, leptin, GIP, and C-reactive protein levels. Furthermore, tirzepatide relative to vehicle, effectively reduced tumor growth in obese and lean mice, inhibited the ErbB signaling and glycolysis/gluconeogenesis in tumors of obese mice, and increased O-linked glycosylation biosynthesis and phospholipase D signaling in tumors of lean mice.

Conclusion: Tirzepatide decreased both mouse weight and tumor growth via effects on metabolic and immune pathways in the EC tumors that differed between obese and lean mice. This novel weight loss treatment deserves further evaluation as an innovative strategy in the management of EC.

Keywords: Body weight; Endometrial cancer; Metabolon; Obesity; Tirzepatide.

Figure 1.. Tirzepatide inhibited EC tumor growth under obese and lean conditions.

Research design diagram. Lkb1^fl/flp53^fl/fl mice were fed a high-fat diet (HFD) or a low-fat diet (LFD) at 4 weeks of age and treated with tirzepatide (TZP) for 4 weeks (A). Tirzepatide significantly reduced tumor weights in both the HFD and LFD groups compared with their control groups (B). Tirzepatide effectively decreased body weight in both HFD and LFD groups compared with their control groups (C). IHC staining results showed that tirzepatide significantly reduced the expression of Ki67, Bcl-xL and phosphorylated S6 in EC tissues in the HFD and LFD groups compared with control mice (D). * or # p<0.05, ** or ## p<0.01. * and **: compared to their control groups.

Figure 2.. Effects of tirzepatide on transcriptomic profiles in the EC tumors.

The profiles of gene expression in EC tissues were determined by RNA seq analysis after 4 weeks of tirzepatide treatment. Comparison of gene expression profiles between HFD and LFD groups (A). Comparison of mRNA expression between tirzepatide-treated obese mice and control mice (B). Comparison of mRNA expressions between tirzepatide-treated lean mice and control mice (C). n=7 mice/group.

Figure 3.. Effects of tirzepatide on metabolomic profiles in the EC tumors.

The changes in metabolomic profiles in EC tissues were assessed by Metabolon after 4 weeks of tirzepatide treatment. Energy and fatty acid metabolisms were compared between the HFD and LFD groups after tirzepatide treatment (A). Aminosugars were decreased in mice fed a LFD treated with tirzepatide compared to control mice (B). Eicosanoid levels were reduced in mice fed a LFD treated with tirzepatide compared with control mice (C). n=6 mice/group.

Figure 4.. Effects of tirzepatide on circulating hormones and inflammatory markers in LKB1^fl/fl p53^fl/fl mice.

Circulating hormones and inflammatory markers were determined by multiplex ELISA assays in obese and lean mice treated with tirzepatide. Compared with LFD group, obese mice had higher levels of insulin, GIP, and resistin (A-C), and lower levels of glucagon (D). Tirzepatide significantly increased adiponectin products in obese and lean mice compared with their controls (E). Leptin levels significantly decreased in obese mice after tirzepatide treatment (F). Tirzepatide effectively reduced CRP products in obese and lean mice after tirzepatide treatment (G). *< 0.05, **< 0.01. n=6 mice/group.