Comparing total-body metabolic PET imaging signatures of lung cancer cachexia to other wasting conditions

Abstract

Cancer cachexia (CC) is a debilitating wasting condition. While anorexia and muscle wasting are features of cachexia, CC is a distinct and poorly understood metabolic syndrome¹. We harnessed preclinical models of lung cancer to study how glucose uptake changes during CC and performed comparative analyses with anorexia and muscle wasting.

Lung K-ras^G12D/+;Lkb1^-/-(KL) mice suffering CC were imaged using [¹⁸F]fluorodeoxyglucose (FDG) PET at 15-19% weight loss alongside K-ras wild-type (WT) non-tumour bearing controls. Mice were injected with 12-18MBq of FDG, imaging 80-100 minutes post injection with the Mediso nanoScan® PET/MRI 1T.

In non-tumour bearing male animals, we modelled anorexia, muscle wasting, and circulation of cachexia factor GDF15 as follows, respectively: fasted overnight for 20 hr, treated with dexamethasone 21-phosphate (dexa) (2mg/kg, i.p. daily, 21 days) and single injection of recombinant human GDF15 hormone (0.1 mg/kg s.c.).

FDG ex vivo biodistribution showed increased uptake in myocardium (p<0.05), brain and liver (both p<0.01) of KL cachexic animals with no significant change in FDG blood pool. 

Like cachexic KL animals, FDG uptake in fasted animals increased in brain (p<0.0001), perhaps due to increased FDG blood pool. FDG uptake in skeletal muscles and brown adipose tissue decreased (both p<0.05) in fasted state suggesting lower muscle activity and decreased thermogenesis respectively. Dexa-induced muscle atrophy also resulted in decreased FDG uptake in gastrocnemius/soleus muscles (SUV_mean 0.63 vehicle vs. 0.45 dexa, p<0.05) but no changes in skeletal muscle FDG uptake were noted in cachexic animals. In contrast to KL animals, GDF15 injection resulted in decreased FDG uptake in myocardium (p<0.05).

Overall, the cachexic FDG signature showed differences to other wasting conditions in this mouse model, suggesting different underlying mechanisms.

Total-body PET can reveal diverse metabolic wasting states. We aim to elucidate mechanisms of metabolic changes in cachexia to allow metabolic subtyping and personalised treatment options.

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