Upadacitinib for Severe Alopecia Areata in Adults and Adolescents: Two Phase 3 UP-AA Randomized Clinical Trials.

Prostate cancer (PCa) is a biologically heterogeneous tumour of elderly men, which counts as the most common type of cancer among men in the European Union (Ref. ) and the second most common cancer in men worldwide (Ref. ), with inevitably rising incidence rates in the future due to the ageing population. The recent cancer statistics reports that PCa alone accounts for 30% of new cancer diagnoses per year in the United States (US) (Ref. ). Besides age, family history and race are well-accepted risk factors for PCa (Ref. ). Moreover, various epidemiological studies revealed that dietary habits, body mass index and lifestyle as well as metabolic disorders such as metabolic syndrome and diabetes have an impact on cancer development and progression (Ref. ). When detected at an early localised stage, PCa can be effectively managed by active surveillance, surgical removal of the prostate or radiotherapy, depending on risk characteristics (Ref. ). Advanced PCa, on the other hand, is usually treated by androgen deprivation therapy (ADT), which is highly effective per se in treatment-naïve patients but suffers from common progression to castration resistance. A number of novel drugs, which are either given alone or in combination, have been developed. This resulted in a significant overall improvement in the survival of patients and – importantly – in a complete change in the clinical management of patients with metastatic PCa (mPCa) (Ref. ). Nevertheless, treatment resistances are a major problem in advanced stages and therefore mPCa unfortunately remains a lethal disease, actually ranging on the second position after lung cancer among all cancer deaths in the US (Ref. ). Hence, early diagnosis together with novel strategies to overcome treatment resistances is highly important. Metabolic reprogramming is a hallmark adaptation of cancer cells to enable energy production and synthesis of cell building blocks for enhanced growth and survival. It therefore represents a valuable and broad working surface to develop novel therapy approaches. In this review, we will focus on the role of the urea cycle (UC) in the metabolic dysregulation of PCa cells and discuss its potential use in the development of diagnostic markers and therapeutic drugs. We will summarise some of the most interesting approaches and also provide their actual status of research from preclinical to clinical testing. The prostate has a very unique metabolic phenotype. Normal prostate epithelial cells accumulate high levels of zinc, which inhibit the activity of mitochondrial aconitase (ACO2) and thus prohibit citrate from entering the TCA cycle (Ref. ) (). This results in an unusually low TCA cycle and oxidative phosphorylation activity but high levels of citrate instead, which are secreted into the seminal fluid (Ref. ). Besides citrate, high levels of spermine are accumulated and secreted by the normal prostate, indicating a high activity of polyamine biosynthesis (Ref. ). PCa cells reprogram this ‘zinc-citrate regulation’ to re-activate the TCA cycle for higher energy production, most likely through reducing the expression of zinc transport proteins, which consequently results in lowering intracellular zinc concentrations (Ref. ). PCa cells typically exhibit high lipid synthesis activity and a preferential use of fatty acids for energy production (Ref. ) together with enhanced oxidative phosphorylation activity (Ref. ). In addition, high choline levels sustain membrane phospholipid production and cellular division (Ref. ). Notably, the metabolic activity of PCa may change during therapy and disease progression. It has been shown, for instance, that tumour cells may shift from a lipogenic phenotype into a more glycolytic phenotype during tumour cell progression (Ref. ), rendering glucose and lactate important energy substrates for advanced stages of PCa (Ref. ). Various studies also reported on metabolic changes within the UC of PCa cells (Ref. ) although the significance of the UC in PCa and its use in diagnosis and treatment has been somehow overshadowed.