Targeting fatty acid metabolism in prostate cancer

Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and the second leading cause of cancer-related mortality in the developed world. Prostate cancers are androgen-dependent and rely on androgen receptor signalling for growth and survival. Hence, the mainstay treatment for patients with advanced metastatic PCa is androgen deprivation therapy. Although initially effective, most patients eventually relapse with castrate-resistant prostate cancer (CRPC), and this stage of the disease is ultimately fatal. Despite the clinical development of more potent anti-androgens, these agents are not curative. Alternative treatment strategies are urgently sought to overcome treatment resistance and progression to CRPC. Targeting cancer metabolism has emerged as a promising therapeutic avenue for cancer treatment, especially by targeting upregulated metabolic pathways that promote cancer cell survival. Dysregulation of lipid metabolism is a prominent feature of prostate cancer, and overexpression of key enzymes involved in lipid metabolism is characteristic of both primary and advanced stages of the disease. Moreover, androgens have been shown to regulate lipid metabolism pathways, either directly or indirectly by coordinating with other oncogenic signalling or metabolic networks. Hence, lipid metabolism represents a promising therapeutic vulnerability for the treatment of PCa and could potentially circumvent treatment resistance. While most studies have focused on targeting de novo lipogenesis and, more recently, lipid uptake pathways in cancer, fatty acid oxidation (FAO) remains an underexplored aspect of lipid metabolism. FAO is the dominant bioenergetic pathway in prostate cancer, which has led to interest in exploiting FAO inhibitors as a potential therapeutic strategy to suppress cancer tumorigenesis and overcome treatment resistance. Despite promising preclinical data, FAO inhibitors (ie. etomoxir and perhexiline) used for metabolic diseases have seen rapid decline in their use due to their severe toxicity and side effects. This is attributed to their broad specificity and subsequent off-target effects by targeting the rate limiting enzyme of mitochondrial FAO, carnitine palmitoyltransferase 1 (CPT1). Therefore, it is important that we identify new and more selective targets of FAO. In this dissertation, we characterise two novel and potential targetable FAO enzymes, 2,4-Dienoyl CoA Reductase 1 and 2 (DECR1 and DECR2) respectively. In Chapter 3, we identified DECR1 as a robustly overexpressed gene in prostate cancer compared to normal or benign tissues and associated with shorter relapse-free survival rates. DECR1 is an auxiliary enzyme involved in polyunsaturated fatty acid (PUFA) oxidation in the mitochondria. Intriguingly, DECR1 is an androgen-repressed gene and besides its fundamental function to produce energy from mitochondrial FAO, DECR1 plays an important role to protect prostate cancer cells from oxidative stress and lipid peroxidation-induced cell death, ferroptosis (caused by the accumulation of peroxidation-prone PUFAs). In Chapter 4, we investigated its peroxisomal counterpart, DECR2, an auxiliary enzyme involved in peroxisomal FAO. To date, there is very limited knowledge on the roles of peroxisomal FAO in PCa and its potential as a therapeutic target. We found that DECR2 is significantly upregulated in prostate cancer and markedly suppressed prostate tumour oncogenesis. Moreover, we uncovered an association between peroxisomal FAO and treatment resistance, as well as a novel link with mitochondrial FAO whereby mitochondrial respiration was maintained in DECR2 knockdown cells likely to support tumour survival. We also provide evidence of cell cycle arrest, a mechanism by which DECR2 or peroxisomal FAO inhibition attenuates prostate cancer cell growth. We utilised thioridazine, a peroxisomal FAO inhibitor as a proof-of-concept that targeting peroxisomal FAO is efficacious and a promising avenue for therapeutic targeting. In Chapter 5, we were also interested whether FAO could play a role as an adaptive survival response in the context of treatment resistance. We analysed a proteomics dataset of AUY922 (heat shock protein 90 inhibitor) treated prostate tumours and found that FAO was a significantly enriched pathway in response to treatment. We then proceeded to evaluate the efficacy of the combination treatment with AUY922 and a clinical FAO inhibitor, perhexiline, and demonstrated enhanced suppressive effects on prostate tumour proliferation compared with individual treatments alone. Taken together, the findings of this thesis support the notion that FAO is a critical survival pathway in PCa progression and treatment resistance. Moreover, targeting FAO represents an exciting and novel therapeutic avenue for PCa treatment and provides a strong rationale for further investigation and clinical development of specific DECR1/2 inhibitors. This thesis also provided novel insights into previously unexplored areas and links of cancer metabolism and opens up new opportunities or questions for future exploration.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 202