Impact of therapy on cancer metabolism in high‐risk localized prostate cancer treated with neoadjuvant docetaxel and androgen deprivation therapy

Abstract

Background The application of neoadjuvant docetaxel and androgen deprivation therapy before radical prostatectomy has been clinically recognized as beneficial for the overall and progression‐free survival of patients with advanced prostate cancer. However, the mechanism underlying its clinical efficacy has not yet been reported. Methods We conducted a randomized comparative study on about 100 patients with high‐risk localized prostate cancer. Through nontarget metabolomics and tissue microarray immunohistochemistry, we investigated the difference in the endogenous metabolism of tumors in patients with prostate cancer who received or did not receive the neoadjuvant therapy. Results Many endogenous metabolic pathways, especially nucleotide synthesis, glutathione metabolism, citric acid cycle, and lipid synthesis, in prostate cancer tissue were altered after the neoadjuvant treatment, and the levels of nearly 90% of the differentially regulated metabolites were significantly decreased. Moreover, the levels of key enzymes in the cellular energy pathways were downregulated in tumor tissues and upregulated in adjacent tissues after the treatment. The positive and negative effects of the neoadjuvant therapy on normal and tumor cells in the prostate, respectively, resulted in the activation of the former and inhibition of the latter, which helped in reducing the number of tumors and weakened their aggressiveness. Conclusions From the perspective of endogenous metabolism in tumors, we have confirmed that neoadjuvant therapy can significantly downregulate important pathways for biosynthesis and energy metabolism in prostate cancer tissue, and thereby, inhibit tumor growth and metastasis.

Carbon Ion Radiotherapy Induce Metabolic Inhibition After Functional Imaging-Guided Simultaneous Integrated Boost for Prostate Cancer

“…Uridine and six acylcarnitines showed a lower level after radical prostatectomy, while the level of other 16 metabolites, such as succinic acid and choline increased eight weeks after surgery (25). Tissue samples from high-risk localized PCa patients who received neoadjuvant docetaxel and ADT represented down-regulation of many endogenous metabolic pathways and a general decline of metabolites (24). Metabolic pathways of nitrogen, pyrimidine, alanine, aspartate and glutamate and porphyrin were significantly altered after photon RT (26).…”

“…As the most downstream of omics cascade, metabolomics provides a comprehensive description of individual phenotypes. Previous studies have investigated the metabolomic changes after several therapeutic strategies: neoadjuvant chemotherapy with androgen deprivation therapy (ADT) (24), radical prostatectomy (25) as well as photon radiation (26,27), and the results pointed out that the metabolite profiles had altered to varying levels after receiving the treatment. However, metabolomic changes after radical radiation therapy with ADT have not been investigated yet, especially in CIRT, as well as the SIB strategy.…”

Pharmacometabolomics Applied to Personalized Medicine in Urological Cancers

“…The main alterations observed in plasma extracts after 3 months of treatment exposure included an increase in the levels of cholate (an intermediate of bile acid metabolism) and a decrease in the levels of steroids and metabolites from lipid β-oxidation (several carnitines and ketone bodies), effects which were associated with the use of androgen-deprivation therapy in PCa patients [84,91]. [90] 22RV1: human prostate carcinoma epithelial cell line; AMP: adenosine monophosphate; AUC: area under curve; AR: androgen receptor; BCAAs: branched chain amino acids; BPH: benign prostatic hyperplasia; CRPC: castration resistant PCa; CV-ANOVA: analysis of variance of cross-validated residuals; DU145: cell line with epithelial morphology isolated from the prostate; GC-MS: gas chromatography-mass spectrometry; GC-TOF-MS: gas chromatography-time of flight-mass spectrometry; GSH: reduced glutathione; GSSG: oxidized glutathione; HPLC: high-performance liquid chromatography; 1 H-NMR: proton nuclear magnetic resonance spectroscopy; HSP90: heat shock protein 90; HSPC: hormone sensitive PCa; LC-MS/MS: liquid chromatography-tandem mass spectrometry; LC-HILIC-MS/MS: liquid chromatography-hydrophilic interaction chromatography-tandem mass spectrometry; LC-HRMS: liquid chromatography-high resolution mass spectrometry; LC-MS: liquid chromatography-mass spectrometry; LNCaP: lymph node carcinoma of the prostate; LPE: lysophosphatidylethanolamine; PA: phosphatidic acid; PC3: prostate cancer cell line; PC: phosphatidylcholine; PCa: prostate cancer; PCA: principal component analysis; PE: phosphatidylethanolamine; PI3K: phosphatidylinositol 3-kinase; PS: phosphatidylserine; OPLS-DA: orthogonal partial least squares-discriminant analysis; TRAMP: transgenic adenocarcinoma of mouse prostate; UMP: uridine monophosphate.…”

“…Human samples have been the preferred model for pharmacometabolomic studies of PCa, but the number of available samples collected before and after treatments has been limited. Table 1 summarizes seven pharmacometabolomic studies performed in serum, plasma, and tissue from PCa patients under hormone therapy (androgen deprivation therapy) [ 84 , 85 , 86 , 87 , 88 ] and chemotherapy regimens [ 89 , 90 ]. The first study was performed by Saylor et al [ 84 ] to investigate changes in plasmatic metabolite levels in patients receiving a gonadotropin-releasing hormone (GnRH) agonist using both GC-MS and LC-MS/MS.…”

“…The authors justified the findings by pointing out important limitations in the study that may have contributed to the results; namely, the inability to identify the circulant lipid species and the small number of patients enrolled, which remains a limiting and dependent factor in studies using human samples. Notwithstanding, a recent study using the combination of docetaxel with a luteinizing hormone-releasing hormone analog (hormone therapy) before prostatectomy addressed the impact of this adjuvant combination on the metabolome of PCa tissue samples [ 90 ]. The results unveiled significant dysregulations in the levels of several metabolites including an increase in the levels of glycerol-3-phosphate, dodecylbenzenesulfonic acid, guanosine, among others, and a decrease in the levels of phospholipids, 27-hydroxycholesterol 3 sulfate, 2-hydroxy-4-methylpentanoate, among others.…”