Molecular basis and therapeutic targets in prostate cancer: A comprehensive review.

Prostate cancer is one of the most significant causes of morbidity and mortality in male patients. The incidence increases with age, and it is higher among African Americans. The occurrence of prostate cancer is associated with many risk factors, including genetic and hereditary predisposition. The most common genetic syndromes associated with prostate cancer risk are BRCA-associated hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. Local-regional therapy, i.e., surgery is beneficial in early-stage prostate cancer management. Advanced and metastatic prostate cancers require systemic therapies, including hormonal inhibition, chemotherapy, and targeted agents. Most prostate cancers can be treated by targeting the androgen-receptor pathway and decreasing androgen production or binding to androgen receptors (AR). Castration-resistant prostate cancer (CRPC) usually involves the PI3K/AKT/mTOR pathway and requires targeted therapy. Specific molecular therapy can target mutated cell lines in which DNA defect repair is altered, caused by mutations of BRCA2, partner and localizer of BRCA2 (PALB2), and phosphatase and tensin homolog (PTEN) or the transmembrane protease serine 2-ERG (TMPRSS2-ERG) fusion. Most benefits were demonstrated in cyclin dependent-kinase 12 (CDK12) mutated cell lines when treated with anti-programmed cell death protein 1 (PD1) therapy. Therapies targeting p53 and AKT are the subject of ongoing clinical trials. Many genetic defects are listed as diagnostic, prognostic, and clinically actionable markers in prostate cancer. Androgen receptor splice variant 7 (AR-V7) is an important oncogenic driver and an early diagnostic and prognostic marker, as well as a therapeutic target in hormone-resistant CRPC. This review summarizes the pathophysiological mechanisms and available targeted therapies for prostate cancer.

The impact of the CYP2C9 and VKORC1 polymorphisms on acenocoumarol dose requirements in a Romanian population.

AIM: To investigate the genotype-phenotype correlation in Romanian patients treated with acenocoumarol. MATERIAL AND METHODS: We studied 301 consecutive patients who required treatment with acenocoumarol, admitted within the Municipal Hospital of Cluj-Napoca and the Heart Institute "Niculae Stanciou" in Cluj-Napoca over a 3-year period. For each patient we recorded clinical parameters which could interfere with the achievement of stable therapeutic international normalized ratio (INR). We performed genetic analysis which consisted of genotyping the CYP2C9 gene and the VKORC1 gene. Patients were divided in three groups according to the acenocoumarol dose needed to reach a stable INR: the low dose group (≤7mg/week), the medium dose group (>7mg and <28mg/week) and the high acenocoumarol dose group (>28mg/week). RESULTS: We found that patients' age was significantly different between groups (p<0.001). No differences existed between groups regarding the pathologies which required anticoagulation therapy or the concomitant treatment. The following parameters increased the odds of receiving a low dose of acenocoumarol: patient's age over 65years (OR, 3.2; p=0.01; 95%CI: 1.24-8.25), the presence of the CYP2C9*3 allele (OR, 3.4; p=0.006; 95%CI: 1.41-8.34), and the GA or AA genotype of c.-1639G>A polymorphism of VKORC1 (OR, 6.5; p=0.01; 95%CI: 1.38-30.5; respectively OR, 11.6; p=0.003; 95%CI: 2.26-59.58). A high acenocoumarol dose was less likely to be administered to an elderly patient (OR, 0.24; p=0.001; 95%CI: 0.1-0.56) or to a patient with the GA or AA genotype (OR, 0.2; p<0.001; 95CI%: 0.09-0.45; respectively OR, 0.05; p=0.006; 95%CI: 0.007-0.43). CONCLUSION: The stable therapeutic dose of acenocoumarol is dependent of patient's age, the presence of the CYP2C9*3 allele and the c.-1639G>A polymorphism of VKORC1.