Nonmetastatic castration-resistant prostate cancer: Novel agents to treat a lethal disease

Nonmetastatic castration-resistant prostate cancer(nmCRPC)-defined as prostate-specific antigen(PSA)>2 ng/mL,testosterone castration levels<1.7 nm/L,and the absence of metastatic lesions on conventional imaging(computed tomography or bone scan)-has been defined as a lethal disease by the Prostate Cancer Work Group.One-third of patients with prostate cancer who receive androgen deprivation therapy for biochemical recurrence after local treatment will develop CRPC,with death occurring an average of 2.5 years after diagnosis of castration resistance.Most patients diagnosed with nmCRPC are asymptomatic or minimally symptomatic at diagnosis due to local treatment.In patients with short PSA doubling times(<10 mo)and high baseline PSA levels,there is a high risk of bone metastases followed by prostate cancer-related mortality.These patients also present significant morbidity that negatively impacts quality of life(QoL).Recently,the results of three randomized trials(PROSPER,SPARTAN,and ARAMIS)were published.Those trials evaluated the efficacy of three different androgen receptor inhibitors-enzalutamide,apalutamide,and darolutamide-in patients with nmCRPC.In all three trials,the study drugs improved both metastasis-free survival and overall survival compared to placebo,plus on-going androgen deprivation therapy without a negative impact on QoL.In patients with nmCRPC,the most important clinical objective is early detection and treatment to maintain a low tumor burden and to prolong the symptom-free interval.For patients with nmCRPC,these novel drugs offer new hope for better QoL and survival outcomes.

Repurposing Loperamide as an Anti-Infection Drug for the Treatment of Intracellular Bacterial Pathogens

Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells.The rapid development and dissemination of antimicrobial–resistant strains have exacerbated this dilemma.With the increasing knowledge of host–pathogen interactions,especially bacterial strategies for survival and proliferation within host cells,host-directed therapy(HDT)has attracted increased interest and has emerged as a promising antiinfection method for treating intracellular infection.Herein,we applied a cell-based screening approach to a US Food and Drug Administration(FDA)-approved drug library to identify compounds that can inhibit the intracellular replication of Salmonella Typhimurium(S.Typhimurium).This screening allowed us to identify the antidiarrheal agent loperamide(LPD)as a potent inhibitor of S.Typhimurium intracellular proliferation.LPD treatment of infected cells markedly promoted the host autophagic response and lysosomal activity.A mechanistic study revealed that the increase in host autophagy and elimination of intracellular bacteria were dependent on the high expression of glycoprotein nonmetastatic melanoma protein B(GPNMB)induced by LPD.In addition,LPD treatment effectively protected against S.Typhimurium infection in Galleria mellonella and mouse models.Thus,our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial pathogens.Moreover,LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.

Enzalutamide:a new indication for nonmetastatic castration-resistant prostate cancer

PROSPER is an international Phase III trial demonstrating the beneficial role of enzalutamide,an androgen receptor antagonist,in prolonging metastasisfree survival in men with nonmetastatic castration-resistant prostate cancer.The trial showed that the median metastasis-free survival was 21.9 months longer for those treated with enzalutamide(36.6 months)compared to those treated with placebo(14.7 months).Enzalutamide also showed prolonged time to PSA progression,PSA response,and time to initiating additional antineoplastic therapy although overall survival is not yet reached.Enzalutamide is the second antiandrogen(next to apalutamide)that has gained the United States Food and Drug Administration(US FDA)label indication for use in the setting of nonmetastatic castration-resistant prostate cancer.