ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity.

PURPOSE: Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC. METHODS: We analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo. RESULTS: OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors. CONCLUSIONS: The transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.

Targeting Key Players of Neuroendocrine Differentiation in Prostate Cancer.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PC) that commonly emerges through a transdifferentiation process from prostate adenocarcinoma and evades conventional therapies. Extensive molecular research has revealed factors that drive lineage plasticity, uncovering novel therapeutic targets to be explored. A diverse array of targeting agents is currently under evaluation in pre-clinical and clinical studies with promising results in suppressing or reversing the neuroendocrine phenotype and inhibiting tumor growth and metastasis. This new knowledge has the potential to contribute to the development of novel therapeutic approaches that may enhance the clinical management and prognosis of this lethal disease. In the present review, we discuss molecular players involved in the neuroendocrine phenotype, and we explore therapeutic strategies that are currently under investigation for NEPC.

Actionable Driver Events in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) stands out as the most aggressive form of lung cancer, characterized by an extremely high proliferation rate and a very poor prognosis, with a 5-year survival rate that falls below 7%. Approximately two-thirds of patients receive their diagnosis when the disease has already reached a metastatic or extensive stage, leaving chemotherapy as the remaining first-line treatment option. Other than the recent advances in immunotherapy, which have shown moderate results, SCLC patients cannot yet benefit from any approved targeted therapy, meaning that this cancer remains treated as a uniform entity, disregarding intra- or inter-tumoral heterogeneity. Continuous efforts and technological improvements have enabled the identification of new potential targets that could be used to implement novel therapeutic strategies. In this review, we provide an overview of the most recent approaches for SCLC treatment, providing an extensive compilation of the targeted therapies that are currently under clinical evaluation and inhibitor molecules with promising results in vitro and in vivo.

[Factors associated with emergency department revisits for acute bacterial prostatitis]. / Factores asociados a la reconsulta en urgencias en la prostatitis aguda bacteriana.

OBJECTIVES: To analyze factors associated with revisits by patients with acute bacterial prostatitis treated in a hospital emergency department. MATERIAL AND METHODS: Descriptive analysis and prospective follow-up of a cohort of patients with acute bacterial prostatitis treated in an emergency department. RESULTS: We included 241 episodes of acute bacterial prostatitis. The mean (SD) age was 63 (16) years. Seventy-three percent reported dysuria, 64% had fever, and between 15.4% and 22.4% had medical histories of cancer, urethral/bladder catheterization, or prostate adenoma. Positive urine cultures were obtained for 48.1% and positive blood cultures for 17.6%. Escherichia coli was the bacterium isolated most often, and 27.7% of the cultures showed resistance to ciprofloxacin and amoxicillin-clavulanic acid. Twenty-nine patients (12%) revisited within 30 days. The only factors associated with revisiting were performance of a rectal examination (odds ratio [OR], 9.23; 95% CI, 1.12-75.82) and bacteremia (OR, 3.81; 95% CI, 1.31-11.04) (P<.05). CONCLUSION: Factors associated with revisiting for acute bacterial prostatitis were bacteremia and performance of a rectal examination.

OBJETIVO: Analizar los factores asociados a la reconsulta del paciente con prostatitis aguda bacteriana (PAB) atendido en el servicio de urgencias hospitalario (SUH). METODO: Estudio analítico de cohorte observacional con seguimiento prospectivo de las PAB atendidas en el SUH durante un año. RESULTADOS: Se registraron 241 episodios de PAB. La edad media fue de 63 (DE: 16) años. Presentaron disuria el 73%, fiebre el 64% y antecedentes de cáncer, manipulación previa de la vía urinaria o adenoma prostático entre el 15,4- 22,4%. El 48,1% de los urocultivos y el 17,6% de los hemocultivos resultaron positivos. Escherichia coli fue el aislamiento mayoritario, presentando con resistencias en el 27,7% a ciprofloxacino y amoxicilina/clavulánico. A los 30 días reconsultaron 29 pacientes (12%). El tacto rectal, con odss ratio (OR) 9,23 (IC 95%: 1,12-75,82), y la bacteriemia, con OR de 3,81 (IC 95%: 1,31-11,04), fueron las únicas variables asociadas a la reconsulta (p <0,05). CONCLUSIONES: Los factores relacionados con la reconsulta del enfermo con PBA fueron la presencia de bacteriemia y el tacto rectal.