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Background and objective: Hypertension (HTN) has been linked to an elevated risk of prostate cancer (PC) development and poorer prognosis in localized cases, and is a common side effect of hormonal PC treatments. However, its relationship with the prognosis of metastatic PC is still unclear. We assessed the prognostic role of treatment-related HTN in patients with de novo metastatic hormone-sensitive PC (mHSPC) undergoing androgen deprivation therapy (ADT) alone or in combination with docetaxel or androgen receptor pathway inhibitors (ARPIs). Methods: Our retrospective analysis included 100 patients with de novo mHSPC treated with ADT, ADT + docetaxel, or ADT + ARPI between 2014 and 2021. Data on clinical variables, antihypertensive drugs, and blood pressure were collected from treatment initiation to 7 mo from ADT start. HTN development within 7 mo from hormonal treatment initiation was graded according to the Common Toxicity Criteria for Adverse Events version 5.0, and Cox analyses were performed for time to castration resistance (TTCR) and overall survival (OS). Key findings and limitations: In the overall population, grade (G) 2–3 HTN development within 7 mo from hormonal treatment initiation was associated with improved TTCR and OS at both univariate (TTCR: 19.8 vs 7.9 mo, hazard ratio [HR]: 0.35, 95% confidence interval [CI]: 0.20–0.63, p

Advanced urothelial carcinoma (aUC) has a dismal prognosis, with a 5-year survival rate of approximately 10%. Platinum-based chemotherapy has been the backbone of the first-line treatment of aUC for over 40 years. Only in the last decade, the treatment of aUC has evolved and been enriched with new classes of drugs that demonstrated pivotal improvements in terms of oncological responses and, ultimately, survival. Thus, the approach to aUC is becoming more and more tailored to the single patient, particularly owing to targeted therapies, such as fibroblast growth factor receptor (FGFR) inhibitors, antibody-drug conjugates (ADCs) targeting TROP2 and Nectin-4, anti-Her-2 therapies and others. However, due to the rapidly evolving scenario, the optimal sequence of systemic treatment is unknown and several important research questions remain unanswered, including the identification of reliable biomarkers to guide treatment decisions. Through ongoing research and clinical trials, we can continue to refine personalized treatment strategies and ultimately enhance patient care in this challenging disease setting. In this review, we provide a comprehensive overview of the current and emerging landscape of targeted therapies for aUC. We delved into the opportunities and challenges presented by personalized treatment approaches and explored potential future directions in this rapidly evolving field.

Pancreatic cancer is characterized by an immunosuppressive microenvironment, leading to immune evasion. Here, based on in vitro and in vivo CRISPR screens, the authors identify Rnf31 and Vps4b as drivers of immune escape, showing that loss of their function leads to an increase in T cell-mediated killing and reduced tumor growth in preclinical pancreatic cancer models.

Summary: The liver's remarkable regenerative capacity is orchestrated by several growth factors and cytokines. Fibroblast growth factor receptor 3 (Fgfr3) is frequently overexpressed in hepatocellular carcinoma and promotes cancer aggressiveness, whereas its role in liver homeostasis, repair and regeneration is unknown. We show here that Fgfr3 is expressed by hepatocytes in the healthy liver. Its major ligand, Fgf9, is mainly expressed by non-parenchymal cells and upregulated upon injury. Mice lacking Fgfr3 in hepatocytes exhibit increased tissue necrosis after acute toxin treatment and more excessive fibrosis after long-term injury. This was not a consequence of immunological alterations in the non-injured liver as revealed by comprehensive flow cytometry analysis. Rather, loss of Fgfr3 altered the expression of metabolic and pro-fibrotic genes in hepatocytes. These results identify a paracrine Fgf9-Fgfr3 signaling pathway that protects from toxin-induced cell death and the resulting liver fibrosis and suggests a potential use of FGFR3 ligands for therapeutic purposes.

Abstract Angiogenesis is a hallmark of cancer, promoting growth and metastasis. Anti‐angiogenic treatment has limited efficacy due to therapy‐induced blood vessel alterations, often followed by local hypoxia, tumor adaptation, progression, and metastasis. It is therefore paramount to overcome therapy‐induced resistance. We show that Apelin inhibition potently remodels the tumor microenvironment, reducing angiogenesis, and effectively blunting tumor growth. Functionally, targeting Apelin improves vessel function and reduces polymorphonuclear myeloid‐derived suppressor cell infiltration. Importantly, in mammary and lung cancer, Apelin prevents resistance to anti‐angiogenic receptor tyrosine kinase (RTK) inhibitor therapy, reducing growth and angiogenesis in lung and breast cancer models without increased hypoxia in the tumor microenvironment. Apelin blockage also prevents RTK inhibitor‐induced metastases, and high Apelin levels correlate with poor prognosis of anti‐angiogenic therapy patients. These data identify a druggable anti‐angiogenic drug target that reduces tumor blood vessel densities and normalizes the tumor vasculature to decrease metastases.

Thioredoxin (Trx), Trx reductase, Txnip and NADPH together comprise the Trx system. Here the authors make a T cell-specific thioredoxin reductase-1 knockout mouse to show how this system reprograms cellular metabolism to enable T cell development, proliferation and responses.

Summary: The HECT domain E3 ligase HACE1 has been identified as a tumor suppressor in multiple cancers. Here, we report that HACE1 is a central gatekeeper of TNFR1-induced cell fate. Genetic inactivation of HACE1 inhibits TNF-stimulated NF-κB activation and TNFR1-NF-κB-dependent pathogen clearance in vivo. Moreover, TNF-induced apoptosis was impaired in hace1 mutant cells and knockout mice in vivo. Mechanistically, HACE1 is essential for the ubiquitylation of the adaptor protein TRAF2 and formation of the apoptotic caspase-8 effector complex. Intriguingly, loss of HACE1 does not impair TNFR1-mediated necroptotic cell fate via RIP1 and RIP3 kinases. Loss of HACE1 predisposes animals to colonic inflammation and carcinogenesis in vivo, which is markedly alleviated by genetic inactivation of RIP3 kinase and TNFR1. Thus, HACE1 controls TNF-elicited cell fate decisions and exerts tumor suppressor and anti-inflammatory activities via a TNFR1-RIP3 kinase-necroptosis pathway. : Tortola et al. report that the E3 ubiquitin ligase HACE1 is a gatekeeper of TNFR1-mediated cell fate. Hace1 deficiency impairs TNF-driven NF-κB activation and apoptosis and predisposes cells to necroptosis. Consequently, hace1–/– mice show enhanced colitis and colon cancer, which can be reverted by inactivation of pro-necroptotic kinase RIP3 and TNFR1.