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Primary mediastinal germ cell tumors (PMGCTs) are a rare type of cancer affecting young adults. They have different molecular and clinical features compared to testicular germ cell tumors. Non-seminoma PMGCTs have the shortest 5-year overall survival and the poorest prognosis among all of the germ cell tumor presentations, while seminomas share the same survival and prognosis as their testicular counterparts. There is an unmet need for better treatment options for patients with non-seminoma PMGCTs in both first-line and salvage therapy, as the available options are associated with underwhelming outcomes. Identifying biological and genetic factors to predict treatment responses would be helpful in improving the survival of these patients.

HSP27 is highly expressed in, and supports oncogene addiction of, many cancers. HSP27 phosphorylation is a limiting step for activation of this protein and a target for inhibition, but its highly disordered structure challenges rational structure-guided drug discovery. We performed multistep biochemical, structural, and computational experiments to define a spherical 24-monomer complex composed of 12 HSP27 dimers with a phosphorylation pocket flanked by serine residues between their N-terminal domains. Ivermectin directly binds this pocket to inhibit MAPKAP2-mediated HSP27 phosphorylation and depolymerization, thereby blocking HSP27-regulated survival signaling and client-oncoprotein interactions. Ivermectin potentiated activity of anti-androgen receptor and anti-EGFR drugs in prostate and EGFR/HER2-driven tumor models, respectively, identifying a repurposing approach for cotargeting stress-adaptive responses to overcome resistance to inhibitors of oncogenic pathway signaling.

Predictive biomarkers of response to immune checkpoint-based therapies (ICI) remain a critically unmet need in the management of advanced renal cell carcinoma (RCC). The complex interplay of the tumour microenvironment (TME) and the circulating immune response has proven to be challenging to decipher. MicroRNAs have gained increasing attention for their role in post-transcriptional gene expression regulation, particularly because they can have immunomodulatory properties. We evaluated the presence of immune-specific extracellular vesicle (EV) microRNAs in the plasma of patients with metastatic RCC (mRCC) prior to initiation of ICI. We found significantly lower levels of microRNA155-3p (miR155) in responders to ICI, when compared to non-responders. This microRNA has unique immunomodulatory properties, thus providing potential biological rationale for our findings. Our results support further work in exploring microRNAs as potential biomarkers of response to immunotherapy.

Treatment‐induced adaptive pathways converge to support androgen receptor (AR) reactivation and emergence of castration‐resistant prostate cancer (PCa) after AR pathway inhibition (ARPI). We set out to explore poorly defined acute adaptive responses that orchestrate shifts in energy metabolism after ARPI and identified rapid changes in succinate dehydrogenase (SDH), a TCA cycle enzyme with well‐known tumor suppressor activity. We show that AR directly regulates transcription of its catalytic subunits (SDHA, SDHB) via androgen response elements (AREs). ARPI acutely suppresses SDH activity, leading to accumulation of the oncometabolite, succinate. Succinate triggers calcium ions release from intracellular stores, which in turn phospho‐activates the AR‐cochaperone, Hsp27 via p‐CaMKK2/p‐AMPK/p‐p38 axis to enhance AR protein stabilization and activity. Activation of this pathway was seen in tissue microarray analysis on prostatectomy tissues and patient‐derived xenografts. This adaptive response is blocked by co‐targeting AR with Hsp27 under both in vitro and in vivo studies, sensitizing PCa cells to ARPI treatments. Synopsis Prostate cancer becomes resistant to treatments targeting oncogenic androgen receptor (AR) via coordinated activity of multiple adaptive responses. This study defines metabolic reprogramming in response to AR pathway inhibition (ARPI) that supports AR reactivation. AR regulatory elements (AREs) were identified in catalytic subunits SDHA and SDHB of succinate dehydrogenase (SDH) enzyme. ARPI inhibited SDH activity resulting in accumulation of intracellular succinate. Intracellular succinate triggered Ca 2+ release to activate p‐CAMKK2/p‐AMPK/p‐p38 axis, increasing levels of the AR co‐chaperone p‐Hsp27 to support AR protein and signaling. Co‐targeting p‐Hsp27 with ARPI abrogated this succinate‐mediated adaptive loop and enhanced prostate cancer sensitivity to ARPI. Graphical Abstract Prostate cancer becomes resistant to treatments targeting oncogenic androgen receptor (AR) via coordinated activity of multiple adaptive responses. This study defines metabolic reprogramming in response to AR pathway inhibition (ARPI) that supports AR reactivation.

Clusterin (CLU) is a stress‐activated molecular chaperone that confers treatment resistance to taxanes when highly expressed. While CLU inhibition potentiates activity of taxanes and other anti‐cancer therapies in preclinical models, progression to treatment‐resistant disease still occurs implicating additional compensatory survival mechanisms. Taxanes are believed to selectively target cells in mitosis, a complex mechanism controlled in part by balancing antagonistic roles of Cdc25C and Wee1 in mitosis progression. Our data indicate that CLU silencing induces a constitutive activation of Cdc25C, which delays mitotic exit and hence sensitizes cancer cells to mitotic‐targeting agents such as taxanes. Unchecked Cdc25C activation leads to mitotic catastrophe and cell death unless cells up‐regulate protective mechanisms mediated through the cell cycle regulators Wee1 and Cdk1. In this study, we show that CLU silencing induces a constitutive activation of Cdc25C via the phosphatase PP2A leading to relief of negative feedback inhibition and activation of Wee1‐Cdk1 to promote survival and limit therapeutic efficacy. Simultaneous inhibition of CLU‐regulated cell cycle effector Wee1 may improve synergistic responses of biologically rational combinatorial regimens using taxanes and CLU inhibitors. Synopsis CLU silencing sensitizes prostate cancer cells to taxane by inducing a constitutive activation of Cdc25C leading to a delay in exit from mitosis. In response, cells up‐regulate protective mechanisms through Wee1 kinase. CLU expression and Cdc25C expression are negatively correlated in prostate cancer cell lines, mice xenografts, and human biopsies. CLU silencing induces accumulation of Cdc25C‐T48 phosphorylation. Constitutive activation of Cdc25C by CLU silencing is compensated by Wee1 up‐regulation. CLU silencing sensitizes PC3 cells to cabazitaxel, and inhibition of Wee1 improves synergistic responses to combination of taxanes and CLU inhibitors. Graphical Abstract CLU silencing sensitizes prostate cancer cells to taxane by inducing a constitutive activation of Cdc25C leading to a delay in exit from mitosis. In response, cells up‐regulate protective mechanisms through Wee1 kinase.

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer resistant to androgen receptor (AR) inhibitors. Our study unveils that AR suppresses the neuronal development protein dihydropyrimidinase-related protein 5 (DPYSL5), providing a mechanism for neuroendocrine transformation under androgen deprivation therapy. Our unique CRPC-NEPC cohort, comprising 135 patient tumor samples, including 55 t-NEPC patient samples, exhibits a high expression of DPYSL5 in t-NEPC patient tumors. DPYSL5 correlates with neuroendocrine-related markers and inversely with AR and PSA. DPYSL5 overexpression in prostate cancer cells induces a neuron-like phenotype, enhances invasion, proliferation, and upregulates stemness and neuroendocrine-related markers. Mechanistically, DPYSL5 promotes prostate cancer cell plasticity via EZH2-mediated PRC2 activation. Depletion of DPYSL5 decreases proliferation, induces G1 phase cell cycle arrest, reverses neuroendocrine phenotype, and upregulates luminal genes. In conclusion, DPYSL5 plays a critical role in regulating prostate cancer cell plasticity, and we propose the AR/DPYSL5/EZH2/PRC2 axis as a driver of t-NEPC progression. Androgen receptor (AR) suppresses DPYSL5, and overexpression of DPYSL5 promotes prostate cancer cell plasticity via EZH2-mediated PRC2 activation, suggesting that the AR/DPYSL5/EZH2/PRC2 axis may act as a driver of treatment-induced neuroendocrine prostate cancer.

Clonal hematopoiesis (CH) is an age-related expansion of white blood cell (WBC) progenitors linked to risk of hematological malignancy. Patients with cancer have increased CH prevalence compared to healthy populations, but the characteristics and relevance of CH in advanced urological cancers are unknown. We interrogated CH and circulating tumor DNA (ctDNA) in 299 patients with metastatic urothelial or renal cell carcinoma using error-corrected targeted sequencing of matched WBC DNA and plasma cell-free DNA (cfDNA). 73% of patients carried CH variants at ≥0.25% allele frequency, with 13% exhibiting large CH populations marked by variants ≥10%. CH presence, clone size, and genotype did not impact patient survival. However, CH variants frequently affected solid cancer driver genes and were not individually discriminable from ctDNA variants based on cfDNA features including fragment length. In contrast, matched WBC DNA sequencing to ≥25% of cfDNA depth sufficiently resolved CH from ctDNA variants. Serial profiling revealed ctDNA and CH temporal dynamics including treatment-related expansion of PPM1D -mutated CH clones following platinum chemotherapy. Our data reveal the molecular landscape of CH in urological cancers and suggest that CH interferes in clinical ctDNA genotyping. We urge test providers to comprehensively filter CH from ctDNA results using matched WBC sequencing and propose a cost-effective framework for its integration into existing plasma-only assays.

Metastatic penile squamous cell carcinoma (PSCC) is associated with dismal outcomes with median overall survival (OS) of 6-12 months in the first-line and <6 months in the salvage setting. Given the rarity of this disease, randomized trials are difficult. Prognostic risk models may assist in rational drug development by comparing observed outcomes in nonrandomized phase II studies and retrospective data vs. predicted outcomes based on baseline prognostic factors in the context of historically used agents. In this retrospective study, we constructed a prognostic model in the salvage setting of PSCC patients receiving second or later line systemic treatment, and also explored differences in outcomes based on type of treatment. : We performed a chart review to identify patients with locally advanced unresectable or metastatic PSCC who received second or later line systemic treatment in centers from North America and Europe. The primary outcome was OS from initiation of treatment, with secondary outcomes being progression-free survival (PFS) and response rate (RR). OS was estimated using the Kaplan-Meier method. Cox proportional hazards regression was used to identify prognostic factors for outcomes using univariable and multivariable models. Sixty-five patients were eligible. Seventeen of 63 evaluable patients had a response (27.0%, 95% confidence interval [CI] = 16.6-39.7%) and median OS and PFS were 20 (95% CI = 20-21) and 12 (95% CI = 12, 16) weeks, respectively. Visceral metastasis (VM) and hemoglobin (Hb) ≤ 10 gm/dl were consistently significant poor prognostic factors for both OS and PFS, and Hb was also prognostic for response. The 28 patients with neither risk factor had a median OS (95% CI) of 24 (20-40) weeks and 1-year (95% CI) OS of 13.7% (4.4-42.7%), while the 37 patients with 1 or 2 risk factors had median OS (95% CI) of 20 (16-20) weeks and 1-year (95% CI) OS of 6.7% (1.8-24.9%). Cetuximab-including regimens were associated with a trend for improved RR compared to other agents (Odds ratio = 5.05, 95% CI = 0.84-30.37, = 0.077). Taxanes vs. non-taxane, and combination vs. single agent therapy was not associated with improved outcomes. The study is limited by its modest sample size. This is the first prognostic classification proposed for patients receiving salvage systemic therapy for advanced PSCC. The presence of VM and Hb ≤ 10 gm/dl was associated with poor OS and PFS. Cetuximab appeared to be associated with better RR. This prognostic model may assist in salvage therapy drug development for this orphan disease by improving interpretation of outcomes seen in nonrandomized data.