Project description:Neuroendocrine bladder cancer is an aggressive variant of bladder cancer with significant metastatic potential and high risk of mortality. Diagnosis of these tumors is currently dependent on morphological criteria and staining for neuroendocrine markers. Using machine learning and multiple validation cohorts in different clinical settings, we developed a model that identifies tumors with transcriptomic profiles consistent with NE bladder cancers with an absence of NE features by morphological criteria. Early and accurate identification of these patients by genomic analysis may improve outcomes through treatment intensification and adaptation of standard treatment regimens.
Project description:ATM plays a central role in the cellular response to DNA damage and ATM alterations are common in several tumor types including bladder cancer. However, the specific impact of ATM alterations on therapy response in bladder cancer is uncertain. Here, we combine preclinical modeling and clinical analyses to comprehensively define the impact of ATM alterations in bladder cancer. We show that ATM loss is sufficient to increase sensitivity to DNA damaging agents including cisplatin and radiation. Furthermore, ATM loss drives sensitivity to DNA repair targeted agents including PARP and ATR inhibitors. ATM loss alters the immune microenvironment and improves anti-PD1 response in preclinical bladder models but is not associated with improved anti-PD1/PD-L1 response in clinical cohorts. Finally, we show that ATM expression by IHC is strongly correlated with response to chemoradiotherapy. Together these data define a potential role for ATM as a predictive biomarker in bladder cancer.
Project description:To identify the therapeutic targets in a treatment-refractroy cancer patient, we performed single-cell RNA sequencing for 3,115 cells from primary bladder cancer (BC159-T#3) and patient-derived xenografts (BC159-T#3-PDX-vehicle and BC159-T#3-PDX-tipifarnib). Matched time-series bulk tumor tissues were also sequenced using whole exome target probe (WES) and whole transcriptome target probe (WTS).
Project description:Bladder cancer is one of the most common cancer types worldwide and is characterized by a high rate of recurrence. Previous studies have demonstrated that plasminogen activator inhibi-tor-1 (PAI1) plays an important role in bladder cancer development. The aim of our retrospective study was to assess the effects of PAI1 mutational status in bladder tumors. In this study, we evaluated the mutational status of PAI1 in a series of independent cohorts, comprised of a total of 660 subjects. We identified two clinically relevant 3’ untranslated region (UTR) single nucleotide polymorphisms (SNPs) in PAI1. Caucasian patients with at least one of the SNPs had high risk of recurrence and shorter survival. Additional studies using cell lines demonstrated that one SNP increased the anti-apoptotic effect of PAI1, and another lose the control of cancer cellular growth. This study underscores the relevance and influence of these SNPs in bladder cancer.