Henry Ho

Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2

Bladder cancer with loss of KDM6A expression is vulnerable to inhibition of EZH2. Cancer’s loss is targeted therapy’s gain A demethylating protein called KDM6A is a known tumor suppressor, and its function is often lost in bladder cancer as a result of inactivating mutations. There is no way to directly target the loss of the tumor suppressor, but Ler et al. found another strategy to effectively treat tumors with this mutation. The authors demonstrated that KDM6A-deficient cells are dependent on the function of another protein, called EZH2. Small-molecule inhibitors of EZH2 were effective against KDM6A-null bladder cancer in multiple mouse models, paving the way for further development of these drugs. Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, KDM6A (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of KDM6A mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type. Further transcriptome analysis found multiple deregulated pathways, especially PRC2/EZH2, in KDM6A-mutated urothelial bladder carcinoma. Chromatin immunoprecipitation sequencing analysis revealed enrichment of H3K27me3 at specific loci in KDM6A-null cells, including PRC2/EZH2 and their downstream targets. Consequently, we targeted EZH2 (an H3K27 methylase) and demonstrated that KDM6A-null urothelial bladder carcinoma cell lines were sensitive to EZH2 inhibition. Loss- and gain-of-function assays confirmed that cells with loss of KDM6A are vulnerable to EZH2. IGFBP3, a direct KDM6A/EZH2/H3K27me3 target, was up-regulated by EZH2 inhibition and contributed to the observed EZH2-dependent growth suppression in KDM6A-null cell lines. EZH2 inhibition delayed tumor onset in KDM6A-null cells and caused regression of KDM6A-null bladder tumors in both patient-derived and cell line xenograft models. In summary, our study demonstrates that inactivating mutations of KDM6A, which are common in urothelial bladder carcinoma, are potentially targetable by inhibiting EZH2.

Robotic prostate biopsy and its relevance to focal therapy of prostate cancer.

Focal therapy is an individualized treatment option for prostate cancer, which destroys localized cancerous tissue but not normal tissue, thus avoiding the morbidities associated with whole-gland therapy. Accurate cancer localization and precise ablation are integral to the success of focal therapy, which remains unproven owing to suboptimal patient selection. Currently, there are no clinical or biopsy features that can identify unifocal prostate cancer and no imaging modality that can accurately diagnose or localize prostate cancer. MRI diagnosis has the best accuracy but high cost and limited access hinder its widespread adoption. New management options, including focal therapy and active surveillance, require prostate biopsy to detect, localize and characterize the cancer. Transrectal prostate biopsy has a high false-negative detection rate, which might be related to an inability to biopsy the anterior and apical part of the prostate or interoperator variation. Transrectal biopsy is also associated with sepsis and bleeding. Robotic transperineal prostate biopsy can overcome the limitations of transrectal procedures. Robotic biopsy is automated with high accuracy, has improved access to the apex and anterior part of the prostate and has low risk of sepsis. Furthermore, it involves only two skin punctures, compared with template-based transperineal prostate biopsy, which can result in multiple wounds. Robotic prostate biopsy fulfills the fundamental needs of focal therapy and might be the platform for future treatment delivery for prostate cancer.

Software design of transperineal prostate needle biopsy robot

This paper focuses on introducing the software design of a robotic system for accurate and consistent insertion of a percutaneous biopsy needle into the prostate guided by transrectal ultrasound images. A set of software modules in the main computer system is designed to guide the urologist to control the biopsy robot and biopsy process. This system functionally undertakes the control of image acquisition, interaction with the urologist for prostate boundary delineation, puncture point planning and biopsy point definition on 2D image (ultrasound) slices. 3D visualization of the prostate surface, needle, biopsy point and needle trajectory is also performed by the software. The system calculates the required parameters of the needles trajectory and guides the urologist in maneuvering the robot to perform the biopsy. System performance and experimental results are presented at the end.

Pathological Outcome in Men with Prostate Cancer Suitable for Active Surveillance after Radical Prostatectomy

Background: Active surveillance (AS) as a treatment option for low risk prostate cancer is gaining recognition. We evaluate the validity of the AS protocol in our patient population, by defining the risk of undergrading and understaging in their pathology. We also aim to determine more accurate inclusion criteria, in order to improve the prediction of early low risk prostate cancer. Materials and Methods: Data was taken from our institutional prostate cancer registry for all men who underwent radical prostatectomy (RP) between Jan 2000 and June 2009. We determined if any of the patients would have met the University of Torontos (UoT) AS inclusion criteria and examined their post-operative pathology. The primary end-point was pathological upgrading and upstaging. The individual inclusion factors i.e. preoperative PSA, were tested for statistical significance and better cutoffs. Univariate, multivariate and ROC curves were used in the statistical analysis. Results: 216 RPs were performed between January 2000 and June 2009. We identified 79 men who fulfilled the UoT AS criteria. 35% of patients had a Gleason score upgrade from biopsy to surgery, and 21.5% of patients had an upstage to T3 disease. Overall, 34 (43%) patients had an unfavourable change in the grade and/or stage of their prostate cancer. Conclusions: There is a significant risk of undergrading and understaging with the current criteria used for AS. There is a need to identify more discriminative AS criteria before it can be offered as an option to patients with clinically early prostate cancer.