John Yuen

The type 1 insulin-like growth factor receptor pathway.

Research conducted over the past two decades has shown the importance of the type 1 insulin-like growth factor receptor (IGF1R) in tumorigenesis, metastasis, and resistance to existing forms of cancer therapy. The IGF1R itself has only recently been accepted as a credible treatment target, however, perhaps reflecting the potential problems for drug design posed by normal tissue IGF1R expression, and close homology with the insulin receptor. Currently ∼12 anti-IGF1R therapeutics are undergoing clinical evaluation, including blocking antibodies and tyrosine kinase inhibitors. This review will summarize the principal signaling pathways activated by IGF1R and the preclinical data that validated this receptor as a treatment target. We will review clinical progress in the testing of IGF1R inhibitory drug candidates, the relative benefits and potential toxicities of coinhibition of the insulin receptor, and the rationale for combining IGF1R blockade with other cancer treatments. An understanding of IGF1R signaling is important because it will guide the incorporation of appropriate molecular markers into clinical trial design. This will be key to the identification of patients most likely to benefit, and so will influence the ability of IGF1R inhibition to make the transition from experimental intervention to clinical therapy.

Targeting the type 1 insulin-like growth factor receptor as a treatment for cancer

Background: The type 1 insulin-like growth factor receptor (IGF1R) plays a critical role in transformation, invasion and apoptosis protection, and is an attractive cancer treatment target. Objective: To review IGF1R antibodies and kinase inhibitors that are in preclinical and clinical development, and to discuss questions that will influence the success of this approach in clinical practice. Methods: This review is drawn from published literature, meeting abstracts and online resources. Results/conclusion: IGF1R blockade is generally well tolerated although it can induce hyperglycaemia. Single-agent activity has been documented in Ewings sarcoma but not thus far in common solid tumours. Key issues include identification of factors that influence sensitivity to IGF1R blockade, and how most effectively to combine IGF1R inhibitors with other treatments.

Ultrasound Guided Robotic System for Transperineal Biopsy of the Prostate

We present a prototype of a robotic system for accurate and consistent insertion of a percutaneous biopsy needle into the prostate. The robot manipulates a transrectal ultrasound (TRUS) probe to collect a series of 2 dimensional (2D) images of the prostate, which are later used to create a 3D computer model of the organ. The urologist defines the needle’s entry point at the perineal wall and the biopsy points within the 3D model following a biopsy protocol or otherwise. The robotic system then calculates the required trajectory of the needle. The path of the needle going into the prostate can also be simulated with the 3D model before the actual insertion. Being satisfied with the predicted outcome, the urologist configures the robot accordingly and manually pushes the mechanically guided needle into the patient to take the biopsy. Cadaveric and human trials have validated the robot’s needle placement error to be less than 2.5mm. Our future work includes the integration of a cancer predictive modality into the system to increase the cancer detection rate. The robotic system could also be modified to accurately place foreign bodies into the prostate, which could improve therapeutic procedures such as Brachytherapy.

Validation of the type 1 insulin-like growth factor receptor as a therapeutic target in renal cancer

Purpose: Expression of the type 1 insulin-like growth factor receptor (IGF1R) confers adverse prognosis in clear cell renal cell cancer (CC-RCC). We recently showed that IGF1R expression is inhibited by the von Hippel-Lindau (VHL) tumor suppressor, and the IGF1R is up-regulated in CC-RCC, in which VHL is frequently inactivated. We tested the hypothesis that IGF1R up-regulation mediates resistance to cancer therapeutics, evaluating the effects of IGF1R depletion on sensitivity to cytotoxic drugs, which are ineffective in RCC, and the mammalian target of rapamycin (mTOR) inhibitor rapamycin, analogues of which have clinical activity in this tumor. Experimental Design: This study used CC-RCC cells harboring mutant VHL, and isogenic cells expressing functional VHL. Cells were transfected with nonsilencing control small interfering RNA (siRNA), or with one of two different IGF1R siRNAs. The more potent siRNA was modified by 2′-O-methyl derivatization for in vivo administration. Results: CC-RCC cells expressing mutant VHL and higher IGF1R were more chemoresistant than cells expressing functional VHL. IGF1R depletion induced apoptosis, blocked cell survival, and sensitized to 5-fluorouracil and etoposide. These effects were significantly greater in CC-RCC cells expressing mutant VHL, supporting the hypothesis that IGF1R up-regulation makes a major contribution to the chemoresistance associated with VHL loss. IGF1R depletion also enhanced sensitivity to mTOR inhibition, at least in part due to suppression of rapamycin-induced Akt activation. Administration of stabilized IGF1R siRNA was shown to sensitize CC-RCC xenografts to rapamycin in vivo. Conclusion: These data validate IGF1R as a therapeutic target in CC-RCC, and support the evaluation of IGF1R-inhibitory drugs in patients with renal cancer. [Mol Cancer Ther 2009;8(6):1448–59]

Optimum slicing of radical prostatectomy specimens for correlation between histopathology and medical images.

PurposeThere is a need for methods which enable precise correlation of histologic sections with in vivo prostate images. Such methods would allow direct comparison between imaging features and functional or histopathological heterogeneity of tumors. Correlation would be particularly useful for validating the accuracy of imaging modalities, developing imaging techniques, assessing image-guided therapy, etc. An optimum prostate slicing method for accurate correlation between the histopathological and medical imaging planes in terms of section angle, thickness and level was sought.MethodsLiterature review (51 references from 1986–2009 were cited) was done on the various sectioning apparatus or techniques used to slice the prostate specimen for accurate correlation between histopathological data and medical imaging. Technology evaluation was performed with review and discussion of various methods used to section other organs and their possible applications for sectioning prostatectomy specimens.ResultsNo consensus has been achieved on how the prostate should be dissected to achieve a good correlation. Various customized sectioning instruments and techniques working with different mechanism are used in different research institutes to improve the correlation. Some of the methods have convincingly shown significant potential for improving image-specimen correlation. However, the semisolid consistent property of prostate tissue and the lack of identifiable landmarks remain challenges to be overcome, especially for fresh prostate sectioning and microtomy without external fiducials.ConclusionsA standardized optimum protocol to dissect prostatectomy specimens is needed for the validation of medical imaging modalities by histologic correlation. These standards can enhance disease management by improving the comparability between different modalities.

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.

Comparison of the UCLA Integrated Staging System and the Leibovich Score in Survival Prediction for Patients With Nonmetastatic Clear Cell Renal Cell Carcinoma

OBJECTIVES To directly compare the models-the UCLA-Integrated Scoring System (UISS) and the Leibovich models-using various survival endpoints. Several Phase III trials of adjuvant therapy in renal cell carcinoma (RCC) have been initiated after advances in targeted therapy. To select patients at high risk of relapse and mortality, 2 aforementioned prognostic models have been incorporated into these trials. These models have not been compared previously. METHODS A retrospective study of 355 patients with unilateral nonmetastatic clear cell RCC undergoing nephrectomy between 1990 and 2006 at the Singapore General Hospital was undertaken. Performance of the UISS and the Leibovich models, as well as corresponding trial inclusion criteria, was directly compared using log-likelihood statistics. Adequacy and concordance indices were also calculated. Study endpoints tested were overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS). RESULTS Likelihood ratio testing demonstrated a significant benefit in prediction when adding the Leibovich model to the UISS model in all outcomes tested, with no benefit using the converse approach (OS: P=.002 vs P=.27; CSS: P=.0001 vs P=.57; DFS: P=<0.0001 vs P=.30). Benefit was seen primarily in disease-free survival when adding the Leibovich trial criteria to UISS trial criteria, with no benefit using the converse approach (OS: P=.16 vs P=.27; CSS: P=.17 vs P=.11; DFS: P=.01 vs P=.26). CONCLUSIONS Both the Leibovich model and trial criteria are superior to the UISS model and trial criteria, respectively, in estimating survival outcomes in patients with nonmetastatic clear cell RCC after nephrectomy.

Mutation signatures implicate aristolochic acid in bladder cancer development

BackgroundAristolochic acid (AA) is a natural compound found in many plants of the Aristolochia genus, and these plants are widely used in traditional medicines for numerous conditions and for weight loss. Previous work has connected AA-mutagenesis to upper-tract urothelial cell carcinomas and hepatocellular carcinomas. We hypothesize that AA may also contribute to bladder cancer.MethodsHere, we investigated the involvement of AA-mutagenesis in bladder cancer by sequencing bladder tumor genomes from two patients with known exposure to AA. After detecting strong mutational signatures of AA exposure in these tumors, we exome-sequenced and analyzed an additional 11 bladder tumors and analyzed publicly available somatic mutation data from a further 336 bladder tumors.ResultsThe somatic mutations in the bladder tumors from the two patients with known AA exposure showed overwhelming AA signatures. We also detected evidence of AA exposure in 1 out of 11 bladder tumors from Singapore and in 3 out of 99 bladder tumors from China. In addition, 1 out of 194 bladder tumors from North America showed a pattern of mutations that might have resulted from exposure to an unknown mutagen with a heretofore undescribed pattern of A > T mutations. Besides the signature of AA exposure, the bladder tumors also showed the CpG > TpG and activated-APOBEC signatures, which have been previously reported in bladder cancer.ConclusionsThis study demonstrates the utility of inferring mutagenic exposures from somatic mutation spectra. Moreover, AA exposure in bladder cancer appears to be more pervasive in the East, where traditional herbal medicine is more widely used. More broadly, our results suggest that AA exposure is more extensive than previously thought both in terms of populations at risk and in terms of types of cancers involved. This appears to be an important public health issue that should be addressed by further investigation and by primary prevention through regulation and education. In addition to opportunities for primary prevention, knowledge of AA exposure would provide opportunities for secondary prevention in the form of intensified screening of patients with known or suspected AA exposure.

Metastatic lung cancer causing bowel perforations: Spontaneous or chemotherapy-related?

Acute abdomen due to perforation of metastatic small bowel deposit from advanced lung cancer is rare. While there are approximately 20 such cases reported in the literature, most of these perforations were spontaneous in nature. We report two cases of small bowel perforations as a result of metastasis from primary lung carcinoma shortly after a course of chemotherapy. This raises the possibility that the perforation might be due to tumour necrosis after chemotherapy. Awareness of the condition is important as delayed surgery in this immunocompromised group of patients decreases their chances of survival significantly.

Molecular targeted therapy in advanced renal cell carcinoma: a review of its recent past and a glimpse into the near future.

Renal cell carcinoma (RCC) is the most lethal of all urologic malignancies. Recent translational research in RCC has led to the discovery of a new class of therapeutics that specifically target important signaling molecules critical in the pathogenesis of the disease. It is now clear that these new molecular targeted agents have revolutionized the management of patients with metastatic RCC. However, the exact molecular mechanism accounting for their clinical effect is largely unknown and a significant proportion of patients with metastatic RCC do not respond to these therapeutics. This review presents the relevant background leading to the development of molecular targeted therapy for patients with advanced RCC and summarizes current management issues in particular relating to the emerging problem of treatment resistance and the need for clinical and laboratory biomarkers to predict treatment outcomes in these patients. In addition, this paper will also address surgical issues in the era of molecular targeted therapy including the role of cytoreductive surgery and surgical safety issues post-molecular therapy. Lastly, this review will also address the need to explore new molecular treatment targets in RCC and briefly present our work on one of the promising molecular targets - the type 1 insulin-like growth factor receptor (IGF1R), which may in the near future lead to the development of anti-IGF1R therapy for patients with advanced RCC.