[Show abstract][Hide abstract] ABSTRACT: Sorafenib, a multikinase inhibitor, is currently used as monotherapy for advanced renal cell carcinoma (RCC). However, adverse effects associated with its use have been experienced by some patients. In this study, we examined the antitumor and antiangiogenic activities of low-dose sorafenib in combination with the MEK inhibitor AZD6244 (sorafenib/AZD6244) in a preclinical model of RCC. Primary RCC 08-0910 and RCC 786-0 cells as well as patient-derived RCC models were used to study the antitumor and antiangiogenic activities of sorafenib/AZD6244. Changes of biomarkers relevant to angiogenesis and cell cycle were determined by western immunoblotting. Microvessel density, apoptosis and cell proliferation were analyzed by immunohistochemistry. Treatment of RCC 786-0 cells with sorafenib/AZD6244 resulted in G1 cell cycle arrest and blockade of serum-induced cell migration. Sorafenib/AZD6244 induced apoptosis in primary RCC 08-0910 cells at low concentrations. In vivo addition of AZD6244 to sorafenib significantly augmented the antitumor activity of sorafenib and allowed dose reduction of sorafenib without compromising its antitumor activity. Sorafenib/AZD6244 potently inhibited angiogenesis and phosphorylation of VEGFR-2, PDGFR-β and ERK, p90RSK, p70S6K, cdk-2 and retinoblastoma. Sorafenib/AZD6244 also caused upregulation of p27, Bad and Bim but downregulation of survivin and cyclin B1. These resulted in a reduction in cellular proliferation and the induction of tumor cell apoptosis. Our findings showed that AZD6244 and sorafenib complement each other to inhibit tumor growth. This study provides sound evidence for the clinical investigation of low-dose sorafenib in combination with AZD6244 in patients with advanced RCC.
International Journal of Oncology 05/2012; 41(2):712-20. · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: To develope a robot (BioXbot) that performs mapping transperineal prostate biopsy (PB) with two perineal skin punctures under ultrasound guidance. Our pilot study's clinical endpoints were complications and its technical endpoints were the duration for each phase.
This institution review board-approved prospective clinical trial included patients with indications for PB. Two urologists performed these PBs. In the lithotomy position and under general anesthesia, the transrectal biplane ultrasound probe acquired transverse images of the prostate gland. The urologist defined its boundaries and planned the biopsy. It guided the PB in 3 axes, passing through a single perineal skin puncture for each prostate side. After each biopsy, it automatically moved to the next position. The steps were repeated on the contralateral side.
Our 20 patients had a mean prostate-specific antigen of 8.4 ± 4.9 ng/mL. Two patients had 2 previous biopsies, whereas the rest had one. The mean number of biopsies taken was 28.5 ± 6.2 in a mean total procedure time of 32.5 ± 3.2 minutes. We detected 3 patients with prostate cancer with Gleason score 3 + 3. Two patients required brief bladder catheterization after their biopsy. Their prostate volumes were >50 mL and the number of biopsies taken was >30 cores. There was no mechanical failure, sepsis, bleeding per-rectal, or perineal hematoma.
This pilot study demonstrated BioXbot's safety and feasibility as a biopsy platform. It can potentially be used for image-guided PB and focal therapy.
[Show abstract][Hide abstract] ABSTRACT: Renal cell carcinoma (RCC) in young patients is uncommon but thought to represent a distinctive clinical entity from older patients with different clinico-pathologic features and outcomes. We evaluated the association of age at the time of diagnosis with pathological staging, histological parameters, disease recurrence and overall survival (OS) following radical or partial nephrectomy for non-metastatic RCC in native kidneys.
A retrospective review of 316 patients with RCC after nephrectomy at a single institution between January 2001 and June 2008 was performed. Eligible patients included all histologically proven primary non-metastatic RCC treated by radical or partial nephrectomy. They were categorised into group A (≤ 40 years at diagnosis) and B (> 40 years). Differences in clinical parameters were analysed using the Mann Whitney U test. The prognostic potential of age at diagnosis was evaluated using Cox proportional hazards regression. Survival was estimated using the Kaplan Meier method.
There were 33 patients in group A and 283 patients in group B. There were more non-clear cell tumours in the younger group (30% vs 14%, P <0.05). No statistical differences were found in the stage and grade of both groups. At a median follow-up time of 41 months, the younger group had a higher metastatic rate (18% vs 10.5%, P <0.05), lower 5-year cancer-specific survival (82% vs 98%, P <0.05) and lower 5-year OS (82 % vs 95%, P <0.05).
Younger patients were more likely to have non-clear cell RCC with higher disease recurrence and lower OS. They should not be assumed to have similar features and outcomes as screen-detected early RCC in older patients.
Annals of the Academy of Medicine, Singapore 09/2011; 40(9):401-6. · 1.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is widely recognised that sorafenib inhibits a range of molecular targets in renal cell carcinoma (RCC). In this study, we aim to use patient-derived RCC xenografts to delineate the angiogenic and non-angiogenic molecular targets of sorafenib therapy for advanced RCC (aRCC).
We successfully generated three patient RCC-derived xenografts in severe combined immunodeficient mice, consisting of three different RCC histological subtypes: conventional clear cell, poorly differentiated clear cell RCC with sarcomatoid changes, and papillary RCC. This study also used clear cell RCC cells (786-0/EV) harbouring mutant VHL to investigate the clonogenic survival of cells transfected with survivin sense and antisense oligonucleotides.
All three xenografts retain their original histological characteristics. We reported that sorafenib inhibited all three RCC xenograft lines regardless of histological subtypes in a dose-dependant manner. Sorafenib-induced growth suppression was associated with not only inhibition of angiogenic targets p-PDGFR-β, p-VEGFR-2, and their downstream signalling pathways p-Akt and p-ERK, cell cycle, and anti-apoptotic proteins that include cyclin D1, cyclin B1, and survivin but also upregulation of proapoptotic Bim. Survivin knockdown by survivin-specific antisense-oligonucleotides inhibited colony formation and induced cell death in clear cell RCC cells.
This study has shed light on the molecular mechanisms of sorafenib in RCC. Inhibition of non-angiogenic molecules by sorafenib could contribute in part to its anti-tumour activities observed in vivo, in addition to its anti-angiogenic effects.
British Journal of Cancer 03/2011; 104(6):941-7. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study evaluated the data completeness in the registration of prostate cancer after robotic radical prostatectomy (RRP) in the Urological Cancer Registry at the Singapore General Hospital (SGH), and its compliance to the international standards of US Commission on Cancer (CoC).
A certified cancer registrar reviewed all RRP cases between June 2003 and July 2008 in the Urological Cancer Registry at SGH.
A total of 365 cases were reviewed. The results showed that 351 (96.2%) of RRP patients' demographic data were captured and 321 (87.9%) of RRP patients were staged. According to the international standards of CoC for an academic institution, the requirement is to capture 100% of all cancer cases and stage at least 90% of them. As for data completeness, 317 (86.7%) of RRP details were captured as compared to the CoC standard requirement of 90%.
The existing manual cancer registry does not fully meet the CoC standards. Hence, the registry increased sources of case-finding and used active case-finding. With improvements made to the data collection methodology, the number of prostate cancer cases identified has been increased by 52.1% from 215 in 2007 to 327 in 2009. The registry is expected to be fully compliant with the CoC standard with the recruitment of more full time cancer registrars when a new web-based cancer registry is in full operation.
Annals of the Academy of Medicine, Singapore 11/2010; 39(11):848-53. · 1.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There 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.
Literature 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.
No 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.
A 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.
International Journal of Computer Assisted Radiology and Surgery 02/2010; 5(5):471-87. · 1.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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).
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).
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.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
These data validate IGF1R as a therapeutic target in CC-RCC, and support the evaluation of IGF1R-inhibitory drugs in patients with renal cancer.
Molecular Cancer Therapeutics 07/2009; 8(6):1448-59. · 5.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We introduce the first robotic ultrasound-guided prostate intervention device and evaluate its safety, accuracy and repeatability.
The robotic positioning system (RPS) determines a target's x, y and z axes. It is situated with a biplane ultrasound probe on a mobile horizontal platform. The integrated software acquires ultrasound images for three-dimensional (3D) modelling, coordinates target planning and directs the RPS.
The egg phantom evaluates the software's safety and workflow protocol. Two random targets are planned in each quadrant and biopsy needles are inserted. All were within three separate eggs. Metal wire tips are targeted and their distances from the biopsy needle tips are measured. With 20 wires, < 1 mm accuracy is obtained. Repeatability is demonstrated when previous positions are returned to with similar accuracy.
Our device demonstrates safety in a defined boundary with a repeatable accuracy of < 1 mm. It can be used for accurate prostate biopsy and treatment delivery.
International Journal of Medical Robotics and Computer Assisted Surgery 01/2009; 5(1):51-8. · 1.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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 approximately 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.
Clinical Cancer Research 11/2008; 14(20):6364-70. · 8.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
This review is drawn from published literature, meeting abstracts and online resources.
IGF1R blockade is generally well tolerated although it can induce hyperglycaemia. Single-agent activity has been documented in Ewing's 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.