A cell-permeable dominant-negative survivin protein induces apoptosis and sensitizes prostate cancer cells to TNF-α therapy

BACKGROUND: Survivin is a member of the inhibitor-of-apoptosis (IAP) family which is widely expressed by many different cancers. Overexpression of survivin is associated with drug resistance in cancer cells, and reduced patient survival after chemotherapy and radiotherapy. Agents that antagonize the function of survivin hold promise for treating many forms of cancer. The purpose of this study was to investigate whether a cell-permeable dominant-negative survivin protein would demonstrate bioactivity against prostate and cervical cancer cells grown in three dimensional culture.

RESULTS: A dominant-negative survivin (C84A) protein fused to the cell penetrating peptide poly-arginine (R9) was expressed in E. coli and purified by affinity chromatography. Western blot analysis revealed that dNSurR9-C84A penetrated into 3D-cultured HeLa and DU145 cancer cells, and a cell viability assay revealed it induced cancer cell death. It increased the activities of caspase-9 and caspase-3, and rendered DU145 cells sensitive to TNF-α via by a mechanism involving activation of caspase-8.

CONCLUSIONS: The results demonstrate that antagonism of survivin function triggers the apoptosis of prostate and cervical cancer cells grown in 3D culture. It renders cancer cells sensitive to the proapoptotic affects of TNF-α, suggesting that survivin blocks the extrinsic pathway of apoptosis. Combination of the biologically active dNSurR9-C84A protein or other survivin antagonists with TNF-α therapy warrants consideration as an approach to cancer therapy.

Efficacy of a referral and physical activity program for survivors of prostate cancer [ENGAGE] : rationale and design for a cluster randomised controlled trial

Background: Despite evidence that physical activity improves the health and well-being of prostate cancer survivors, many men do not engage in sufficient levels of activity. The primary aim of this study (ENGAGE) is to determine the efficacy of a referral and physical activity program among survivors of prostate cancer, in terms of increasing participation in physical activity. Secondary aims are to determine the effects of the physical activity program on psychological well-being, quality of life and objective physical functioning. The influence of individual and environmental mediators on participation in physical activity will also be determined.
Methods/Design: This study is a cluster randomised controlled trial. Clinicians of prostate cancer survivors will be randomised into either the intervention or control condition. Clinicians in the intervention condition will refer eligible patients (n = 110) to participate in an exercise program, comprising 12 weeks of supervised exercise sessions and unsupervised physical activity. Clinicians allocated to the control condition will provide usual care to eligible patients (n = 110), which does not involve the recommendation of the physical activity program. Participants will be assessed at baseline, 12 weeks, 6 months, and 12 months on physical activity, quality of life, anxiety, depression, self-efficacy, outcome expectations, goals, and socio-structural factors.
Discussion: The findings of this study have implications for clinicians and patients with different cancer types or other chronic health conditions. It will contribute to our understanding on the potential impact of clinicians promoting physical activity to patients and the long term health benefits of participating in physical activity programs.

Living with prostate cancer: randomised controlled trial of a multimodal supportive care intervention for men with prostate cancer

Background: Prostate cancer is the most common male cancer in developed countries and diagnosis and treatment carries with it substantial morbidity and related unmet supportive care needs. These difficulties may be amplified by physical inactivity and obesity. We propose to apply a multimodal intervention approach that targets both unmet supportive care needs and physical activity.

Methods/design: A two arm randomised controlled trial will compare usual care to a multimodal supportive care intervention “Living with Prostate Cancer” that will combine self-management with tele-based group peer support. A series of previously validated and reliable self-report measures will be administered to men at four time points: baseline/recruitment (when men are approximately 3-6 months post-diagnosis) and at 3, 6, and 12 months after recruitment and intervention commencement. Social constraints, social support, self-efficacy, group cohesion and therapeutic alliance will be included as potential moderators/mediators of intervention effect. Primary outcomes are unmet supportive care needs and physical activity levels. Secondary outcomes are domain-specific and healthrelated quality of life (QoL); psychological distress; benefit finding; body mass index and waist circumference. Disease variables (e.g. cancer grade, stage) will be assessed through medical and cancer registry records. An economic evaluation will be conducted alongside the randomised trial.

Discussion: This study will address a critical but as yet unanswered research question: to identify a populationbased way to reduce unmet supportive care needs; promote regular physical activity; and improve disease-specific and health-related QoL for prostate cancer survivors. The study will also determine the cost-effectiveness of the intervention.

Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer

Background: Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC.

Patients and methods: We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m2 dose every three weeks

Results: Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6–99 weeks) and 1-year survival was 71%.

Conclusions: The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.

A randomised trial of robotic and open prostatectomy in men with localised prostate cancer

Background
Prostate cancer is the most common male cancer in the Western world however there is ongoing debate about the optimal treatment strategy for localised disease. While surgery remains the most commonly received treatment for localised disease in Australia more recently a robotic approach has emerged as an alternative to open and laparoscopic surgery. However, high level data is not yet available to support this as a superior approach or to guide treatment decision making between the alternatives. This paper presents the design of a randomised trial of Robotic and Open Prostatectomy for men newly diagnosed with localised prostate cancer that seeks to answer this question.

Methods
200 men per treatment arm (400 men in total) are being recruited after diagnosis and before treatment through a major public hospital outpatient clinic and randomised to 1) Robotic Prostatectomy or 2) Open Prostatectomy. All robotic prostatectomies are being performed by one surgeon and all open prostatectomies are being performed by one other surgeon. Outcomes are being measured pre-operatively and at 6 weeks and 3, 6, 12 and 24 months post-surgery. Oncological outcomes are being related to positive surgical margins, biochemical recurrence +/ the need for further treatment. Non-oncological outcome measures include: pain, physical and mental functioning, fatigue, summary (preference-based utility scores) and domain-specific QoL (urinary incontinence, bowel function and erectile function), cancer specific distress, psychological distress, decision-related distress and time to return to usual activities. Cost modelling of each approach, as well as full economic appraisal, is also being undertaken.

Discussion
The study will provide recommendations about the relative benefits of Robotic and Open Prostatectomy to support informed patient decision making about treatment for localised prostate cancer; and to assist in treatment services planning for this patient group. Trial Registration ACTRN12611000661976

Role of the EpCAM (CD326) in prostate cancer metastasis and progression

Despite significant advances in surgery, radiotherapy and chemotherapy to treat prostate cancer (CaP), many patients die of secondary disease (metastases). Current therapeutic approaches are limited, and there is no cure for metastatic castration-resistant prostate cancer (CRPC). Epithelial cell adhesion molecule (EpCAM, also known as CD326) is a transmembrane glycoprotein that is highly expressed in rapidly proliferating carcinomas and plays an important role in the prevention of cell–cell adhesion, cell signalling, migration, proliferation and differentiation. Stably and highly expressed EpCAM has been found in primary CaP tissues, effusions and CaP metastases, making it an ideal candidate of tumour-associated antigen to detect metastasis of CaP cells in the circulation as well as a promising therapeutic target to control metastatic CRPC disease. In this review, we discuss the implications of the newly identified roles of EpCAM in terms of its diagnostic and metastatic relevance to CaP. We also summarize EpCAM expression in human CaP and EpCAM-mediated signalling pathways in cancer metastasis. Finally, emerging and innovative approaches to the management of the disease and expanding potential therapeutic applications of EpCAM for targeted strategies in future CaP therapy will be explored.

Knowledge, attitudes and practices of clinicians in promoting physical activity to prostate cancer survivors

Objectives: 

An internet-based psychosocial Intervention for men treated for prostate cancer

This thesis developed and evaluated an internet-based program addressing many of the unmet psychological and social needs of men treated for localised prostate cancer. The program was found to be appealing to men and there were trends towards significant improvement across areas of sexuality and relationship function.

CD44 variant 6 is associated with prostate cancer metastasis and chemo-/radioresistance.

Prostate cancer (CaP) is the second leading malignancy in older men in Western countries. The role of CD44 variant 6 (CD44v6) in CaP progression and therapeutic resistance is still uncertain. Here, we investigated the roles of CD44v6 in CaP metastasis and chemo/radioresistance. Expression of CD44v6 in metastatic CaP cell lines, human primary CaP tissues and lymph node metastases was assessed using immunofluorescence and immunohistochemistry, respectively.