2015 - Funded Research

Project title: A Phase II randomised controlled trial of high-dose Vitamin D in localised prostate cancer cases with intermediate risk of progression (ProsD)

Aims of project: There is evidence to suggest that vitamin D may prevent prostate cancer progression. This proposal is a Phase II randomised controlled trial of monthly oral high-dose vitamin D supplementation. The subjects are men diagnosed with localised prostate cancer who have intermediate risk of progression, and are on active surveillance. This trial will firstly establish the safety and efficacy of high-dose vitamin D supplementation in prostate cancer cases. The aim is to examine if vitamin D supplementation will prevent prostate cancer progression in these men while on active surveillance. It also aims to determine if supplementation raises serum vitamin D (25OHD) levels optimally to levels above 75nmol/L, and if it improves genome integrity. Information regarding the utility of multi-parametric magnetic resonance imaging, in conjunction with biopsy, to improve the classification of disease grade, will also be derived from this trial.

Potential impact: If vitamin D supplementation does prevent prostate cancer progression, this will be the basis for a phase III trial. This intervention has potential to reduce anxiety in men with low- to intermediate-risk prostate cancer. It will allow these men to take control in managing their cancer during clinical monitoring, and improve perseverance of active surveillance, which will consequently reduce the uptake of unnecessary active treatment.

Project title: A prospective multicentre study of the impact of Ga-68 PSMA-PET/CT imaging in the management of prostate cancer (proPSMA study).

Aims of project: If prostate cancer is detected early, when disease has not spread there is a high chance of cure. More accurate scanning may improve outcomes by redirecting patients with disease spread from futile local treatments to more appropriate management. This clinical trial will investigate a new type of scan which provides whole body images of prostate cancer spread. Early experience suggests that this new technology, called PSMA PET/CT (prostate specific membrane antigen positron emission tomography/computed tomography), is superior to current scanning techniques. PSMA PET/CT has capacity for wide availability at relatively low cost. Performing a single better test rather than several less accurate scans will also be cheaper, improve patient experience and expose patients to lower amounts of radiation. We will perform a randomised study at multiple centres around Australia comparing PSMA-PET/CT to conventional imaging.

Potential impact: If it can be shown that PSMA-PET/CT has superior diagnostic performance, it should be used as a first-line test for staging prior to surgery or radiotherapy and will result in significant changes to patient management.

Project title: Precision medicine in advanced and oligometastatic prostate cancer

Aims of project: Precision medicine is the notion of treating each patient on the basis of genetic changes specific to the individual's cancer which can be targeted, or which may indicate response or resistance to various treatments. Cancer cells from the patient can also be treated with drugs in the laboratory to assess responses prior to treatment in the patient. The aim is to improve outcomes due to using the right treatment, at the right time, in the right patient. Liquid biopsies from sources such as cancer cells in patient's blood may allow minimally invasive methods to access cancer cells in order to perform such precision medicine approaches. Our new technology has allowed, for the first time, growth of metastatic prostate cancer and prostate cancer cells from the blood of patients. A precision medicine program will be established for men with advanced and metastatic disease to identify potential effective treatment strategies. These will based on the genetic analyses of individual patient's cancers and the response of their cancer to various treatments in the laboratory in order to direct treatment or identify appropriate specific clinical trials.

Potential impact: Precision medicine holds great promise as an approach for treating cancers, but its use for prostate cancer is still in an early testing phase. This project will establish and test a program for using precision medicine to treat men with metastatic prostate cancer.

Project title: Docetaxel resistance in advanced metastatic prostate cancer

Aims of project: In the setting of metastatic prostate cancer, in which cancer has spread to other parts of the body, chemotherapy improves symptoms and survival, however, around half of all patients do not improve with chemotherapy. Patients receive around 9 weeks of chemotherapy treatment before their response can be determined, which means that half of all patients potentially suffer significant side effects for no benefit. Our research group has identified blood markers that can determine if chemotherapy is not working at an earlier stage, after around 3 weeks, saving patients from side effects and allowing them to go on to receive other treatment options sooner. This project aims to test these markers in much larger groups of patients in order to verify that they work and allow them to be used in the clinic to benefit many more people. Obesity has been linked to aggressive prostate cancer and poor outcomes, however, this association remains poorly understood. We also aim to identify if changes in body fats after chemotherapy are related to how chemotherapy works in prostate cancer and use these changes to predict who will benefit from chemotherapy. This will also provide opportunities to test new drugs that may help chemotherapy work more effectively.

Potential impact: By identifying those who will not benefit from chemotherapy early during treatment, the serious side-effects of therapy can be avoided in these patients, who move to more appropriate treatment pathways.

Project title: A novel liver-targeted testosterone therapy for sarcopenia in androgen-deprived men with prostate cancer: anabolism without peripheral androgenism.

Aims of project: Androgen deprivation therapy is an effective treatment for prostate cancer but it comes at a cost. This treatment stops the production of testosterone, which stimulates growth of the tumour. Unfortunately stopping testosterone also causes muscle weakness and wasting. Professor Ho’s team have developed a new treatment by exposing only the liver to testosterone. Taken by mouth, this form of testosterone treatment, targeted at the liver, stimulates the synthesis of protein in muscle. This project will determine whether this new treatment prevents muscle wasting in men taking androgen deprivation therapy.

Potential impact: The side effects of androgen deprivation therapy are a considerable burden for many men and their families. We have funded the clinical testing of a new treatment that will hopefully improve the quality of life for these men.

Project title: A new achilles' heel in prostate cancer: novel regulators of polyamine homeostasis

Aims of project: Polyamines are abundant cellular molecules that are vital for cancer cell growth and survival. The prostate has one of the highest polyamine concentrations of any tissue. This project will ask if we can treat prostate cancer by inhibiting the production of polyamines.

Potential impact: Treatment options for men with metastatic prostate cancer are limited, so new types of treatment are desperately needed. This project will look for "proof-of-principle" evidence that stopping polyamine production could be the basis for a new prostate cancer treatment.

Project title: KLK14 as a novel therapeutic target in muscle wasting induced by androgen deprivation therapy.

Aims of project: An unfortunate side-effect of androgen deprivation treatments is muscle-wasting. Professor Clements group have shown that a protein called KLK14 is increased in cancer cells when they are treated with anti-androgen drugs. KLK14 is also present in skeletal muscles, where it can break down muscle tissue. This project will ask whether KLK14 is involved in the muscle degradation that is caused by anti-androgen drugs.

Potential impact: The side effects of androgen deprivation therapy are a considerable burden to men and their families. If KLK14 is shown to be important for the muscle-wasting effects of androgen deprivation therapy, then KLK14-inhibiting drugs could be used to help prevent these side-effects.

Project title: Investigating the effects of localised radiotherapy on prostate cancer immune signature.

Aims of project: Cancers have the ability to shield themselves from immune attack despite the large numbers of immune system cells present within the tumour. Currently, the immune response to prostate cancer is poorly characterised. This project will use recent technological advances to determine which immune cells are present in prostate cancer tumours and how they are affecting the tumour. Immune responses will be compared before and after radiotherapy.

Potential impact: Immune responses are often clearly linked to tumour growth and can be used to fight against cancers. This project could provide the knowledge needed to design future immunotherapeutic strategies for prostate cancer.

Project title: Development of a highly sensitive diagnostic test for the active form of prostate specific antigen.

Aims of project: All prostate cancer treatments are most effective when the cancer has been detected at early stages. The most broadly used prostate cancer blood test relies on a single marker. This project aims to design ultrasensitive and inexpensive tests for prostate cancer that can be performed using widely available electronic devices such as smart phones. Such a test will allow in-depth analysis directly in the doctor’s office or even in the patient's home. In addition to early diagnosis the test could allow long term monitoring of patients who have undergone prostate cancer treatment and require this monitoring for cancer relapse.

Potential impact: If we can accurately detect all prostate cancers early, the treatment will be more effective, potentially saving lives.

Project title: MRI visible fiducial markers and brachytherapy seeds to improve target localisation during delivery of radiotherapy for prostate cancer

Aims of project: Precise placement of radiation-emitting seeds in the prostate during brachytherapy is necessary for effective treatment. Unfortunately, there is a risk that the seeds end up in the wrong position or that they displace over time. This may reduce the effectiveness of the treatment. This project will develop specialised brachytherapy seeds that can be seen using MRI. Using MRI is an advantage, as this allows us to see the seeds and the prostate at the same time.

Potential impact: If we can use MRI to trace the position of brachytherapy seeds, we can better predict how effective this treatment will be.

Project title: Identification of biomarkers associated with prostate cancer radio-resistance

Aims of project: Recurrence of prostate cancer after radiotherapy occurs due to a feature of cancer cells called radio-resistance. Biomarkers (molecular indicators) of radio-resistance are needed to predict which cancers are less likely to respond to radiotherapy. This project will look for new biomarkers of radio-resistance. Good biomarkers will be the proteins that are present at different levels in radio-resistant prostate cancer tumours, compared to the tumours that respond to therapy.

Potential impact: New biomarkers for radio-resistant prostate cancer can be the basis of a test that would inform clinicians on how effective radiotherapy will be for the patient. This would allow clinicians to better chose the most appropriate treatment for prostate cancer.

Project title: Using bioengineered 3D in vitro models to replicate the tumour microenvironment in prostate cancer bone metastasis

Aims of project: When prostate cancer recurs after initial therapy, bone is privileged site for metastasis. In the bone tissue there are fat cells, referred to as adipocytes, which are considered a major source of energy for cancer survival in other cancers. Both androgen deprivation therapy and age can increase the amount of bone adipocytes. This project will ask whether more adipocytes in men on androgen deprivation therapy increases the chances of cancer progression and incurable bone metastasis. The project will be the first to investigate the interactions between bone adipocytes and prostate cancer cells in bioengineered 3D laboratory models.

Potential impact: The results of this project could help determine whether bone marrow adipocytes are legitimate targets for new drugs and treatments to combat bone metastasis in prostate cancer.