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Potential for radiotherapy and VTP multimodality therapy for prostate cancer

Each year in the UK around 48,500 men are diagnosed with prostate cancer, and 11,900 die from this malignancy. The most common radical treatments for prostate cancer are surgical removal of the prostate gland (prostatectomy), or radiotherapy (usually combined with hormone treatment).

However, there is a need to improve the overall patient outcomes from radical treatment, as many cases of high-risk prostate cancer recur. Moreover, there is an unmet clinical need to reduce radical treatment side effects.

Vascular targeted photodynamic therapy (VTP) is a novel minimally invasive precision surgery technique that has been developed to focally treat prostate cancer. VTP destroys the vasculature supply of blood to the tumour, thereby providing tumour control.

To date, VTP has been investigated in clinical trials as a monotherapy for low-volume, low-risk prostate cancer. Whilst VTP has been combined with other treatments such as hormone therapy in pre-clinical models, to date it has not been investigated alongside external beam radiotherapy to assess the effects of combined treatment on prostate cancer tumour control.

A recent study from Richard Bryant and Freddie Hamdy of the Nuffield Department of Surgical Sciences, alongside collaborators in the Institute of Biomedical Engineering & Department of Oncology, and collaborators from the Weizmann Institute of Science (Israel) and the National Cancer Institute (National Institutes of Health, USA), has investigated the impact of combining VTP with external beam radiotherapy treatment, and the potential improvement to treatment outcomes.

In a recent publication in the British Journal of Cancer, the team used a multi-modality treatment approach to test the sequential combination of fractionated radiotherapy and VTP – which have previously not been used together.

They found that, whilst fractionated radiotherapy or VTP alone can help delay tumour growth, combination therapy using fractionated radiotherapy followed by VTP suppressed tumour growth to a greater extent than either treatment alone. Radiotherapy induced changes to the blood vessels within the tumour, which may be a contributing factor to the increased effectiveness of subsequent VTP as part of combination therapy. Ongoing studies are now investigating the immunological effects of the combined treatment.

This is the first time that VTP has been evaluated in combination with external beam radiotherapy treatment, either for prostate cancer or any other solid-organ tumour. This pre-clinical study provides the proof-of-concept necessary to go on and test this multi-modality approach in first-in-man early phase clinical trials. Following future testing of safety and efficacy in patients, this combined radiotherapy and VTP approach could help to redefine best practice for treating certain prostate cancer patients in a more effective way.

About the study

This study was a collaboration between Richard Bryant (Nuffield Department of Surgical Sciences), Freddie Hamdy (Nuffield Department of Surgical Sciences), Ruth Muschel (Department of Oncology) and Avigdor Scherz (The Weizmann Institute of Science, Israel). It was funded by a Cancer Research UK & Royal College of Surgeons of England Clinician Scientist Fellowship (reference C39297/A22748) and by a research grant from The Urology Foundation.

New prostate cancer risk tool

Each year in the UK around 48,500 men are diagnosed with prostate cancer and 11,900 die from the disease. To improve survival, Professor Julia Hippisley-Cox (Nuffield Department of Primary Care and Health Sciences) and Professor Carol Coupland (University of Nottingham) have developed a tool to calculate personalised risk of prostate cancer using the health records of 1.45 million men in the QResearch database. The new risk prediction algorithm aims to diagnose more tumours earlier when they are easier to treat.

The tool is designed to be used for asymptomatic individuals and combines the prostate specific antigen (PSA) blood test result with factors such as age, ethnicity, body mass index, smoking status, social deprivation and family history. Compared to using the PSA test alone, the new algorithm is more accurate at predicting prostate cancer cases (68.2% compared to 43.9% using PSA-only), high-grade aggressive tumours (49.2 % versus 40.3%) and prostate cancer deaths (67% versus 31.5%).

The decision in most primary care practices to refer men who are asymptomatic is based on binary PSA thresholds, although this can lead to too many false-negative and false-positive results. Furthermore, a binary threshold does not give any indication for the patient as to their absolute risk of developing prostate cancer and/or clinically significant disease requiring immediate intervention. The results show that the risk equation provides a valid measure of absolute risk and is more efficient at identifying incident cases of prostate cancer, high-grade cancers and prostate cancer deaths than an approach based on a PSA threshold. The intended use is to provide a better evidence base for the GP and patient to improve decision-making regarding the most appropriate action, for example, reassurance, repetition of PSA test, referral for MRI, regular monitoring, referral to a urologist, or use of preventative interventions should any become available.

 – Professor Julia Hippisley-Cox (Nuffield Department of Primary Care and Health Sciences)

More research is now required to assess the best way to implement the algorithm and evaluate the health economics and the impact on prostate cancer diagnosis and subsequent survival.

Read the full publication in the British Journal of General Practice.

Read the feature in the Daily Mail

Further funding secured to hunt out cancer using innovative radiotherapy techniques

Professor Bart Cornelissen and Dr Tiffany Chan, from the Department of Oncology, have received an additional £408,338 award from the charity Prostate Cancer Research (PCR) to continue their innovative work to help a new type of radiotherapy, designed to hunt out cancer even after it has spread, to benefit even more men with prostate cancer. Prostate cancer is now the most commonly diagnosed cancer in the UK and their work could lead to more personalised treatment for those with prostate cancer.

Bart and Tiffany are working with a type of radionuclide therapy called 177Lu-PSMA. PSMA seeks out a protein found almost exclusively on prostate cancer cells, and by linking it to radioactive Lutetium (Lu), it can guide the radiotherapy directly inside tumour cells. ‘An advantage of 177Lu-PSMA is that we don’t need to know where all the cancer cells are before treatment, unlike in external beam radiotherapy’ explains Tiffany. ‘In theory, even if we just have a single cell that has split away from the main tumour, if it expresses PSMA, we should still be able to target it.’

Some Lu-PSMA treatments are already used in the UK, but on a private basis only and at the moment they are primarily used for pain relief. The Oxford researchers aim to combine Lu-PSMA with other therapies, and their initial results, from testing nearly 2,000 drugs, have led to the discovery of a group of drugs that may be able to help 177Lu-PSMA hunt out prostate cancer better and make it more effective for more patients. This discovery, which led to further funding from PCR for them to continue this exciting work, comes at an important time for radionuclide therapies. ‘There’s a very large Phase 3 clinical trial with Lu-PSMA and that seems to suggest that you actually get benefits in overall survival from this treatment’ explains Bart. ‘Rather than just being pain relief, we can now start to think of these as cures as well.’

“Speaking as a patient whose prostate cancer has been previously treated with radiotherapy and is likely to be so again in the future, I find this work to be a very welcome addition to the treatments available for the disease,’ said prostate cancer patient David Matheson. ‘It is heartening to see such progress with this treatment, and I look forward to it becoming more widespread in the future.’

During lockdown, the closure of their lab meant they had to find alternative ways to reach their goal. They found an innovative solution – reversing their original plans and developing new and efficient ways to analyse results in lockdown first, and then conducting the experiments when they could return to the lab. Tiffany developed a network analysis tool to enable them to predict which combinations might work. ‘I’m a Londoner, so I like to think of it like a tube map, where have all of our different tube stops, connected by different tube lines, with some lines being more efficient than others. The idea behind mapping the system in this way is that we can hopefully find the best line, or in this case, the best biological pathway, that is most likely to lead to synergism with Lu-PSMA,’ she said. PCR initially awarded £100,000 to Bart and Tiffany in 2019 to test up to 1,000 drugs in combination with 177Lu-PSMA. Despite the challenges brought on by the Covid-19 pandemic, the team surpassed their target and managed to test an incredible number of drugs.

Bart and Tiffany are hopeful that Lu-PSMA could become more widespread in the clinic but believe more research needs to be done. ‘Lu-PSMA is the new kid on the block, it’s a very new technology. I think there’s still a lack of understanding about how Lu-PSMA itself works, and there’s a lot of biology we can learn to improve its efficacy’ says Tiffany. ‘So that’s what we’re trying to achieve, particularly with our network analysis approach to map out the biology behind it.’

‘Bart and Tiffany’s project is already showing promising results on the route to improving radiotherapy for men with prostate cancer. We look forward to continuing to support their project on a larger and long-term basis and hope it will mean that more people can benefit from enhanced radiotherapy, without the side effects’

– Dr Naomi Elster, Head of Research and Communications, PCR

‘There are Lu-PSMA treatments that are already given in the UK but on a private basis’ Bart explains. ‘Whether that will hit the NHS depends on approval by NICE but given the fantastically positive data out there, the upcoming results of the VISION Phase 3 clinical trials that are very positive, and given the improvement in actual survival of patients, I think there is good hope there that that will be approved.’

– Professor Bart Cornelissen

“Perhaps, what is most exciting is that, by targeting PSMA, this therapy delivers the radiotherapy directly to the sites of the cancer, wherever they are located. It is heartening to see such progress with this treatment, and I look forward to it becoming more widespread in the future.”

– David Matheson, prostate cancer patient

For more information, please visit: www.pcr.org.uk. Full story on the Department of Oncology website.

Novel sequencing techniques reveal microRNA influence on prostate cancer development

Researchers from the Nuffield Department of Surgical Sciences, Nuffield Department of Medicine and Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, have been investigating microRNA sequences and their influence on the migration and wider metastasis of prostate cancer cells around the body.

Prostate cancer is the second most fatal cancer in males, due in part to its slow growth and difficulties in early diagnosis before it spreads. Once spread, standard treatments are less effective and the disease is often incurable. Understanding mechanisms that modulate and cause the process of cancer metastasis is important in order for us to better understand how to detect, prevent and treat it.

Led by Claire Edwards, postdoctoral researcher Srinivasa Rao Rao devised a  series of transcriptomic and functional screening strategies. This novel combination of migrational and morphological analysis allowed the team to focus on the wider biological relevance of microRNA in the development of prostate cancer.

After studying the entire microRNA genome, the team focused on overexpressing microRNAs belonging to specific families, specifically, those known as miR-372 and miR-302 clusters, which emerged as interesting candidates in the regulation of prostate cancer. 16% of microRNAs screened in this novel method, were found to decrease the rate of cell migration when dysregulated. Similarly, 19% of microRNAs were found to alter the morphology and shape of cancer cells.

This publication demonstrates an application using a series of integrated screening approaches to enhance the specificity and accuracy of screens. By using a variety of screening strategies in succession, the team were able to narrow down the microRNA candidates to those more likely to be directly involved in prostate cancer progression. There are additional applications of this work through the use of these relatively stable microRNAs as diagnostics markers for the earlier detection and diagnosis of prostate cancer.

Claire Edwards, Associate Professor at the Nuffield Department of Surgical Sciences, says;

“Through our collaboration with Daniel Ebner, we have been able to develop a screen to rapidly discover those microRNAs that could reduce migration and so deduce which of them may play a role in prostate cancer metastasis.”

To read the publication in full, see here.

This research is a result of a collaboration between senior researchers Claire Edwards, Daniel Ebner and Freddie Hamdy.

Claire Edwards is an Associate Professor of Bone Oncology. Her main focuses are on obesity and adipokines in cancer-induced bone disease, metabolism and miRNA in prostate cancer bone metastases and bone marrow stromal cells in the pathogenesis of cancer-induced bone disease.

Daniel Ebner is a Principle investigator at the Nuffield Department of Medicine. He worked with the Target Discovery Institute to develop new target screening methodologies, investigate disease pathways as a means for identifying ‘drug targets’ and advance therapeutically relevant targets for drug development.

Freddie Hamdy is a Nuffield Professor of Surgery with a research focus on management of urological malignancies, in particular prostate and bladder cancer He is the Chief Investigator of many studies including the ProtecT (Prostate testing for cancer and Treatment) study of case-finding and randomised controlled trial of treatment effectiveness in prostate cancer – the largest of its kind worldwide.

This work was supported by the FP7 Marie Curie Initial Training Network PRO-NEST, Cancer Research UK, through the Cancer Research UK Oxford Centre Development Fund and through the University of Oxford Medical Research Fund.

 

Using Artificial Intelligence and Deep Machine Learning to Improve Treatment and Diagnosis of Prostate Cancer

Combining Radiotherapy, Minimally Invasive Surgery and Immunotherapy to Enhance Cure Rates in Prostate Cancer

Using Spatial Transcriptomics to Support Accurate Decision-making in Early Stage Prostate Cancer