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Research Update from Dr Paul Wood – March 2017

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Research Update from Dr Paul Wood – July 2014 

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Research Update from Dr Paul Wood – March 2011: 

My research to date is progressing very well and is yielding some very encouraging results.  To date, we have been able to establish that by inhibiting the P13K cancer-causing pathway to our mouse model we can not only significantly prolong the survival of the mice but also significantly reduce the tumour burden of the mice. The mice receiving the drug live longer, and remain much healthier than the mice that get no drug.

What is also important is that we can reduce the amount of Nmyc expressed in the tumours of the mice. Nmyc expression is associated with a very bad prognosis in children that get neuroblastoma, making this an important result.

We are currently working on a combination drug therapy which is showing more promise than when the individual drugs are used alone. In this way we are reducing the impact of the cancer-causing pathway from multiple approaches. Importantly, these drugs appear to enhance each other’s effect making them more potent in combination.

International research into this cancer-causing pathway is now showing that it is important in how the tumour becomes resistant to drug therapy and this will form part of our future research. Early results suggest that by inhibiting the pathway, the previously resistant tumours become more sensitive to drug treatment. This will become an important focus in our work in the upcoming year.

In summary, these new drug therapies are showing enormous promise as effective therapies in both the initial treatment of neuroblastoma and the more difficult treatment when it relapses.


Research Update – Dec 2010

My research continues to progress well and I am in the final stages of submitting my first paper for publication. We believe that the cancer causing pathway we are studying is important in neuroblastoma because if we give drugs that inhibit it the mice survive much longer and their abdominal tumours, when measured on ultrasound, do not grow (Fig 1.).

Figure 1. (a) Survival of mice (days) when given placebo (vehicle) or drug (b) corresponding tumour volume when measured on ultrasound.

a:

b:

At present we are using two drugs that inhibit the pathway in different ways. If we inhibit the pathway in two places, using a dual inhibitor, this results in a type of cell death caused apoptosis.

If, however, we inhibit the pathway in a different way, we do not get apoptosis. Once again we can show a benefit in survival of the mice and a reduction in their tumour size, but this appears to be due to inhibition of blood vessel formation, a process called angiogenesis. All tumours need a blood supply to survive so if we can inhibit that blood supply then it makes it difficult for tumours to grow. This demonstrates that this pathway is involved in multiple processes that help neuroblastomas thrive.

As well as the mice experiments, we have been using human cell lines to look at possible drug combinations. We have identified several potential drug combinations that may have potential both in newly diagnosed neuroblastoma as well as the type of neuroblastoma that is associated with relapsed disease. The relapsed neuroblastoma tends to be resistant to drug therapy. These results will be tested in the mouse model.


Molecular analysis and therapeutic targeting of the PI3K/AKT/mTOR pathway in paediatric neuroblastoma.

Principal Investigators:

Dr Paul J. Wood, Childrens Cancer Centre, Royal Childrens Hospital (RCH)(VIC)

A/Prof. Grant McArthur, Peter MacCallum Cancer Centre

A/Prof. David Ashley, Childrens Cancer Centre, RCH (VIC)

I currently have training as an Oncology Fellow at the Children’s Cancer Centre, Royal Children’s Hospital and am undertaking a PhD in collaboration with the expertise available at the Peter MacCallum Cancer Centre. The main impetus of my research revolves around neuroblastoma, the most common solid malignancy in children not involving the brain.

Neuroblastoma accounts for 6-10% of all childhood cancers and 15% of childhood cancer deaths, cancer being the leading cause of death in Australia of children aged 0-14 years old. At present, even with aggressive chemotherapy, only about 25% of children with advanced disease survive. Approximately 600 children are diagnosed with cancer in Australia each year, with up to 50 of these cases being neuroblastoma.

In some ways neuroblastoma is a unique tumour in that it often spontaneously resolves in children less than one year of age without any treatment. These children go on to live normal lives without any evidence of this tumour. However in older children it is much more aggressive, and up to 75% of children over 1 year old have evidence that it has spread to other sites when diagnosed.

This makes it extremely difficult to treat and this has devastating consequences for those children and families despite our most aggressive treatment. If we can work out why this disparity exists it may provide insights into how tumour cells can be treated or even programmed to regress. This tumour is associated with a family of oncogenes, cancer promoting genes, called MYC which are responsible for over 1 million cancers worldwide per year.

This represents an enormous worldwide disease burden that extends beyond childhood cancer. Importantly any positive findings from this research can be potentially extended to a broad range of tumours including adult cancers. N-Myc amplification in neuroblastoma is clearly associated with a poor prognosis and aggressive disease at presentation.

My research focuses on a specific cancer-causing pathway that is activated in a variety of cancers including those caused by the MYC oncogenes. Previous research at the Peter MacCallum Cancer Centre and other worldwide institutions has clearly demonstrated an association between this pathway and MYC driven cancers. Research at Peter MacCallum has also demonstrated that drugs blocking this pathway can treat MYC driven cancers in mice. I will be extending this research to study neuroblastoma using a mouse model that has been engineered to develop neuroblastomas in a way that is almost identical to those seen in children.

This provides an invaluable tool to examine this pathway and its relationship to MYC and the initiation of neuroblastoma. I will also be applying novel imaging techniques including small animal ultrasound & PET scans which are widely used in the diagnosis of cancers in children. This will allow us to monitor the impact of any drug interventions more accurately. This research will ultimately test whether these drugs are effective in the animal model, therefore making a more compelling argument to trial them in patients with neuroblastoma.

I will then extend this work to stored human neuroblastoma tissue, for which I have ethics approval, to examine to relationship of this pathway to the actual disease we see in children. In order to perform the most up to date and detailed analysis we will need to use modern technology such as “next generation sequencing” which is costly but worthwhile.

The overall costs of such research, including both the experiments in mice & the evaluation of human tissue are extensive. A conservative estimate, over a two-year period, would be in the vicinity of $130,000. In order to get the most out this research, however, it needs to be performed methodically & thoroughly. This essentially requires devoting your entire efforts to research, thus effectively becoming a full time Research Fellow.

Currently the process of obtaining funds for any research in Australia, particularly cancer research, is highly competitive. Because of the relative small numbers of children diagnosed with neuroblastoma, when compared with adult malignancies, it is often difficult to secure funding as it as not seen as being as important in the overall scheme of cancer research. However, clearly the benefits of this research may extend well beyond childhood cancers.

Additionally, and just as importantly, any research that we can do to relieve the emotional burden that this disease places on the children and their families would be much appreciated. Neuroblastoma, although relatively rare, can have devastating consequences to those children & families that it affects.

Trying to describe the value and importance of scholarships and financial support for research, such as is provided by the philanthropic contributions and organizations such as the YAMS Foundation, is difficult because it really does make an enormous difference in so many ways. The research performed by this generation is part of the legacy that we leave future generations, including our own children. To be able to contribute in a meaningful way to this legacy means being able to incorporate an element of research into your career.

This would be impossible without the financial support provided by foundations such as the YAMS, and the generous donations of its benefactors. Quite simply I would not be able to perform my research into childhood cancer without such funding.

Finally what I find most rewarding about the potential outcomes of my research are the patients that it will benefit. Working with children and seeing the way in which they tackle adversities such as cancer and its associated treatment is inspiring. It never ceases to amaze me that often, despite the treatments we inflict, they manage to maintain the raw enthusiasm and playful spirit that is childhood itself. They are our future. We, as a medical and scientific community have an obligation to look after such a precious resource.

Dr. Paul J. Wood

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