New approaches in cardiovascular disease and cancer

Thursday 7 June 2012

Media Release

New approaches in cardiovascular disease and cancer - New Zealand’s top-two killers

The Health Research Council of New Zealand (HRC) has announced $65.2M of government research funding investment into issues that impact most heavily on the health of New Zealanders.

Of the New Zealanders that will die in 2012, two-thirds will do so as a result of cancer or cardiovascular disease. While we think of these diseases each as a single entity, both are a complex mixture of pathologies and include in their causes factors that affect more of us every day, such as obesity, poor diet, lack of exercise, smoking and drinking. While a strong focus on prevention is vital, improved understanding is driving the search for new treatments that will make a greater difference for those already affected.

Dr Christian Soeller and his team at the Department of Physiology at The University of Auckland, are focusing their attention on heart failure and a new protein that they have identified called junctophilin. Heart failure is a debilitating condition and, once it progresses to an advanced stage, the only option is a heart transplant. As this is major surgery and donor hearts are scarce, the hunt to find alternatives is a pressing one. By looking at cells taken from patients’ failing hearts, Dr Soeller and the team will test their theory that small changes to tiny internal cell structures in the heart can result in a much weaker pumping action. These tiny structures are called junctions and the team have previously isolated a protein, junctophilin, which is important in maintaining them. Junctophilin is progressively lost in heart failure and the researchers will trial gene-therapy to restore it and see if this improves the structure and function of the failing heart. This preliminary work will provide greater understanding of how heart failure develops and determine whether this novel approach could herald more treatment options in the future.

Our understanding of cancer biology has increased dramatically in recent years, and the new knowledge highlights the scope and scale of the challenges that face those trying to develop highly effective treatments. Chief among the problems is that drugs that are toxic to tumour cells are also toxic to healthy cells. This issue was sidestepped by the invention of drugs that only became active inside the tumour - prodrugs. However, the first prodrugs had to be delivered via the blood supply and many aggressive tumours outstrip their blood supply, leaving malignant areas untreated by the drug and free to grow and spread. These areas are

also low in oxygen carried by blood, and so are called ‘hypoxic areas’. Adding further complexity is the fact that tumours are as genetically diverse as the people they affect, meaning that a drug that works well in one individual may not work at all in another.

Researchers at the Auckland Cancer Society Research Centre have been at the forefront of cancer drug development for decades, and the HRC has supported their advances against all of these issues. This year, Dr Frederik Pruijn will lead research on up to 15 second-generation drug candidates from a new class of prodrug that not only penetrates the hypoxic areas of tumours, but is specifically activated by hypoxia. The team will identify the best four candidates and simultaneously study the genetic profile of cancer cells that respond to the drugs – so that a test can be developed to predict effectiveness in advance, so that clinical trials can be undertaken only in patients that are likely to respond and future chemotherapy targeted towards those most likely to benefit - preventing the cost to the patient and the health service of ineffective treatment.

Associate Professor Gordon Rewcastle heads a project in which scientists will use improved understanding of how tumours develop to create drugs that will prevent their growth. Nearly a third of tumours have mutations in genes that result in the activation of a pathway that allows cells to grow uncontrollably and form tumours – the PI 3-kinase pathway. There is a major global effort to find drugs that effectively block this pathway, and the team has already had HRC support to develop a drug that is in early clinical trials in the USA. The new funds will be spent on finding a more targeted ‘second-generation’ drug that works just on PI 3-kinase, and not the other enzymes in the same family, which also play important roles in cell regulation.

Associate Professor Mark McKeage and colleagues at The University of Auckland will use their HRC funding to try and reduce the side-effects of an existing, important, treatment for patients with large bowel cancer. In New Zealand, 3,000 people a year are diagnosed with this malignancy. The drug oxaliplatin has greatly improved the outcomes for patients with this disease, utilising platinum as a means of attacking the cancer cells. Unfortunately, during chemotherapy, platinum also builds up in the nerve cells of the bowel leading to damage that can interrupt treatment, compromise the outcomes, and affect quality of life long after the chemotherapy ceases. The team has found that a protein in cell membranes called OCTN1 is involved in the accumulation of high levels of platinum in the nerve cells, and hope to establish its role in mediating the damage, and the potential for treatments to prevent it from happening.

Dr Nicola Smith is also seeking to reduce the adverse consequences of treatments for cancer patients. Based at the Medical Research Institute of New Zealand, Dr Smith and her colleagues will trial an alternative way of managing a distressing condition most commonly associated with lung cancer – a collection of fluid between the lung and the chest wall (malignant pleural effusion). Every year, over 1,600 New Zealanders develop this problem, which causes disabling breathlessness. There is no agreement on the best way to manage malignant effusions. Conventional care involves inserting a chest tube, draining the fluid and inserting talc into the space- a talc pleurodesis. It requires a stay in hospital and is painful, with a success rate of only about 70 per cent. A new approach is to insert a catheter into the space that can stay in place and allows the regular drainage of fluid – an indwelling pleural catheter. Requiring only outpatient management, this treatment is free from the side effects of talc pleurodesis. The research team will compare the efficacy and safety of indwelling pleural catheters compared with pleurodesis. The study has the potential to change the way

patients with this condition are currently cared for, reducing time in hospital and improving quality of life.

Massey University researcher Dr Andrea ‘t Mannetje is contributing to our knowledge of how new technologies affect our risk of cancer. The massive increase in the use of mobile phones worldwide initially sparked concern that the radio frequency electromagnetic fields that they produce may cause brain cancer. A number of studies have been done to test this theory and the results have been largely reassuring. However, several recent studies have reported an increased risk in people who use their mobile phones extensively. Most of the studies to date have been conducted in adults, who have thicker skulls than children and adolescents. Only one small case-control study has been done in children. The use of mobile phones in younger age groups is increasing exponentially, meaning that evidence is urgently needed to establish if there is any increased risk of brain cancer in younger age groups. The team from Centre for Public Health Research at Massey University, Wellington, have joined the international teams of 15 other countries in the MOBI-KIDS study to look at the risk of brain cancer in 10-24 year olds. MOBI-KIDS is the largest childhood/adolescence brain cancer study to date including 2,200 cases and 4,400 controls from 15 countries. The study addresses a wide range of risk factors for brain cancer in this age group, thus providing an important evidence base for the primary prevention of this disease. Brain cancer is the second most common cancer after leukaemia in children.

This project is being co-funded by Cure Kids, whose work contributes to funding vital medical research into life-threatening childhood illnesses in New Zealand.

-Ends-

2012 HRC annual funding round results
The HRC processed 180 full applications for four different types of awards and will offer 51 contracts to the successful applicants. Project proposals were processed through a two-stage process beginning with 378 Expressions of Interest leading to 97 full applications assessed in the second stage. Successful applications were chosen by an assessment process involving national and international expert referees, detailed discussion by Science Assessing Committees, and further review by the Grant Approval Committee before final approval by the HRC Board. The total value of new research to be undertaken within universities, research institutes and District Health Boards is $65.2 million (excluding GST). For detailed results, please visit the HRC website, www.hrc.govt.nz.

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