The Gene Therapy Program
Summary
The goal of the Program is to develop a gene therapy approach to cancer treatment that will reduce side-effects and dramatically improve the recovery rate of children with cancer. In particular this proposed treatment will improve the prospects of children with soft-tissue cancers including brain tumours and cancer of the nervous system - where a more aggressive approach to treatment is required but the severity of side effects means it is currently not an option.
Chemotherapy delivers highly toxic chemicals to the body in order to cause damage to the DNA of growing tumour cells - however the effect of these drugs also permanently damages bone marrow cells, which lack the ability to rejuvenate.
Gene therapy aims to protect bone marrow by inserting therapeutic genes into the bone marrow cells, in effect giving them the ability to heal and therefore guard against the toxic effects of chemotherapy. If the side effects and recovery time between treatments can be reduced and the chemotherapy dosage increased, then it may be possible to more effectively eradicate tumour cells.
Small improvements are being made in the fight against cancer but what is needed is radical research to improve outcomes and treatment strategies significantly - and that's what this program represents.
There is insufficient Government funding to cover radical research. The Oncology Research Unit (ORU) at The Children's Hospital at Westmead is reliant on third party funding. The Oncology Children's Foundation (OCF) is underwriting the $2,500,000 cost of the five year program. Without this funding the program would not have proceeded.
Trial results for the Cancer Gene Therapy Program to date have shown very positive results, and the ORU team at The Children's Hospital at Westmead, are now preparing to commence human trials as early as the New Year.
The program in more detail
One reason that cancer sometimes comes back after treatment is that not all of the cancer cells are killed off by the chemotherapy. Most chemotherapy drugs kill cancer cells by damaging their DNA - but sometimes cancer cells are able to repair the damage and survive until after the chemotherapy has finished. One way that cancer cells can repair their DNA is with an enzyme called MGMT.
All cells in the body have MGMT to repair their DNA if they need to - but some cells have more than others. Cancer cells have more MGMT than bone marrow stem cells - so the dose of chemotherapy that's needed to kill them will also badly affect the bone marrow. This is one reason why chemotherapy has such a big impact on a patient's blood counts, since all red cells, platelets and white cells are produced in the bone marrow.
There are a few ways that chemotherapy can be made to work better in cells that have lots of MGMT - and one of these is to use a new drug, called 06BG to stop the MGMT from working. If the MGMT isn't working then the chemotherapy can do its job and kill the cancer cell.
A big problem with this strategy is that the 06BG also stops MGMT in bone marrow stem cells from working - and that means the bone marrow is more badly affected than before.
One way of getting over this problem is to take out the bone marrow stem cells and keep them safe from the 06BG and chemotherapy (frozen down in liquid nitrogen).
After the chemotherapy, the stem cells can be given back, and help all the blood counts recover.
Another way to protect the bone marrow, would be to give them an extra dose of MGMT - so they could repair the damage to their DNA which is caused by the chemotherapy.
Even better would be to give them a dose of a new type of MGMT called MGMT(P140K) - which can work even after cells have been treated with 06BG. Protecting bone marrow stem cells from 06BG and chemotherapy using MGMT(P140K) might mean that the side effects of treatment would be less, and that the chemotherapy might work better, with fewer delays between treatments.
This kind of strategy is called Gene Therapy - since the ORU will be putting in a gene as a part of the treatment. In the past few years, the ORU have made an agent (or vector) that can carry the MGMT(P140K) gene into stem cells. The ORU have tested the vector to check that the MGMT(P140K) gene can be protected from cells that are treated with 06BG and chemotherapy.
The results of laboratory studies have given the ORU the belief that this strategy might be able to alleviate the side effects of chemotherapy in patients, and for this reason the ORU is working towards setting up a clinical trial.
The first step is for the ORU to make a large amount of vector to use in a clinical trial. To do this, they are going to use a clean room facility called HAL (Human Applications Laboratory). This set of labs is specially designed to grow the vector in especially clean conditions.
HAL can also be used to do the gene transfer step, which involves incubating the bone marrow stem cells for 5 days in the vector, and keeping them happy with growth factors before they are given back to the patient.
Projects like this one - where the ORU is trying to translate research findings into a complicated clinical protocol, take a long time. They describe it as being like a game of snakes and ladders - where they build a few rungs and get going, only to slide backwards when faced with a new problem.
The ORU does have a sound plan, a terrific team of skilled scientists and clinicians, specialised facilities, and ongoing financial support from OCF who are underwriting the cost of the $2,500,000 five year program.
Oncology Children's Foundation
‘In pursuit of a cure....the gift of life'
October 2007
www.ocf.com.au
02 8394 7777
