The University of Melbourne
	Department of Surgery
	Royal Melbourne Hospital and Western Hospital

Photodynamic Therapy Laboratory

Unit Head : Professor Andrew H. Kaye
Research Officer : Stan Stylli

Research Over the past 17 years, Professor and his team have worked on an innovative way of using lasers to selectively kill brain cancer while not harming the adjacent normal brain. This process is called photodynamic therapy (PDT).

In PDT, there is a selective uptake of a special chemical, called a sensitiser, by the brain cancer. This chemical is taken up only into the cancer cells and is excluded from the normal brain tissue. A special laser is then used to produce light that will activate the sensitiser chemical within the cancer cell. This produces a local toxic reaction that kills the cancer cell while not harming the adjacent brain.

Experiments on this therapy commenced in 1986. Since then Professor Kaye has investigated the best way to get the photosensitizer to the cancer cells, how these cells take up the photosensitizer (while being excluded from the normal brain), and how the laser light interacts with the photosensitizer producing a toxic reaction and killing the tumour cells. Some of the studies undertaken in thie laboratory have been to target with PDT the ‘invading roots of the tumour’ that cannot be removed by surgical means.This laboratory has investigated many different sensitiser chemicals, and chemical trials have been performed at the hospital.Clinically, over 200 patients have been treated with Haematoporphyrin Derivative (HpD) at The Royal Melbourne Hospital, which is the largest study of this type of therapy in the world for brain tumours.. The results of thie trial show that the therapy is well tolerated and the median life expectancy with primary malignant glioma is extended from nine months using conventional therapies of surgery and radiotherapy, to 26 months using surgery, PDT and radiotherapy. Nearly 25% of patients have survived more than 5 years. These results are particularly encouraging and exciting.

Considerable research is being undertaken into developing new photosensitiser drugs for use in PDT.
Collaborations with local and international universities and companies has seen many photosensitizers being investigated in the laboratory.

Professor Kaye and a former laboratory head, Dr. John Hill, now at a U.S. company, Miravant, are collaborating on a project involving a new photosensitizer called MV6401. MV6401 was developed at Miravant and they approached the laboratory to evaluate its efficacy in the treatment of brain tumours using the C6 tumour model. The in vivo studies are showing very encouraging results in causing selective tumour necrosis.
There has been a long standing collaboration with Professor Stephen Kahl from the Department of Pharmaceutical Chemistry at the University of California. San Francisco. A photosensitiser drug called BOPP (boronated protoporphyrin) has been developed and research in the laboratories in the Department of Surgery has confirmed that this drug is nearly 10 times as sensitive for PDT as previous drugs. A Phase I clinical trial has been undertaken at RMH and over 20 patients have been treated.

Another area of interest is to investigate the role of apoptosis in the photodynamic process. The inhibition of apoptosis, a form of prgrammed cell death, has been shown to be one of the major obstacles to treatment resistance in many cancer cells, especially with radio- and/or chemotherapy. Photodynamic therapy is no exception to this process.The proto-oncogene family BCL-2 and its members are critical players in the regulation of apoptosis. Therefore, they can be involved in tumour progression and/or the resistance to treatment in many cancers. The family consists of pro-apoptotic (eg) bax, bak, bid and anti-apoptotic (eg) bcl-2, bcl-xl and the ratio of these in a cell can affect its ability to undergo apoptosis.

In vitro studies examining the relationship between these family members and their effect on the PDT process, especially at sub-lethal doses at the boundary of laser light penetration into tissue are underway. Different photosensitizers are being investigated with brain tumour cell lines over-expressing the anti-apoptotic member, bcl-2. The ratio of the family members as well as the varying localization of different photosensitizers within a cell may affect the overall outcome in a cells response to PDT.

Also, a retrospective study exploring the expression of the BCL-2 family members in archival brain tumour material from patients who have undergone photodynamic therapy at the Royal Melbourne Hospital. The expression profile, levels of photosensitizer that has been taken up by the tumour cells, treatment doses and grade of tumour will all be collected to see if there is a relationship between survival and apoptotic profile.