The search for new and better anti-cancer drugs received a significant boost this year when the Genesis Oncology Trust awarded a three-year PhD scholarship to medicinal chemist Caryn Burgess of the University of Auckland.

 

PhD candidate Caryn Burgess, left, and Professor Margaret Brimble in The Department of Medicinal Chemistry, University of Auckland.		How the enzyme telomerase helps to make cancer cells immortal, and is therefore a good target for anticancer drugs. (Click to view PDF document)

She will be working on the development of a new class of drug called telomerase inhibitors that will attack cancer cells but leave normal cells alone.

Caryn will work under the supervision of Professor Margaret Brimble at the University of Auckland’s Department of Organic and Medicinal Chemistry. Professor Brimble is an internationally regarded chemist whose contribution to science was recognised in last New Year’s Honours list with the award of a New Zealand Order of Merit. She was awarded the 2004 chemistry lectureship by the international pharmaceutical company Novartis for her outstanding contributions and innovation to the field of organic synthesis.

Since her return to New Zealand in 2000 Professor Brimble has gathered a group of about 14 medicinal chemists around her, including several post-doctoral researchers from Germany and Switzerland. Says Professor Brimble, "the education system in these European countries produces superb medicinal chemists and the support and guidance they give to our own graduate students such as Caryn is creating a wonderful research environment."

Natural World Source of New Drug
"The mainstay of cancer treatment remains chemotherapy, and each year new drugs become available that are more effective in treating cancer and less damaging to the body," says Professor Brimble. "However, in spite of these advances, adverse side effects are still the major factor limiting the usefulness of chemotherapy and the hunt for superior drugs continues."

For Caryn this research is much more than a means to an academic qualification. She explains, "during my Honours year my aunt died of breast cancer at the age of 37. I decided to dedicate my research thesis to my aunt and this gave me an incentive to finish what had become a very difficult year. I was working on anti-fungal agents for my undergraduate research, however, my aunt’s death changed my focus and for my PhD study, I asked to join the cancer-drug development team, and happily was able to."

Professor Brimble’s medicinal chemistry research team specialises in synthesising naturally occurring bioactive compounds that have been isolated from plants, animals or bacteria. The starting point for Caryn’s synthesis is a unique class of antibiotics called rubromycins that were originally isolated from a strain of the bacteria Streptomyces.

Caryn Burgess says uncontrolled cell reproduction is the defining feature of all cancers and most anti-cancer drugs target the reproductive mechanisms of cells. Unfortunately, these drugs also attack normal dividing cells, including those of the immune system.

"Oncologists do a great job in mixing, matching and timing drug administration to minimise side effects, but all too often therapy has to be interrupted when patients become ill due to infections that arise due to a damaged immune system," she says. "The ideal anti-cancer drug is one that attacks cancer cells but leaves normal cells alone and telomerase inhibitors look very promising in this respect."

Telomeres the Key
So how do telomerase inhibitors kill cancer cells and spare normal cells?

Caryn explains that each time a cell divides, be it a normal cell or a cancer cell, the chromosomes which carry the genetic code are duplicated. The ends of the chromosomes are protected by structures called telomeres - a bit like the whipping used on the end of ropes to stop them unravelling. During cell division these telomeres are not reproduced and over the course of many cell divisions they become shorter and shorter. Once this telomere cap is lost, the chromosomes can no longer replicate accurately and the cell dies.

This cell death or "senescence" is a natural process, designed to make sure old cells are replaced by new cells in an orderly and programmed way.

"It had been noted that the telomeres in cancer cells do not shorten and cancer cells can reproduce many, many times - in fact they usually become immortal," says Caryn. "Any difference in the way that cancer cells and normal cells function provides a potential target for drugs, and research discovered that the enzyme telomerase was responsible for maintaining the telomere end-caps in cancer cells. Telomerase is active in the developing embryo and stem cells, but is generally switched off in most body tissue cells."

Japanese scientists discovered that a class of antibiotics called the rubromycins were potent telomerase inhibitors. The original rubromycins were isolated from cultures of live bacteria, but this is an uneconomic way to manufacture drugs and efforts are now underway to synthesize the molecule. Professor Brimble specialises in this field and has already established the methodology to make rubromycin in the laboratory.

Synthesise and Improve
Says Caryn Burgess, "synthesising drugs not only makes the process economical, it gives us the opportunity to modify the molecule to maximise efficacy and minimise side effects. This will form the core of my PhD and my main task will be to make other analogues of the naturally occurring material. These will then be tested for their ability to inhibit telomerase by Professor A. Scherf at the Institute Pasteur in Paris."

Caryn has already completed the first important step - the synthesis of the chemical skeleton that will be used as the basis for the new drugs; according to Professor Brimble, "this is no mean feat in only four months and augers well for the success of Caryn’s project".

Students’ financial burden
Professor Brimble says she was extremely pleased when Caryn received the award from the Genesis Oncology Trust which will allow her to continue in research.

"By the time students have completed four or five years undergraduate study, many are carrying a heavy financial burden and further study without a scholarship is not an option.

"Caryn is an outstanding young scientist, but without financial support she would have been lost to research. The Genesis Oncology Trust has had a significant impact on her career."