Chemotheraphy with no side effects: A targeted approach

Dr Kara Perrow
Vice Chancellor's Postdoctoral Fellow, Illawarra Health and Medical Research Institute

Like a sharpshooter with one eye on the bullseye, Dr Kara Perrow has a target in her sights.

That target is the destruction of cancer cells, utilising the body’s own biological systems as ammunition to deliver toxic drugs directly to a tumour. The direct hit will more effectively destroy tumours by focusing higher doses of drugs only on cancer cells, with the ultimate aim of reducing treatment-related side effects for the patient.

Perrow’s research relies on a combination of novel methods: firstly, the cytotoxins – or cell toxins – that she is using to destroy the tumour are unusually potent; secondly, a human system will be exploited to courier the toxin directly to the tumour; and finally, a combined approach will seek out the different types of malignant cells in a tumour for destruction at the same time.

Her approach has a singular, major prospective benefit for patients receiving chemotherapy: the elimination of treatment-related side effects.

The development of the novel cytotoxins is an element of Perrow’s work that reaches back to her Honours year working with Dr Kristen Benkendorf, where she received a solid grounding in testing new compounds from nature by screening samples from sea molluscs from the Illawarra coastline for their anti-bacterial properties.

“We found that these compounds were potent towards bacteria, but we needed to make sure they weren’t toxic to healthy human tissue,” Perrow says.

Using human cancer cells, which are hardy as well as being easier to culture in the laboratory, her aim was to show that these potential antibiotics killed bacteria and not human cells.

“As I was screening through these sea snail extracts I found hits with some of the samples: they were actually extremely toxic to the cancer cells and this led us to see that these compounds had anti-cancer activity as well.”

This path then took Perrow onto a PhD, examining exactly how this class of compounds, with origins in sea life, destroyed the cancer cells.  

“I found that they interacted with the skeleton of the cell, the ‘scaffolding’ which gives cells their shape. When cells are dividing, this skeleton is very susceptible to damage and this is how the compounds were disrupting the cancer.”

This finding led her to a research project, funded by the Cure Cancer Foundation and Cancer Australia, focusing on attaching the mollusc-inspired compounds to molecules that directly target cancer cells.

Encouragingly, this project showed that the targeted drug – containing just one molecule of cytotoxin– significantly reduced tumour growth, with no toxicity related side effects.

“This work led us to think that we could provide some advantage over what’s currently being done and provided confidence that there was a way to reduce the side-effects of current chemotherapy treatments,” she says.

These early career projects saw Perrow establish a solid grounding in the development of targeted therapeutics and critically, her research ethos of developing improved cancer treatments without the toxicity related side effects.

With local and national chemistry connections, her approach has further evolved into one using nanoparticles as the vehicle to deliver the cytotoxin to the cancer cells. This work has been boosted thanks to a three-year Vice Chancellor’s Fellowship, awarded to her in April.

She is focusing on placing the cytotoxin in a nano-sized ‘container’, which is then modified at the surface with the targeting molecules for specific delivery to cancer cells.

The ‘targeting’ of this nanocarrier to the correct cells is crucial, and Perrow is harnessing a human system called the plasminogen activation system to do it: an area of particular expertise among biologists at the University of Wollongong, who are investigating its role in illnesses from cancer to infectious disease.

The plasminogen activation system plays a critical role in the body. It controls blood clotting, both in terms of keeping blood flowing, and initiating clotting when needed, for example, when you cut yourself. It also controls tissue remodelling and cell migration, which are important in healing and the immune response.

However, this system is also known to be a critical one in tumour development and growth.

A particular enzyme involved in this system, known as uPA, has been found to be exploited by cancer cells as the primary vehicle for them to metastasise, or move from the primary tumour site into the blood stream and then into other organs in the body.

“Sometimes our regular, healthy cells express elevated levels of uPA – for example, during wound healing or immune responses – but under normal circumstances, uPA is undetectable. However, cancer cells constantly express uPA at high levels, so that gives us a ‘marker’ to selectively target,” Perrow says.

uPA has an inhibitor (a molecule that binds to the enzyme and blocks its action) called PAI-1 and these two molecules expressed in high levels together is a recognised, independent marker of poor prognosis for node negative breast cancer, where Perrow is focusing her work.

As in most tumours, the cells making up a breast tumour are not homogenous, yet current chemotherapy treatments only treat one type of malignant cell. This means that a chemotherapy drug might destroy one nasty cell, but leave other potentially metastatic cells untreated. Treating more than one type of cell at a time is also difficult because individual chemotherapy drugs, as they are currently administered, are toxic and cause significant side effects.

The nanotechnology that Perrow is nurturing is potentially ground-breaking as it will allow the targeting of different tumour cells by the nanoparticle carrying the cytotoxin to be delivered directly to the tumour via the plasminogen activation system. Using this natural biological system aims to avoid the body launching an immune response and destroying the nanoparticle before it reaches the tumour.

To demonstrate the targeting of more than one type of malignant cell, Perrow is focusing on breast cancers that express both uPA and the protein HER-2. A current treatment, herceptin, targets HER-2, but is only effective in about 25 per cent of cases. Of those patients large proportions suffer a relapse after one year.

HER-2 makes the cancer more aggressive, and there is a positive correlation with uPAR and HER-2 in around 70 per cent of cases.

Perrow’s approach aims to more effectively treat these aggressive breast cancers by enclosing the killer cytotoxin in a ‘nanocarrier’ and attaching herceptin, which interferes with the HER-2 receptor, and a second uPA inhibitor, PAI-2.

Unlike PAI-1, PAI-2 does not coexist with uPA in high levels when cancer is present, and although it’s not found in high levels in the body generally, there is one stage where it is expressed at levels over 100 times compared to normal – in pregnancy. “So we know that at higher levels, it’s not toxic to our body,” Perrow says.

The nanocarrier decorated with PAI-2 and herceptin will seek out the combination of uPA and HER-2 being expressed solely by these breast cancer tumours and deliver the nanoparticle to the cancer cells to release the lethal cytotoxin.

So far, the results of this multifaceted approach, drawing on principles of both biology and chemistry, are one that Perrow is drawing much confidence from.

“It builds on what’s available currently because it allows firstly the delivery of greater concentrations of the drug directly to both pre-malignant and malignant cells, and secondly, greater stability in the blood, because the drug is enclosed in a delivery vehicle. Altogether, this will aid in reducing any untoward side effects,” Perrow says.

Removing the association of toxic side effects with cancer treatment will continue to be the driving philosophy behind Perrow’s research.

“My overall aim is to develop a new generation of chemotherapy-based drugs that are safe, effective and eliminate the association of toxicity and sickness with chemotherapy.”