Designing drugs inside cancer cells

Life-changing funding for Dr Laura Leighton could also transform the lives of patients with hard-to-treat cancers, by helping her progress a potential new class of mRNA-based treatments.

“My aim is to transform cancer into a manageable chronic disease,” she said.

Dr Leighton has received a Cancer Council Queensland Next Generation Cancer Research Fellowship to advance the technology and establish an independent research program over the next five years.

Tackling ‘undruggable’ cancer proteins

The novelty of Dr Leighton’s work is that she is using mRNA-encoded monobodies to pursue what have been called “undruggable” targets inside liver cancer cells.

Among these targets are transcription factors, which act like switches turning specific genes on or off.

Transcription factors that trigger cells to divide are attractive targets for cancer treatment because they are overactive in many cancers, driving fast and unchecked tumour growth.

Urgent need for new therapies

Liver cancer affects nearly 1 per cent of Australians over their lifetime, with approximately 3,000 new cases diagnosed annually.

It is frequently diagnosed late, when patients are no longer candidates for surgery.

“More effective and tolerable treatments for liver cancer are desperately needed,” Dr Leighton said.

The challenge is that transcription factors are located inside cells, which means any therapies targeting them must be able to enter cancer cells.

“Antibodies have revolutionised cancer treatment through immunotherapy, due to their exquisite specificity and affinity, but they are too large to cross the cell membrane so can only target things on the outside of cells,” Dr Leighton said.

Getting treatment inside the cell

This is where monobodies can help.

These proteins are designed to recognise specific targets like antibodies do, but they are much smaller and simpler.

“Monobodies are much easier to work with than antibodies – we can easily encode them as mRNA and get them inside of the cell to find and block particular proteins,” Dr Leighton said.

When inside the cell, the mRNA provides instructions for the cell to produce the monobody.

The monobodies can then fold easily into their functional shape and bind to cancer-driving transcription factors.

Dr Leighton likens the mechanism to “sticking chewing gum into a lock,” preventing the transcription factors from binding with their usual partners to drive cancer cell growth.

Accelerating drug development using AI

Dr Leighton’s project uses artificial intelligence (AI) models to predict protein-protein interactions and improve monobody binding properties.

This allows her to prioritise the most promising candidates for laboratory testing, reducing the number that must be tested experimentally.

“This can really accelerate drug development, because the more that I can predict, the fewer candidates I need to test – helping me achieve more with the funding and time that I have,” she said.

Supporting early-career researchers

For Dr Leighton, the five-year fellowship provides the security to move towards independence, establish her own research direction and take promising ideas further.

“I'm incredibly grateful for the vote of confidence in my work and my ability as a scientist."

“Five years of funding means that I can now take on more PhD students and get real momentum behind my research.”

An AIBN-wide research effort

“AIBN is fantastic, I love it here, it’s a really supportive place to be”

The project draws on expertise and infrastructure across AIBN.

Dr Leighton works within AIBN’s National Biologics Facility (NBF) where she uses their protein discovery libraries.

She also has ready access other NCRIS facilities hosted at AIBN, sourcing research-grade mRNA from the BASE facility and examining tumour responses at AIBN’s Centre for Advanced Imaging.

“The NCRIS facilities are so important for enabling research,” she said.

“It frees up so much of my time having proteins and mRNA manufactured at NBF and BASE –we need such vast quantities for this type of pre-clinical research.”

Potential beyond liver cancer

The initial project focuses on liver cancer because the lipid nanoparticles carrying the mRNA naturally accumulate in the liver.

However, the underlying approach could potentially be adapted to other cancers as researchers can direct the nanoparticles to different tissues.

“Our main target gene is unusually active in over 70 per cent of human cancers, including lung cancer and triple-negative breast cancers which currently have fewer treatment options,” said Dr Leighton.

“If we can adapt the delivery technology, the same approach could be used against targets in those cancers.

“This technology also has the capability to target other disease-causing proteins, not only those involved in cancer.”

Investing in promising science

The fellowship forms part of a funding initiative that allows Cancer Council Queensland to support highly rated applications from the NHMRC Investigator Grant process.

The model enables promising cancer research proposals to be considered without applicants completing an entirely separate funding round.

Cancer Council Queensland’s Chief Research Officer, Professor Haitham Tuffaha, said the Next Generation Cancer Research Fellowship Scheme marked an exciting era of cancer research in Queensland.

“Through these fellowships, Cancer Council Queensland is providing long-term funding and stability to early career cancer researchers, including Dr Leighton, who are driving innovation in cancer prevention, detection, treatment and survivorship,” Professor Tuffaha said.

“Our mission is to lead Queenslanders in a partnership against cancer and these fellowships are a vital investment in the future of cancer research.”

More years of healthy life

Dr Leighton is excited about the opportunities that lie ahead and the possibility of developing a new drug class for those hard-to-treat cancers.

“Working on an mRNA therapeutic for cancer – the time is right.”

“There’s real momentum and it's lovely to be in a field that's really active, exciting and going places – and ultimately helping people” she said.

“If we can turn a life-limiting cancer diagnosis into a disease that you manage over the next couple of decades with a normal quality of life, then that's a good outcome for most people.”