Professor Palli Thordarson from the UNSW RNA Institute and Associate Professor Joshua McCarroll from the Children’s Cancer Institute discuss 'Is RNA the answer to cancer?'
RNA is at the core of our biology – the software of life – translating our DNA into the very products and processes that make us human. As well as being the key ingredient in COVID-19 vaccines, RNA technology might become the key to treating conditions like cystic fibrosis, schizophrenia and cancers.
To explore such a future, Â on August 17th from 6.30, with Professor Palli Thordarson, Director of the UNSW RNA Institute and Conjoint Professor Maria Kavallaris AM, Head of the Translational Cancer NanoMedicine Theme and UNSW Children's Cancer Institute.
Before the panel, we asked a few questions of Prof. Thordarson and Associate Professor Joshua McCarroll, Team Leader at Children’s Cancer Institute and Conjoint Associate Professor at UNSW Medicine & Health.
What is RNA and how does it relate to mRNA? And what does the term ‘RNA’ mean to the public since COVID-19?
Professor Palli Thordarson: I'll take the chemist's view first. RNA is a class of molecules. Another class of molecules is DNA. Another class of molecules is proteins. Just as DNA is an essential molecule in life, RNA is its complementary. Both play a central role in life. In fact, between them – DNA, RNA and proteins – these are the three most important macromolecules [long, chain-like molecules] for life.Â
Conventional wisdom, taught in high school biology, is that DNA stores the genetic information; proteins do all the work; and RNA is just a messenger between the two. (That’s what the ‘m’ stands for in mRNA – ‘messenger’.) But that's an over-simplification. RNA does a lot more within the cell, and we need a more holistic view.
In addition to messenger RNA, there are many different forms of RNA, all performing different roles within the cell. There are shorter RNAs: microRNAs (miRNA). There are the transfer RNAs: tRNAs, the ribosomal RNAs: rRNAs. There are non-coding RNAs. There are myriad different types of RNA molecules just within our own cells – and mRNA is just one of them. It's probably the most important variety, but it's only one type.
Associate Professor Joshua McCarroll: [In terms of what RNA means to the public] I think the average person knows that the COVID-19 virus is made up of RNA, and that these viruses can rapidly mutate and are highly transmissible. [The public] also recognise that RNA is a major component of COVID-19 vaccines, and that these are a new class of vaccines that work differently from other traditional vaccines and can be modified to target different COVID-19 virus mutations. There is also a sense that RNA vaccines may be used in the future to target other human diseases such as cancer.
How is RNA already being used as a therapeutic in medicine?
A/Prof. McCarroll: Up to this point, my relationship with RNA has been purely aimed at harnessing its power as a new class of cancer therapeutics which can target and selectively silence key cancer-causing genes. However, RNA biology has so much more to offer in terms of increasing our understanding of its role in regulating tumour development, growth and chemotherapy drug resistance. RNA can also be used as tumour biomarkers in liquid biopsies (i.e. blood) to help clinicians monitor and know when a tumour is growing or responding to treatment. This is an area our research team has recently been investigating.
Why do we need an alternative to current cancer treatments?
A/Prof. McCarroll: Cancer is a major cause of death worldwide. Despite aggressive multimodal treatments, failure to respond to treatments, relapse and metastases are common. Advancements made in genomics have generated a wealth of new knowledge on the tumour microenvironment in different adult and childhood cancers and identified a host of new therapeutic gene targets. However, some of these genes are difficult to selectively target using chemotherapy or small molecule inhibitors.
There is an urgent need to develop new innovative therapeutic strategies that can inhibit these gene targets. There is also a need to consider developing therapeutic drugs to be more selective to tumour cells and avoid or limit off-target treatment toxicity to non-tumour cells which often leads to short-and long-term side effects. These new drugs have potential to increase the survival and quality of life for adults and children diagnosed with cancer.
What qualities of RNA are so promising for the treatment of cancer?
A/Prof. McCarroll: RNA – particularly small interfering RNA (siRNA) – has the power to inhibit the expression of any cancer-causing gene of choice with selectivity. This includes genes that play a critical role in promoting the growth and survival of cancer cells, which cannot otherwise be targeted using pharmacological drugs. RNA also has great potential to target other key non-tumour cell types in the tumour microenvironment. As witnessed with COVID-19 mRNA vaccines, there is also potential to harness the power of RNA to engage with the immune system to help recognise and destroy tumours.
I think one of the many useful features of RNA molecules is their ability to be readily modified in the lab. One use for RNAs, here, is to increase our knowledge on tumour development and growth as well as to identify new therapeutic targets. One subject for further investigation is small, non-coding RNAs known as miRNAs. These miRNAs can be dysregulated in cancer cells and have the potential to regulate the expression of hundreds of gene targets simultaneously.
Chemically modified double-stranded RNA that is produced in the lab can be delivered into cancer cells to act as miRNA mimics. This allows researchers to understand the role of the target miRNA in regulating tumour growth and its effect on signalling pathways. RNA drugs that target the expression and function of miRNA are currently being tested in clinical trials for cancer.Â
Prof. Thordarson: Yes, and in terms of producing RNA in the lab – there are two main techniques. One technique uses biological components, enzymes from nature that use ‘DNA’ as a template, adding nucleotides to create the RNA strand, very much like what our own cells do. The other method is chemical synthesis, where you start with a foundation and you add one nucleotide at a time, basically like threading pearls on a string. You custom-make your sequence that way. The chemical synthesis of RNA is the method of choice for really short RNA.
The chemical method only works with RNA up to a certain length, where it’s limited both by the chemistry and the economics. There’s a crossover point. The biological method works well at longer scales.Â
What are some of the challenges when it comes to using RNA as a therapeutic?
Prof. Thordarson: Developing RNA therapeutics is relatively easy compared with the main challenge: getting the RNA into the cell where it does its magic. It is getting the RNA cargo into many different types of tissues and cell types that presents the struggle. Lipid nanoparticles, which are used in the COVID-19 vaccines, work great when they’re used for vaccinations – and other applications, such as treating liver diseases. But if you want to specifically target a tumour in a particular part of the body, it can be really hard to develop the delivery vehicle for the RNA.Â
A/Prof. McCarroll: Solid tumours are made up of a complex microenvironment that contain non-tumour cells, scar tissue and highly disrupted blood vessels which can make it difficult for drugs to reach the tumour cells at high concentrations.
What is nanomedicine and how might it solve the delivery of RNA for use in therapeutics?Â
A/Prof. McCarroll: Nanomedicine is the application of nanotechnology to design and synthesise tiny nanoparticles which act as highly effective carriers for therapeutic drugs used to treat a host of different human diseases. Nanoparticles are used in the clinic for the treatment of several different cancers. Nanoparticles are packaged with chemotherapy drugs and delivered to tumour cells. Our team has a strong interest in developing polymer-based nanoparticles which can package RNA drugs. The nanoparticles, and their RNA package, can penetrate solid tumours to inhibit key genes that promote tumour growth, chemotherapy drug resistance and metastases.
Therefore, nanoparticles need to be purpose-fit for penetrating solid tumours and recognising tumour cells. This can be achieved by ensuring the size of nanoparticles is less than 100nm [nanometres] to enable them to enter tumour blood vessels. We can also modify the surface of nanoparticles and chemically attach antibodies or peptides which recognise proteins on the surface of tumour cells, helping them to bind more strongly. This enables active tumour targeting for the RNA drugs which can boost therapeutic efficacy and reduce toxicity to healthy cells.
What’s next for RNA as a therapeutic?
Prof. Thordarson: Developing effective methods of delivery is a challenge, but it's also an opportunity – especially here in Australia. Australia is very strong – internationally – in the field of nanomedicine and nanoparticle delivery systems.Â
There's been a lot of research in this space for more than a decade, so [Australia is] something of a world-leader in this space. We're in a good position to help solve these challenges. It’s actually one of the main motivations behind establishing the UNSW RNA Institute. The Institute brings together the chemists and engineers who work on delivery systems and the medical and biological researchers who work on the basics of RNA biology and its applications in medicine. That's really what we're trying to do in the institute: bring those people together, have their work inform each other, and deliver better RNA therapeutics in that way.
A/Prof. McCarroll: Our team has been working to optimise nanoparticles to deliver therapeutic RNA, like siRNA, to silence the genes that are highly expressed in cancer cells, genes that play a major role in promoting tumour growth and which are otherwise difficult to target using small molecular inhibitors. We focus on three different cancers with poor outcomes, pancreatic, lung and childhood brain cancer. All have unique challenges in terms of drug delivery. So far, we have shown that our nanoparticles carrying siRNA can inhibit pancreatic and lung tumour growth in clinically relevant in vitro and in vivo models. We also have early data to suggest that our nanoparticle-siRNA drugs can enter mouse brain tumours. We are excited to be part of the UNSW RNA Institute and believe this is a unique opportunity to bring together clinicians, cancer biologists and nanotechnologists to help us tackle these terrible cancers and help bring RNA nanomedicines to the clinic.
Is RNA the answer to cancer?
The live-streamed panel event featuring RNA and cancer researchers from UNSW took place as part of National Science Week 2022. The full discussion with Professor Palli Thordarson and Conjoint Professor Maria Kavallaris AM, with Associate Professor Joshua McCarroll in absentia, is available now.