Sarah Muller

PhD Candidate, Griffith University

Cancer has plagued mankind for centuries. Even the ancient Egyptians worried about the disease and stated that “there is no treatment”. You might think that nowadays we are already a big step ahead of the Egyptians, which is certainly true, but cancer remains one of the leading causes of death worldwide.

Did you know, that one in two Australian men and women will be diagnosed with cancer by the age of 85? It is estimated, that in 2020 there will be just under 150,000 people diagnosed with cancer and just under 50,000 people will die from this disease.

There is comparably slow progress in terms of treatment methods and drug development. On average, of ten experimental cancer drugs, only one is successful…why is that? Well, cancer is not a single disease, but a term used for a collection of pathologies related to the uncontrolled proliferation of cells. This is what makes cancer therapy so difficult. Besides radiotherapy and antibodies, the most common treatment is chemotherapy which comes with immense side effects. Patients often suffer from nausea, vomiting, exhaustion, hair loss and inflammation of mucous membranes. But for many cancer patients, these drugs are still their greatest hope of surviving their disease. Chemotherapeutic drugs usually contain toxic substances that kill fast-growing cancer cells but, at the same time, unfortunately affect also healthy cells such as hair follicle cells that have high division rates. This explains the side effects from chemotherapeutic drugs.

An alternative strategy to conventional drugs works by targeting specific proteins that play an important role in cancer development and growth. Such a strategy has led to treatments with a better differentiation between healthy and cancer cells, with much reduced side effects.

The idea is to identify specific molecules that can bind to these proteins to make them less effective or inactive, hence reducing cancer growth. There are a gazillion candidate molecules out there, and finding the right ones is not easy. This is the research topic of my PhD.

One way to find such molecules is through fragment-based drug discovery (FBDD). FBDD is based on the identification of very small organic molecules, called fragments, that bind to a biological target. The development of an anticancer drug that tackles at the molecular level has led to a growing number of successful therapies that have affected the lives of cancer patients. These include Tykerb, used for breast cancer, Zelboraf, used for skin cancer, and Balversa, recently approved by the FDA for the treatment of urothelial carcinoma.

I am working with scientists at the Griffith Institute for Drug Discovery (or GRIDD) at Griffith University (Brisbane) and at the Commonwealth Scientific and Industrial Research Organisation (CSIRO, Melbourne) to study proteins involved in cancer and other diseases. I am interested in the structure and function of proteins to optimise their therapeutic usage. For the fragment screening experiments we combine native state mass spectrometry and X-ray crystallography to observe and confirm binding interactions between the protein and the fragments. Using these methods, we screen thousands of fragments and then select those with the strongest binding affinities in the expectation that this fragment will provide the foundation for the development of a cancer drug at the protein level.

One of our targets is a membrane protein, called ASCT2 (Alanine-Serine-Cysteine Transporter 2), which is over-produced in cancer cells. This means that cancer cells are overly reliant on this protein for their function, much more so than normal cells. Targeting ASCT2 has therefore enormous potential for the development of anticancer therapeutics. The main function of ASCT2 is to deliver the amino acid glutamine into the cell. Glutamine is a conditionally essential amino acid and serves both as an energy source and as a component to build more complex products such as essential proteins for the cell. It has been shown that the growth of many cancers is significantly dependent on ASCT2- mediated glutamine uptake. Inhibition of ASCT2 has also been shown to effectively slow down tumour growth in preclinical models, and modulation of ASCT2 is considered a promising cancer-fighting strategy.

At the Collaborative Crystallisation Centre (C3) at CSIRO we are working on a high-resolution crystal structure of ASCT2, which will provide us with a better understanding of the molecular interactions for further development/optimisation of better inhibitors. ASCT2 is associated with many different tumour types, such as breast cancer, prostate cancer, lung cancer, endometrial cancer and gastric cancer. For me it offers great motivation to work on a project that contributes to gaining knowledge that could help people one day.

In Australia the most common cancers are prostate, breast, colorectal, melanoma and lung cancer. But there is hope that although the number of cancer diagnoses is increasing, with the progress made so far, many more people will survive this disease than ever before. What is more, only 5-10% of all cancers are fully hereditary. Most cancers develop through a combination of hereditary and environmental factors, including smoking, alcohol, obesity and diet. It is estimated that cancer deaths could be reduced by 50% (that’s huge!) if we took better care of our health and stuck to what we have known for a long time, and stopped smoking, ate a healthy diet and remembered to use sunscreen when out and about…what are we waiting for?

Working on this project and being able to contribute to the search for therapies for a disease that affects so many people is very exciting for me. As an international student coming from Germany to do a PhD in Australia, it’s kind of an adventure. And working with experts in the field of drug discovery really inspires and motivates me every day.

I would like to acknowledge the support of the Australian Research Council Centre for Fragment Based Design (ARC CFBD), Griffith University and the Commonwealth Scientific and Industrial Research Organisation (CSIRO).

Photo by National Cancer Institute on Unsplash