Targeting sugar metabolism in youth brain cancer

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Image1467878096?1467878096  You Can Innovate Award

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1. Summary of your project

Cancer cells, like all cells in our body, require sugars and protein from our diet to survive and flourish. While healthy/normal cells mostly produce energy from these nutrients, cancer cells use the nutrients to rapidly grow, divide and spread to surrounding organs - ultimately resulting in fatal consequences.


Brain tumours are among the most difficult and uncontrollable of all cancers. My research is on glioblastoma, the most common and malignant brain tumour. It is a debilitating disease, and is essentially a terminal illness in young Australians. There are currently no effective therapies; most patients do not survive more than 15 months after diagnosis, and those who do have less than a 5% chance of surviving longer than 5 years – giving great cause to increase our focus on this line of research and significantly increase our understanding of the disease in order to develop effective drugs and therapies.


The main aim of this project is to progress a project that has recently – and successfully – completed phase I clinical trials. My lab have developed  a unique drug, PENAO, that interrupts and blocks cancer cell metabolism, thereby starving the cells and ultimately shrinking the tumour. This gives new hope for the treatment of brain cancer.


Our goal now is to expand the project scope and test another metabolism-targeted therapy already approved for clinical use to increase effectiveness and apply this, in combination with PENAO – to a larger cohort (patient group) study – ultimately getting us closer to providing better treatment and increasing chances of survival for young Australians with cancer.

2. Describe your approach and any preliminary findings.

For decades now, cancer researchers and clinicians have focused on identifying specific genetic changes that are associated with cancer, and developing therapeutics that target these changes. It is becoming increasingly evident that a different approach needs to be taken to tackle cancer cells as they are so adept at adapting quickly and bypassing specific functional blocks that most targeted therapies are only transiently effective. This reality has led to a renewed focus on a fundamental property of cancer cells that was identified eight decades ago: their aberrant metabolism of nutrients.


Healthy brain cells/tissue use sugars as the main nutrient to make the energy required to function. Normal brain cells are well supplied by oxygen from the blood and use this oxygen to metabolise sugar and produce energy. Brain tumours are usually starved of oxygen because their blood supply is not sufficient to provide the amounts of oxygen needed by a growing tumour. A product of this oxygen-poor cancer cell metabolism is the production of acid that poisons surrounding tissue, resulting in the tumour being able to grow and spread to distant organs in the body.


This project will take an innovative approach following a discovery that allowed us to better understand how brain cancer cells uptake and metabolise nutrients at a cellular and molecular level. We will tackle this cancer by inhibiting the growth of the diseased cells.


This project is a follow-on (stage 2) from the development of a novel metabolism inhibitor for the treatment of cancer, which recently completed a Phase I clinical trial in patients with solid tumours resistant to standard therapy in hospitals around Australia. The metabolic-inhibitor drug, named PENAO, was well tolerated in patients, and a dose for Phase II studies has been defined.


Preliminary findings have shown us that cancer cells rely heavily on specific proteins to meet their metabolic demand in order to grow; proteins which are of lesser importance in normal brain cell metabolism. This difference in behaviour has presented a target in brain cancer cell metabolism. PENAO specifically targets cysteine residues 57 and 257 in the protein adenine nucleotide translocase (ANT); which is responsible for transporting of energy to the cell – therefore disrupting metabolism and causing cell death. PENAO only reacts with ANT when cells are growing rapidly, as cysteines 57 and 257 appear to be bonded in dormant cells; and so unreactive towards PENAO.


We reasoned that combination of PENAO with another metabolism-targeted inhibitor (mTORC1) should profoundly impair tumour cell metabolism and survival – borne about in preliminary findings. We showed combination of PENAO and mTORC1 inhibitors at near maximal tolerated doses was well tolerated in mice. Both compounds are generally well tolerated in mice and humans as single therapies, so we anticipate a therapeutic window for the combination therapies. 

3. What is the impact of your research to help cancer patients?

Our research project will potentially lead to a new treatment for young people with brain cancers – one of the most uncontrollable cancers for which there are very limited treatment options. The primary aim of this research is to better understand how to utilise our drug, PENAO, to achieve maximum benefits for cancer patients – increasing the chance of survival rates and enhancing their quality of life.

 

Our investigations are targeting the disease at its core. We are confident that our investigation of glucose metabolism therapeutics and our track record of developing novel metabolism-targeted drugs will provide a greater number of treatment options for patients.

 

Due to the large focus on children and adults, there is an obvious lack of funding and research into treating youths with brain cancer. The long-term effects of invasive and toxic treatments, such as chemotherapy and radiotherapy, heavily impact everyday life. If we can complete the development and fully understand PENAO’s bioactivity, we hope to lower the risk of long-term effects, and assure a better quality of life for youth cancer patients.

 

Results from the Phase I clinical trial of PENAO showed one adult patient with a brain tumour had stable disease over 10 cycles of PENAO (30 weeks). This outcome is promising for youths, as there was no significant toxicity observed during the trial and a dose for Phase II studies has been defined.

 

We are about half-way there to the discovery of better treatments that will increase survival rates for youth brain cancer. The development of a new class of anti-cancer drugs that target the cancer’s metabolism may transform that way cancer patients are treated. PENAO, inactivates a key protein in energy-producing structures known as mitochondria. PENAO is unique and we are the only group targeting cancer in this way. All cancer cells appear to have an altered cell metabolism, so with this approach may benefit not only young people with brain cancer, but other cancers as well. 

4. What ideas would you like to explore, or currently are exploring, to take this research further?

Our current goal is to identify the best combination therapies for PENAO, and to gather the pre-clinical support for combination Phase I and II trials in young people with brain tumours. We decided to explore the combination of PENAO and inhibitors of mTORC1; a protein known to be responsible for promoting cancer cell survival. We observed strong combination effects of PENAO and mTORC1 inhibitors at a cell and animal level; so we anticipate similar results in the clinic.


We plan to initially test the combination therapy by using the maximum tolerated dose of PENAO, together with the standard dose of the nominated mTORC1 inhibitors. Inhibitors such as everolimus, rapamycin and tacrolimus are already approved for clinical use, and available in Australia, thus readily facilitating their integration into clinical setting.


So far, PENAO has only been trialled on adult patients with solid tumours and has yet to be given to youths with cancer. PENAO showed stable disease in an adult patient with a brain tumour, so we are optimistic that is will benefit young people with brain cancer. PENAO unexpectedly showed a half-life of 3-4 days, which has warranted further exploration of a more convenient dosing schedule. Our long-term aim is to develop and test a prodrug version of PENAO, and validate proteins in brain tumours as a marker for drug effectiveness.

5. Please demonstrate your track-record. Share a selection of publications, citations, awards etc.

As an undergraduate, I was awarded the Sydney Medical School Summer Research Scholarship. My work was presented at various national and international conferences: Transplantation Society of Australia and New Zealand Annual Scientific Meeting in Canberra, American Transplant Congress in Philadelphia, USA and International Congress Of The Transplantation Society in Hong Kong. We have submitted to Nephrology Dialysis Transplantation and the article is currently under review.


I graduated from UNSW with a double degree in Advanced Science (Honours First Class) and Music, conferred in 2015. Currently, I am a PhD student at the University of Sydney. I am a recipient of an Australian Postgraduate Award, Centenary Institute Top-Up Scholarship and the Eldon and Anne Foote PhD top-up Scholarship for Young Women in Science.


In the first year of my PhD candidature, I published in the Journal of Gynecologic Oncology. I was also given the opportunity to present my Honours research findings at multiple national conferences including the Lorne Cancer Conference, Australian Cancer Metabolism Meeting and Lowy Cancer Symposium.


In my second year, I was given the opportunity to present my PhD work at both national and international levels; Sydney Catalyst 2016 Post Graduate & Early Career Research Symposium, ASMR Annual Scientific Meeting, Bosch Institute Annual Scientific Meeting and FASEB Science Research Conference in Colorado, USA; for which travel funds were granted by the Postgraduate Research Student Support.

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