Targeting glucose metabolism in cancer

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1. Please give a brief summary of your work.

Cancer cells, like all cells in our body, require sugars and protein from our diet to survive and proliferate. 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.


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


Our goal is to expand the 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 patients with cancer.  

2. Describe your approach and broader 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 cells/tissue use sugars as the main nutrient to make the energy required to function. Normal cells are well supplied by oxygen from the blood and use this oxygen to metabolise sugar and produce energy. Cancer cells 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 the next vital step (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 wider contribution, or impact, to your scientific field(s)?

Our research project will potentially lead to a new treatment for people with various solid tumours. 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.

 

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 cancer patients.

 

We are getting much closer to the discovery of better treatments that will significantly increase survival rates for 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 further study, as there was no significant toxicity observed during the trial and a dose for Phase II studies has been defined.

 

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 – 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 all types of cancer patients. 

4. Are there any potential ideas you would like to explore 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 patients with solid 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.


So far, PENAO has only been trialled on patients with solid tumours as a single agent. 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 solid tumours as a marker for drug effectiveness.


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. 

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