Our treatment resistance research
Garvan researchers collaborate with each other as well as with labs around the world to combat treatment resistance in cancer. We're examining how resistance develops at cellular and genetic levels in a broad sense, as well as in specific types of cancer.
Treatment resistance leads to a poorer prognosis and disease relapse. We're looking at novel treatments to overcome this hurdle as well as possible ways to reverse the cellular changes that result in resistance — to re-sensitise the disease to treatment.
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Key areas of investigation
Treatment resistance development in cancer
Prof David Thomas and Dr Arcadi Cipponi (right) of the Genomic Cancer Medicine Lab led a team to research the underlying mechanisms that allow cancer cells to adapt to treatments and become resistant. They wondered if cancer cells developed resistance in a similar way to antibiotic resistant bacteria. These bacteria undergo stress-induced mutagenesis, which is where bacteria acquire new genetic mutations in order to adapt and survive.
The team first looked at the differences in the genes between pre-treated and post-treated cancer biopsy samples. It was discovered that the stress of undergoing targeted cancer treatments resulted in the post-treated biopsy samples having very high levels of genetic mutations, even though the treatments did not target the DNA.
Genome sequencing was used to find out what exactly was causing this high mutation rate. Different genes in the cancer cells were individually silenced to see if they were the culprit; it was revealed that the mechanistic target of rapamycin (MTOR) gene played an important role. During cell growth, the genetic material within the DNA is copied for each new cell with very few mistakes. When cancer cells were subjected to targeted treatment, MTOR reacted by encouraging mistakes in the production of DNA causing genetic mutations in the new cancer cells. Once there were enough mutations to render the treatment useless resulting in treatment resistance and less stress, MTOR switched off. The newly mutated, resistant genes would then be copied into each new cancer cell allowing for progression of the cancer despite treatment.
Knowing how treatment resistance develops in cancer and what genes are responsible is important for the improvement of future therapeutics. Targeting the genes that help cause mutations could be a useful approach in preventing or reversing treatment resistance.
Pancreatic cancer has one of the lowest survival rates of all cancers with an average survival rate of 6 months. One of the reasons for this is its high rate of resistance to treatment.
A common characteristic in pancreatic cancer is the presence of a constantly moving low-oxygen region, called a hypoxic region, within the tumour. These hypoxic regions allow the cancer cells to be more aggressive and resistant to many different forms of treatment. A/Prof Paul Timpson and his team were able to use intravital microscopy to visualise these hypoxic regions in real time.
They used this to observe the combination of a cancer treatment with a drug that is activated in low-oxygen environments. The results demonstrated this combination to have a prominent improvement in treatment response compared to the cancer treatment alone, and it also prevented further growth of the tumour. This shows promise in being able to treat drug resistant pancreatic cancer and other hypoxic cancers more efficiently in the near future.
Another approach that A/Prof Timpson has looked into is manipulating the environment surrounding the tumour, or stroma. It was shown that certain genetic mutations increased the presence of perlecan, a type of protein, in the stroma. Perlecan was found to encourage metastases and delay chemotherapy response. When perlecan was removed from the stroma, response to chemotherapy was improved. This provides support for future treatments that target the stroma.
Dr Marina Pajic devotes much of her research to pancreatic cancer and has also looked in to treatment resistance. P21-activated kinases (PAKs) are enzymes that are known to encourage cancer cell growth and metastases and can also promote resistance to anti-cancer drugs. Dr Pajic and her team demonstrated that inhibiting PAKs combined with various different chemotherapies resulted in an improvement in treatment response. This provides a new target for treatment of pancreatic cancer.
Several Garvan research groups study treatment resistance in breast cancer.
A/Prof Marina Pajic has studied breast cancer resistance to radiotherapy. Micro-ribonucleic acid (miRNA) is a small piece of genetic material that can regulate parts of the DNA. A/Prof Pajic and collaborators were able to show that a particular miRNA, miR-139-5p, was able to re-sensitise a breast cancer tumour to radiotherapy. They were also able to use miR-139-5p to determine which tumours would be more likely to be resistant to radiotherapy. This shows promise in being able to first predict the likelihood of radiotherapy resistance and also being a targeting treatment.
The Connie Johnson Breast Cancer Research Lab, led by A/Prof Elgene Lim, has looked at novel treatments to use on endocrine treatment resistant breast cancers. The majority of breast cancers diagnosed are oestrogen receptor (ER) positive, meaning they have ER on the surface of the cancer cells. Endocrine therapies involve blocking the ER to prevent further tumour growth; however, the eventual decline of ER on the cell surface resulting in treatment resistance remains a frequent problem. Novel therapies such as those targeting the androgen receptor (AR), another endocrine receptor, and MDM2, which affects cell growth and death, have been tested in vivo in mice models. They have also looked at ways to combat CDK4/6 inhibitor resistance. CDK4/6 inhibitors are recently approved treatments for ER positive breast cancers that have produced great results in preventing disease progression, but unfortunately resistance to this treatment is also an issue. A/Prof Lim aims to use this research in aiding treatment movement in to clinical trials and approval for these new therapies in the future.
Dr Joanne Achinger-Kawecka of the Epigenetics Research Lab, led by Prof Susan Clark, has looked in to the changes in DNA that leads to treatment resistance in ER positive breast cancer. They found that the structure of the DNA was 'rewired' in endocrine treatment resistant cancers affecting genes such as those that control the level of ER in cancer cells. This information will be used to see if the rewiring changes are able to be reversed which would re-sensitise the cancer to endocrine therapy.
Lung cancer is generally treated using platinum-based chemotherapy. Unfortunately, less than 30% of lung cancer patients benefit from it; many experience serious side effects or are resistant.
Garvan researchers in collaboration with the Hudson Institute for Medical Research in Melbourne studied the effects of a hormone, called follistatin, in mice models in combination with the platinum chemotherapy. Prof Neil Watkins and his team discovered that the chemotherapy was much more effective when combined with follistatin and even prevented kidney damage, a serious side effect of the chemotherapy. Our team hopes to use these results to improve on platinum-based chemotherapy efficacy in highly resistant lung and other cancers.
Another tactic studied the role of enzymes in the chemotherapy resistant cells. Dr David Croucher and his team discovered that the enzyme P70S6K was present in high levels in cancer cells that were treatment resistant. The effects of inhibiting P70S6K either via drugs or genetically were tested in vitro and in mouse models. Results showed that when the enzyme’s levels were lowered, the cells became more sensitised to the platinum chemotherapy.
The Clinical Prostate Cancer Research Group led by Prof Lisa Horvath focuses on prognostic markers for prostate cancer and resistance to chemotherapy. Docetaxel is a chemotherapy drug used in metastatic prostate cancer; however, it only benefits approximately 50% of the patients. The remaining patients who do respond to docetaxel ultimately develop resistance.
Prof Horvath’s group discovered that focal adhesion kinase (FAK) mediates cancer cell resistance to docetaxel as it becomes activated during treatment. Further studies in the use of a FAK inhibitor in docetaxel-resistant prostate cancer cells in combination with docetaxel were conducted. Results showed that this combination prevented further tumour growth and increased cancer cell death. This shows potential in future treatments to prevent docetaxel resistance in advanced prostate cancer.
National and international collaborations
- ANZAC Research Institute, Sydney, Australia
- Australian Pancreatic Genome Initiative
- Australian Prostate Cancer Research Centre, Sydney, Australia
- Australian Regenerative Medicine Institute, Melbourne, Australia.
- Azienda Socio Sanitaria Territoriale di Cremona, Cremona, Italy
- Blacktown Hospital, Sydney, Australia
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
- CancerCare Manitoba, Winnipeg, Canada
- Cardiff University, Cardiff, United Kingdom
- Chris O'Brien Lifehouse, Sydney, Australia
- Cornell University, Ithaca, United States of America
- Crown Princess Mary Cancer Centre, Sydney, Australia
- Flinders University, Adelaide, Australia
- Hudson Institute of Medical Research, Melbourne, Australia;
- John Wayne Cancer Institute, Santa Monica, United States of America
- Key Laboratory of Carcinogenesis and Translational Research, Beijing, China
- Kolling Institute of Medical Research, Sydney, Australia
- La Trobe University, Melbourne, Australia
- Lowy Cancer Research Centre, Sydney, Australia
- Mater Hospital, Sydney, Australia
- Melanoma Institute Australia, Sydney, Australia
- Monash Medical Centre, Melbourne, Australia.
- Monash University, Melbourne, Australia
- Netherlands Cancer Institute, Amsterdam, Netherlands
- Peking University Cancer Hospital and Institute, Beijing, China
- Peninsula Health, Frankston, Australia
- Peter MacCallum Cancer Centre, Melbourne, Australia
- Royal Melbourne Hospital, Melbourne, Australia
- Royal North Shore Hospital, Sydney, Australia
- Royal Prince Alfred Hospital, Sydney, Australia.
- South Australian Health and Medical Research Institute, Adelaide, Australia
- St George Hospital, Sydney, Australia
- St Vincent’s Clinical School, Sydney, Australia
- St Vincent’s Hospital, Sydney, Australia
- St Vincent's Centre for Applied Medical Research, Sydney, Australia
- UNICANCER, Paris, France
- Université Claude Bernard Lyon, Lyon, France
- University College Dublin, Dublin, Ireland
- University of Adelaide, Adelaide, Australia
- University of California San Francisco, San Francisco, United States of America
- University of California, San Diego, United States of America
- University of Glasgow, Glasgow, United Kingdom
- University of Illinois, Urbana, United States of America
- University of Manitoba, Winnipeg, Canada
- University of Melbourne, Melbourne, Australia.
- University of New South Wales, Sydney, Australia
- University of Otago, Dunedin, New Zealand
- University of Oxford, Oxford, United Kingdom
- University of Sydney, Sydney, Australia.
- University of Trieste, Trieste, Italy
- University of Western Australia, Perth, Australia.
- VIB-KU Leuven and Center for the Biology of Disease, Leuven, Belgium
- Victor Chang Cardiac Research Institute, Sydney, Australia
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Westmead Hospital, Sydney, Australia