Melanoma Institute Australia has many active research projects at any one time. These are just a few of note.
- Overcoming resistance to immunotherapy
- Identification of genes involved in early brain metastasis
- Acral and Uveal Melanoma
- The Australian Melanoma Genome Project
- Predicting response to immunotherapy
- Surgery Support Clinic
- Patterns of Care Study
- Saving our next generation
Overcoming resistance to immunotherapy.
Immunotherapy has saved countless lives in advanced melanoma. However, approximately 50% of people do not respond to treatment. One of the biggest barriers to improving survival rates is drug resistance.
New research from Melanoma Institute Australia (MIA) has given us a greater understanding of how cancer becomes resistant to immunotherapy. Immunotherapy works by harnessing the body’s own immune system to destroy melanoma cancer cells.
The researchers previously discovered that melanoma tumours that are resistant to immunotherapy often stop expressing basic protein machinery called antigen-presenting molecules (specifically MHC-I and MHC-II). These molecules make the tumour visible to the immune system so that they can be destroyed.
Using tumour biopsies from MIA’s BioSpecimen Bank, the researchers developed a technique that can screen for the presence of these molecules before patients commence treatment, providing clinicians with an evidence-based rationale for selecting a certain drug treatment regime.
Combination immunotherapy (e.g. nivolumab + ipilimumab) is a more effective treatment than a single-agent immunotherapy (e.g. pembrolizumab or nivolumab alone), however the side effects of combination treatment are more common and can often be intolerable.
“This research provides a means of selecting the most effective immunotherapy for each patient,” said the study’s senior author Professor Helen Rizos. “Patients with high MHC-I are likely to benefit from the less-toxic single-agent treatment, whereas patients with low MHC-I may require combination immunotherapy.”
“We now want to build upon this ground-breaking research and are working to overcome this resistance mechanism so tumour cells are more visible to the immune system,” said study author and Co-Medical Director, Professor Georgina Long AO. “When we can do this, we may overcome resistance to immunotherapy.”
Publication: Shklovskaya E, Lee JH, Lim SY, et al. Tumor MHC Expression Guides First-Line Immunotherapy Selection in Melanoma. Cancers 2020, 12, 3374.
Identification of genes involved in early brain metastasis
A primary melanoma of the skin that spreads to the brain (known as metastasis) typically occurs late in the disease process once melanoma has spread to other parts of the body first, like the liver, bones or lungs. They also usually arise from patients who have thick primary tumours.
However, for about 1 in 5 of patients with brain metastases, the first distant location their melanoma spreads to is the brain. Suprisingly, these patients usually had thin and non-ulcerated primary melanomas – characteristics that would typically give them a more favourable prognosis.
Early detection of melanoma in the brain is critical as treatment is more effective when lesions are small and before symptoms, like seizures and paralysis, have begun. Being able to identify early on which patients are more likely to get brain metastases could be life-saving.
Observations of tumours that develop ‘early brain metastases’ suggest that they could have distinct biological properties, and therefore our researchers were keen to work out which genes in the melanoma, not the person with melanoma, are involved.
In a recent publication, we found that patients who develop early brain metastases tend to have many gene mutations in their melanoma, and in particular, mutations to a gene called KRAS. Very little is known about KRAS-mutant melanoma and further research is needed, but there is a possibility that one day KRAS will be a predictive biomarker for the development of early brain metastasis.
By understanding the genes involved in the development of early brain metastases, in the future, we may be able to provide a more accurate prognosis for patients, and be able to closely monitor them and intervene with treatment at an earlier stage, ultimately saving lives.
Rabbie, R., Ferguson, P., Wong, K. et al. The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence. Br J Cancer (2020).
Acral and Uveal melanoma
In the last decade, treatment options have come a long way for melanoma of the skin. But melanoma also occurs in other parts of the body and our understanding of those subtypes of melanoma is, by comparison, still in its infancy. However, new research is shining a light on the underlying causes of these forms of melanoma in attempt to find new effective therapies.
Research from Melanoma Institute Australia and its international collaborators was recently published in the prestigious Nature Communications. Using whole-genome sequencing, researchers have identified changes in the genes that cause uveal melanoma (originating in the eye) and acral melanoma (originating on the palms of the hands, soles of the feet or nail bed).
Acral melanoma is the most common form of melanoma in non-Caucasian people, particularly in people of Asian and African descent. Until now, it was believed that acral melanoma was not directly associated with UV exposure because the main sites of acral melanoma have lower sun exposure than other body parts like the face or neck. It was also previously thought that UV radiation cannot penetrate the nail. However, this research has demonstrated that it can, as the genetic signature for UV radiation appears in the subungual (under the nail) form of acral melanoma.
Acral melanoma is a difficult form of melanoma to treat once it metastasizes. Acral melanomas generally lack genetic changes that can be targeted with molecular drugs and these patients often have a lower response to immunotherapies. This study found frequent genetic mutations in genes which confer sensitivity to molecular CDK4/6 inhibitors, while identifying a greater number of genetic mutations in the melanomas from the nail, which may confer a greater sensitivity to immunotherapies. This study highlights the genetic differences in acral melanomas and treatment strategies which can be applied to treat the specific biology of these melanomas.
This research is the largest whole-genome analysis of acral melanoma and comes out of the Australian Melanoma Genome Project. The samples provided were almost entirely supplied by patients who had donated samples to MIA’s BioSpecimen Bank and Melanoma Research Database, which is part-funded by The Cameron Family.
With uveal melanoma, around half of all patients progress to metastatic disease, even after surgical or radiation treatment. There are few effective therapeutic options available once disease progression has occurred.
In this study, researchers identified a genetic signature for UV radiation in a subtype of uveal melanoma that originates in the iris – the coloured part of the eye – as well as other ‘driver genes’ responsible for other forms of the disease.
What does this mean for prognosis and treatment?
Targeted therapy and immunotherapy have been game changers for treating melanoma of the skin, however they have been much less successful in treating patients with acral and uveal melanoma.
By identifying the genes that drive the development of these rarer forms of melanoma, researchers can categorise patients based on their genetic subtype of acral and uveal melanoma. This information can be used to guide treatment selection for acral and uveal melanoma patients. Researchers have determined that patients with different subtypes have a different prognosis and respond to treatments differently.
“Melanoma is not just one disease,” says co-author and Co-Medical Director of Melanoma Institute Australia, Professor Richard Scolyer. “By identifying the genes involved in the development of all forms of melanoma, we can identify the most effective treatment for each subtype of melanoma and provide effective personalised medicine.”
- Johansson, PA, Brooks, K, Newell, F et al. Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours. Nat Commun 11, 2408 (2020).
- Newell, F, Wilmott JS, Johansson PA et al. Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity. Nat Commun 11, 5259 (2020)
Melanoma Genome Project
Melanomas develop following the accumulation of genetic mutations that enable the cells to grow uncontrollably. The Australian Melanoma Genome Project is using cutting-edge whole genome sequencing technologies to identify the common genetic mutations that cause melanoma so that doctors can better personalise its treatment.
The project has made major progress by comparing the genetic code of normal cells and melanoma tumours and identifying all the mutations present in nearly 500 Australian melanoma patients. It is the largest melanoma research effort ever undertaken in this country, with a national coalition of over 50 researchers from Melanoma Institute Australia, The University of Sydney, Royal Prince Alfred Hospital, Westmead Institute for Medical Research and the QIMR Berghofer Medical Research Institute working together.
- Fully characterise all the genomic alterations in over 500 melanomas patients (currently 468 melanomas sequenced).
- Identify mutagenic processes and carcinogens responsible for the development of a range of melanomas.
- Discover new drug targets and better select patients for current therapeutics.
Highlights so far
Whole-genome landscapes of major melanoma subtypes
The study presents the whole genome sequencing data from the first 183 melanoma patients. The study highlighted some major difference in the types of genetic mutations, the affected genes and the carcinogens that drive melanomas that arise in sun exposed skin compared to those have arisen in mucosal surfaces and on the palms and soled of the hands and feet:
Identifying drugs for patients: Acral and mucosal melanomas are dominated by large scale genetic changes that may offer new druggable targets to treat patients.
Novel findings of the causes of a range of melanomas: The carcinogenic process or factors that cause a melanoma can be identified from the types of genomic mutations in a patient’s tumour. The study identified new mutation- causing processes driving melanoma development and found major differences in the causes of melanomas affecting sun exposed compared to those involving sun shielded sites.
Original article: Hayward, N.K. et al. Whole-genome landscapes of major melanoma subtypes. Nature. 03 May 2017. doi: 10.1038/nature22071. [Epub ahead of print]
- Public release of genomic data on freely available platforms
Our Melanoma Genome Project team recently played a crucial role in a global study that discovered cutaneous melanoma has four distinct subtypes. The breakthrough helps pave the way for more tailored individual, ‘personalised’ medicine for melanoma patients. Samples from the MIA BioSpecimen Bank made up almost one third of the global contributions to ‘The Cancer Genome Atlas’ (TCGA) melanoma project, a five year study of tumours from over 300 patients.
In addition, the Melanoma Genome Project was endorsed by the International Cancer Genome Consortium early in 2015. All of the data that has been generated by the project has been uploaded to the ICGC data portal to make it available for researchers, clinicians or the general public to interrogate thereby assisting the global cancer research community to accelerate progress to cure melanoma.Original article: Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell 161, 1681–1696 (2015).
ICGC data portal
- Unexpected UVR and Non-UVR mutation burden in some acral and cutaneous melanomas
Analysis of the first 183 melanoma patients found sun exposure induced mutations in a two melanomas involving subungual (finger nail) region and one on the sole of the foot, regions generally considered to be protected from sun related mutations.
Original article: Rawson R.V., et al. Unexpected UVR and non-UVR mutation burden in some acral and cutaneous melanomas. Lab Invest, 97 (2), 130-145 (2017)
- Mutation load in melanoma is affected by MC1R genotype
Patients who harbour a germline (inheritable) mutation to the MC1R gene display increased sensitivity to sun light induced mutations.
Original article: Johansson P.A., et al., Mutation load in melanoma is affected by MC1R genotype. Pigment Cell Melanoma Res., 30: 255–258 (2017)
- Best practices for sample preparation, sequencing and data analysis in clinical melanoma samples
Study outlined lessons learnt from the large-scale Australian Melanoma Genome Sequencing Project.
Original article: Wilmott J.S., et al. Tumour procurement, DNA extraction, coverage analysis and optimisation of mutation-detection algorithms for human melanoma genomes. Pathology, 47:683–693 (2015).
- Clinical utility of whole exome sequencing in routine archival melanoma biopsies
This study assessed the accuracy of whole exome sequencing on routine archival formalin fixed melanoma biopsies.
Original article: De Paoli-Iseppi R, et al. Comparison of whole-exome sequencing of matched fresh and formalin fixed paraffin embedded melanoma tumours: implications for clinical decision making. Pathology. 48:261–6 (2016).
- Genomic determinants of melanoma patient response to immune checkpoint inhibitors
- Genomic landscapes of mucosal and acral melanomas
- Youth melanomas - Mutations and mutational processes responsible for melanoma development in young Australians (<30yrs old)
The Australian Melanoma Genome Project was funded directly by Melanoma Institute Australia, the NSW Ministry of Health, Cancer Council NSW and the Australian Government through Bioplatforms Australia.
The project has been enabled by Program Grants and Fellowships of the National Health and Medical Research Council, Translational Program Grants of Cancer Institute NSW, and infrastructure of the University of Sydney, Bioplatforms Australia, Westmead Institute for Medical Research, NSW Health Pathology, Royal Prince Alfred Hospital, Peter MacCallum Cancer Institute, The Olivia Newton-John Cancer Research Institute and Melanoma Institute Australia.
From Melanoma Institute Australia:
- Prof Graham Mann – Co-Principal Investigator
- Prof Richard Scolyer – Co-Principal Investigator
- Dr James Wilmott – Project manager
From QIMR Berghofer Medical Research Institute:
Predicting response to immunotherapy
To realise the promise of personalised medicine, clinicians need to know ahead of time which patient with melanoma will respond to which therapy. Currently, a set of genetic signatures are used as molecular biomarkers to predict therapeutic response.
One highly successful immunotherapy, in patients who do respond to it, is the anti-PD1 antibody MK-3475. PD1 is a protein (programmed death) which is expressed on the surface of immune cells to form a biochemical shield protecting melanoma cells from the immune system. Deploying an antibody to PD1 blocks this protective action. But this only works in 60% of patients.
This research project involves working with tissue samples from the MIA Biospecimen Bank donated by patients treated with MK-3475, both responders and non-responders. The RNA is first extracted from the samples, followed by sequencing using advanced high-throughput technologies to profile differentially expressed genes which are associated with good response to anti-PD1 immunotherapy.
Already, a list of genes has been identified which distinguish good and poor response for anti-PD1 immunotherapy. The next step is to tease out the biochemical and immune signalling pathways these genes are affecting.
Adjuvant Therapy Clinical Trial
In high risk Stage III patients (where the melanoma has travelled to lymph nodes), a combination of two targeted therapies is given for 12 weeks prior to lymph node removal surgery, with the aim of shrinking the tumour to facilitate as easy and simple an operation as possible, and to prevent the risk of recurrence (normally around 50%). Following surgery, the same therapies are given for another 40 weeks (in total, drug therapy is received for 52 weeks). An interim analysis presented at ASCO in June 2016 revealed the fantastic news that at the point of surgery, all patients had marked tumour reduction or complete disappearance on scans, and around 50% of patients had no melanoma cancer cells left in their tissue.
The protocol has been further developed to investigate the next stage of this promising approach. The Neo-Trio trial, which will commence recruitment in 2017, will test whether treating Stage III melanoma
patients with either immunotherapy or immunotherapy plus targeted therapy before and after complete lymph node dissection can prevent Stage IV melanoma from developing. This will be revolutionary if it
Surgery Support Clinic
One of the most significant surgeries which has to be performed in patients with melanoma which has spread to lymph nodes is an ilio-inguinal dissection. This operation involves taking out affected lymph nodes in the groin and the pelvis. It entails a week in hospital, followed by four to six weeks’ convalescence and up to six months for full recovery. This surgery can have wide-ranging physical impacts including lymphoedema (swelling of a limb) but also impacts on family life, work, psychological state and more.
Thanks to a two-year grant from Friends of the Mater, MIA is conducting qualitative research to determine the value of providing such patients with the services of a dissection clinic. The clinic is offered to patients who have undergone groin dissection as well as lymph nodes removed from the armpit (axillary dissection) or the neck (neck dissection) if the melanoma has spread to these areas. The clinic provides physiotherapy to assist with lymphoedema assessment and an ongoing relationship with a surgical clinical nurse consultant (CNC). The CNC offers information regarding the surgery, its effects and guidance about how best to navigate its impact on life. The CNC first sees the patient prior to the surgery and then in hospital and subsequently in the clinic at varying intervals.
Patients were surveyed before and after their surgery using a quality of life survey and a depression scale. A similar study was conducted with a cohort of patients who did not have access to the dissection clinic, for comparison purposes. Detailed analysis of the results is still pending, but early findings show that patients facing dissections find the clinic extremely valuable and need such services for up to a year. Without such a clinic, their experience is typically that they do not cope very well after the surgery. Earlier referrals for lymphoedema treatment and also to a psychologist may also be beneficial.
Patterns of Care
This is a population-based, observational study based on clinicians’ reported management over a 12-month period of melanoma patients across New South Wales. The aim was to assess the patterns of medical care for patients against best practice guidelines and identify any variations and therefore areas for improvement. Once the Cancer Registry received notification of a new diagnosis of melanoma, the referring doctor was sent a questionnaire and similarly with any other
clinicians subsequently involved in the patient’s care. Over 70% of clinicians responded and almost 4,000 questionnaires were received, providing data for about 2,700 patients.
This has been an ambitious and very productive study done in collaboration with The NSW Melanoma Network with three papers accepted, another two under revision with the journal and three more in preparation. Just a handful of the more interesting findings include:
- Adherence to clinical guidelines for surgical management and follow-up is not what it should be. Surgical margin guidelines were only adhered to in 35% of cases, while 45% were over-treated and 21% under-treated. Such factors as clinician caseload, age and socio-economic status of practice location were associated with variations.
- 74% of patients’ doctors were aware of their risk factor status with respect to personal and family history of melanoma and the presence of moles. Doctors were more likely to know the family history of younger melanoma patients (under 40) than those over 80 and were more likely to give early detection advice to the younger age group.
- Clinical management of higher risk patients was more likely to conform to best practice guidelines for diagnosis and skin surveillance than that of lower risk patients.
Saving Our Next Generation
Postdoctoral Fellow, Dr James Wilmott is hoping to help by searching for early-detection genetic markers and treatment options that are specific to this age group.
“New drugs that target genetic mutations specific to a patient’s melanoma look extremely promising. But young patients have been largely overlooked in this kind of research. This study will address that gap by characterising all the gene mutations in blood and melanomas from young people with melanoma.”
The study is the first of its kind in the world. Data benefitting a range of research groups will be made available in Australia and abroad, bringing together pathologists, oncologists, surgeons, epidemiologists, computational biologists and researchers to focus on youth melanoma.
The goal is to identify the best genes for new drugs to target and uncover genetic mutations that predispose young patients to melanoma. It’s a unique and inventive way to detect melanoma in young people. And it will have the side benefit of helping them understand the benefits of sun safe behaviour and regular skin checks to reduce their risk of melanoma.
The data generated by the project will ensure that young melanoma patients are not left behind in innovations in personalised medicine, making a real difference to people in the prime of their lives.