Head and neck cancer in New Zealand
There are several different types of cancer of the head and neck, such cancer of the tongue, parts of the mouth, and throat. Several common causes, such smoking and alcohol and associated with certain occupations, have been found for some cancers of the head and neck but for some other cancers the causes are less clear. Human Papilloma Virus (HPV) infection has also been identified as a contributor to some head and neck cancers but its effect on the development of cancer in the presence of other causes is not clear. HPV infection also appears to affect survival after diagnosis of some head and neck cancers. This study will elucidate the action of HPV infection on the development of head and neck cancer in the presence and absence of other causes and provide important information for the future prevention of head and neck cancer.
FaR-RMS: Frontline And Relapse study in RhabdoMyoSarcoma
Rhabdomyosarcoma (RMS) is a rare soft tissue cancer that is most frequently diagnosed in children. Many patients with localised RMS survive after intensive treatment with chemotherapy, surgery and radiotherapy. However, if the disease spreads or is particularly aggressive, the majority of patients do not survive. The Frontline and Relapse study in RMS (FaR-RMS) has been developed by world-leading clinical researchers from the European paediatric Soft tissue Sarcoma Group, and will enrol patients across the United Kingdom, Europe, Australia and New Zealand. FaR-RMS is a revolutionary, overarching clinical trial, designed to simultaneously examine multiple aspects of treatment to improve survival and quality of life for all RMS patients (newly-diagnosed and relapsed). Research questions include adding new agents to standard chemotherapy, extending maintenance chemotherapy, optimising radiotherapy, and identification of new genetic biomarkers. Importantly, the trial design will enable promising new agents to be rapidly incorporated as they become available, without the need to open a new trial each time. New Zealand participation in this ground- breaking international trial will offer children and adolescents the opportunity to be involved in the most comprehensive and ambitious program of research undertaken for RMS, and offers the best chance to improve outcomes for these patients.
Lung cancer impacts thousands of Kiwi families annually, disproportionally impacting Māori and those vulnerable in our communities, making it a significant burden to Aotearoa’s health system. Despite advancements in lung cancer therapies, relapse in patients remains common, leading to death. Recent evidence suggests that a subset of lung cancer cells called “drug tolerant persisters” (DTPs) are largely behind relapse. This project aims to determine how DTPs survive treatment and how DTPs are regulated by types of RNA called long non-coding RNAs. By understanding these principles, we hope to prevent DTPs from contributing to relapse, limiting the toll of lung cancer.
The ultimate goal of cancer therapy is to kill cancer cells. However, in many cases, a population of cancer cells do not die in response to treatment, but rather enter a state that we call “senescence”. Recently, we have come to learn that these senescent cancer cells behave aggressively in the long run and might underpin the ultimate failure of many cancer treatments. In my research, I will study the biology of senescent cancer cells in unprecedented detail, and also perform cutting-edge experiments that identify new drugs that can kill them, thereby improving our chances of completely eradicating tumours.
Cancer patients living distant from cancer treatment centres face the additional burden of travel. While some surveys examining this issue exist, no research exploring people’s stories of the impact of travel for cancer treatment and supportive care had previously been undertaken in New Zealand. We are currently completing a small study exploring the impact of travel on people with cancer and their whānau living outside Dunedin in the Otago/Southland region. Preliminary findings indicate a range of impacts, both positive and negative, challenges and barriers associated with travel to access treatment and supportive care. While our findings are a useful starting point for understanding the issues, they are not necessarily transferable to other parts of the country. Building on the findings of our small study, the overall aim of this research is to better understand the impact of travel on people with cancer, and their whanau, in different geographical contexts in NZ. Our findings will help improve the rural cancer experience.
Immune therapy is already curing some patients with cancer, but we need new types of immune therapy to increase the number of patients who can benefit. One form of immune therapy is cell therapy, where immune cells called T cells that can recognise and kill cancer cells, are grown outside the body then given back to the patient. We have discovered a new technique to grow T cells for cell therapy, and now wish to develop it so we can use it in clinical trials. In this project we will optimise our technique so it can be efficiently and routinely carried out in a special facility where the T cells can be grown safely for patient treatment. Following this work we will be able to seek approval from government agencies to begin clinical trials of T cell therapy in cancer patients.
Although the role for papillomaviruses (PVs) in cancer of the cervix is very well-described, the role of PV in cutaneous squamous cell carcinoma (cSCC) is less clear. There is accumulating evidence that some types of PVs can increase the risk of skin cancer caused by ultraviolet rays. DNA methylation is a type of epigenetic change that can permanently alter the expression of genes. Through our previous work, we have found profound methylation changes to the DNA in skin that was previously infected with a papillomavirus. In this study we will investigate the impact of these changes on susceptibility to UV-induced cSCC and gather data to determine how this might work. This will help understand the role of PV as a contributor to skin cancer development, helping clinicians to better treat this prevalent disease.
Radiotherapy is an important component of cancer treatment for approximately half of all cancer patients. Radiotherapy kills cells by causing DNA damage, repair of which is critically dependent on an enzyme called DNA-dependent protein kinase (DNA-PK). Thus inhibition of DNA-PK could improve radiotherapy effectiveness. DNA-PK inhibitors (DNA-PKi) do indeed enhance tumour radiosensitivity in mice which has led to human clinical trials. However, preclinical evaluation of normal tissue toxicity has been conspicuously lacking. We recently found that a clinical stage DNA-PKi, AZD7648, radiosensitises tumour and normal tissues similarly, suggesting that lack of tumour selectivity may confound its use in patients. Hypoxia (lack of oxygen), which causes resistance to radiotherapy, is a common feature of tumours but not normal tissues, suggesting that selective delivery of a DNA-PKi to hypoxic tissue would enhance tumour selectivity. We have recently discovered a novel DNA-PKi and corresponding hypoxia-activated prodrug which we will use to test this hypothesis in the present study. We will further develop our methods for detection of radiation toxicity in normal tissues, and will use these tools to test whether release of a DNA-PKi from a hypoxia-activated prodrug will improve tumour selectivity. This investigation will inform clinical development of DNA-PKi in radiotherapy.
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, accounting for approximately 400 new diagnoses and 300 deaths in New Zealand each year. Males are more than twice as likely to be diagnosed with ccRCC than females and Māori are disproportionately affected. The key genetic mutation that drives almost all cases of ccRCC is loss of the von Hippel-Lindau tumour suppressor gene that results in sustained activation of the “hypoxic response” in the cancer cells. Normally, the hypoxic response is only induced in cells that are oxygen-starved and is controlled by two hypoxia-inducible factors, HIF1 and HIF2. While HIF2 acts to promote tumourigenesis in ccRCC, HIF1 has antitumour effects. We have discovered that in some ccRCCs the antitumour effects of HIF1 can be amplified using drugs that are in clinical development for treating anaemia. In this project we will study the anticancer effects of these drugs using cell line and tumour models of ccRCC. This approach may provide a new therapeutic avenue for treating ccRCC.
Radiation therapy is widely used for cancer treatment and there has been a surge in interest in sensitisers that improve the benefit of radiation treatment for cancer patients. Scientists at the Auckland Cancer Society Research Centre at the University of Auckland have identified a new drug that inhibits one of the key enzymes that mediates DNA repair and resistance to radiotherapy. This enzyme, DNA dependent protein kinase (DNA-PK), repairs the double strand breaks caused by radiation that cause cell death. We have shown that the new drug is an inhibitor of DNA-PK and is an effective sensitiser of radiation in tumour models. However, a more potent analogue would be advantageous to advance the class to clinical development. We will use computer software to model the active site of the DNA-PK protein to design new and more potent inhibitors and test their ability to inhibit the enzyme and sensitise tumour cells to radiotherapy. The successful identification of a more potent lead molecule would lead to full evaluation in tumour models and selection for development into clinical trial for head and neck cancer in combination with radiotherapy.
Melanoma is the most aggressive form of skin cancer which can spread to draining lymph nodes to form secondary tumours. Accurately locating these ‘sentinel’ lymph nodes for biopsy is therefore critical for patient treatment and can be done using the nuclear medicine imaging technique called lymphoscintigraphy. We previously developed a computational model and software tools using lymphoscintigraphy data from over 5000 patients, to analyse and predict potential lymph node sites of melanoma spread. In this study we aim to extend this work significantly by adding over 10,000 new imaging studies and linking it with patient demographic, pathological and follow-up information from the Melanoma Institute of Australia. We will perform detailed statistical analyses of the data to produce 3D visualisation and interactive displays of the data. Our goal is for the updated software tools to inform the selection of appropriate courses of treatment and guide treatment follow-up for patients with skin cancers that can spread to lymph nodes (i.e. not just melanoma). The displays generated will provide an important medical education resource describing lymphatic anatomy, not just relevant for those treating skin cancer patients but also for those who treat lymphatic diseases such as lymphoedema.
Immunotherapies are revolutionising the way we treat some cancers, including melanoma, which is a cancer of high significance to NZ. One type of immunotherapy works by unleashing the body’s own immune system to kill rogue cancer cells. Clinical trials indicate that this type of therapy, which targets ‘immune checkpoint inhibitors’, can be an effective treatment in approximately 30% of people with melanoma. Whilst these response rates are promising, the limited efficacy in most patients suggests that the mechanisms underlying immune checkpoint pathways are poorly understood. An ability to select responsive patients is urgently needed because these drugs can have significant immune-related side effects and treatment is expensive (>NZ$100,000 per year). One issue is that a key target of immune checkpoint inhibitor drugs is expressed on cancer cells at variable levels but the correlation between drug target expression and responsiveness to treatment is not exact. This project, which uses a unique application of gene editing, aims to understand how variation in drug target expression impacts responsiveness to immune checkpoint inhibitor drugs. Our results will help to inform the selection of patients for drug treatment which will lead to improved patient outcomes and cost savings in the clinic.
Immunotherapy is the future of cancer care. By stimulating the patient’s immune cells to destroy cancer cells, immunotherapy can essentially cure cancer. Yet, sadly, this does not happen for many patients because the cancer sabotages their immunity. Two key saboteurs hired by most cancers are proteins called IDO1 and TDO. They produce a molecule called kynurenine that paralyses the patient’s cancer-killing immune cells. To make more patients benefit from immunotherapies, we need to stop cancers from making kynurenine. An obvious approach is to make drugs that safely inactivate both IDO1 and TDO but making such drugs appear harder than first anticipated due to problem such as toxicities.
We have a ground-breaking idea to stop kynurenine production by inactivating a protein called arylformamidase that both IDO1 and TDO need to make kynurenine. In this project, we will test if genetic inactivation of arylformamidase stops kynurenine production in cancer cells and mice. If we confirm that AFMID inactivation is a safe and effective approach to disrupt kynurenine production, we will then investigate if AFMID inactivation boosts immunotherapy in a mouse model of cancer. If successful, we start developing anti-AFMID drugs that have potential to optimise cancer patients’ responses to life-saving cancer immunotherapies.
Informed cancer risk assessment for women who test positive for pathogenic (disease causing) DNA variants in the BRCA1 gene is critical for reducing their risk of developing and dying of cancer and limiting unnecessary intervention. Individuals with inherited pathogenic variants in BRCA1 can have very different outcomes. For example, an individual may develop breast cancer before the age of 45 whereas a second individual may never develop disease. Through our collaboration with the world leading CIMBA Consortium, we are uniquely positioned to investigate BRCA1-associated breast cancer risk across different variant types. In particular, we have identified differences in breast cancer risk based on the type of BRCA1 variant in an individual. Women with BRCA1 deletions exhibit significantly greater disease risk compared to other variants. We propose to examine a new mechanism that results from genetic changes activating other genes that can partially negate the effects of some BRCA1 pathogenic variants. To our knowledge, this will be the first time this compensatory effect has been studied in human cancer susceptibility genes. This study will help us better understand the relationship between genetic risk factors and breast cancer, with the goal of using this information for personalised prevention and early detection programmes.
The Dunedin Colorectal Cohort (DNCRC) was established to facilitate research into colorectal cancer, enhance understanding of the disease and to improve patient outcomes in New Zealand. The Cohort comprises tissue and blood samples gifted by over 1,500 people with colorectal cancer and continues to actively recruit patients undergoing elective surgery to remove a colorectal cancer at Dunedin Hospital. With tumour samples and follow up data spanning more than 20 years this cohort represents a valuable research resource and samples have been used in studies to contribute new knowledge across the continuum of cancer detection, diagnosis, treatment and fundamental cancer biology.
To attend a training course hosted by McGill University, Canada.
To complete Masters of Social Work Thesis (Part 2) through Massey University in 2022.
To attend the Australia New Zealand Gynaecological Oncology Group annual meeting in March 2022.
The sixth Melanoma Summit 2021
Travel support for Professor Cliff Rosendahl to attend the Summit. Professor Rosendahl is a Queensland primary health care practitioner recognised internationally for his work in the early detection of melanoma. He will attend the 2021 Summit to share his expertise and provide crucial learning opportunities to upskill those responsible undertaking skin checks.