|Australia (Postdoctoral Fellowship)||1|
Identifying novel therapeutic targets for acute myeloid leukaemia
Acute myeloid leukaemia (AML) is a particularly aggressive form of blood cancer and many patients do not respond to current treatment. Although new drug targets have been identified, their success has been limited due to their inability to eradicate leukaemia stem cells. These cells often do not respond to chemotherapy and serve as the source of resistance in patients who do not respond. To address this critical problem, unique tools have been developed which will allow us to discover potential vulnerabilities in leukaemia stem cells. Ultimately, we plan to exploit these vulnerabilities and develop new treatments for AML.
A bio-inspired method to address antibody-drug conjugate payload toxicity.
Antibody-drug conjugates (ADCs) are an exciting class of anti-cancer agents featuring an exquisitely cytotoxic drug (or payload) appended to an antibody that recognises cancer cell specific features. This design is intended to make ADCs selectively active against tumour cells, but in practise significant ‘off-target’ toxicity is still observed. We have designed a novel molecular off-switch to keep payloads inactive until inside the target cell. We will examine our design with a particular class of promising, yet problematic, payloads to test its potential to deliver improved tumour selectivity.
Regulation of costimulation by small extracellular vesicle microRNAs in dendritic cells
Human papillomavirus is a potentially fatal virus, causing close to 100% of cervical cancers and upwards of 30% of head and neck cancers. In order to cause cancer, it needs to evade the immune system. We have evidence that extracellular vesicles (small particles shed by cells) can block immune cells from properly attacking the virus. We plan to investigate the microRNA carried by extracellular vesicles and test whether it causes the immune suppression in humans. If so, extracellular vesicles could be packaged to contain microRNAs that block this suppression, allowing the immune system to recover and properly attack virus-infected cells.
Universal CAR T cells for cancer therapy
CAR T cells are an exciting new way of treating cancer. Healthy patient T cells are removed and modified in the laboratory, becoming highly efficient killers. They are then given back to the patient to kill their cancer. However, the need to make new T cell modifications for each patient increases the cost, complexity and usefulness of the therapy. In this proof-of-concept study, we will make a ‘universal’ modification to the T cells so that they recognise a specific tag which will target cancer cells for destruction. The tags are specially designed so they will bind only to tumour cells.
The role of mTOR signalling in mediating T-DM1 resistance
Trastuzumab emtansine (T-DM1, Kadcyla) is an effective anticancer agent for the treatment of HER2-positive breast cancer; however, its use is limited by drug resistance. Using gene editing techniques we have identified two genes involved in mTOR signalling that are potentially implicated in T-DM1 resistance. In this project, we will investigate the roles of these genes in T-DM1 resistance and will evaluate whether mTOR signalling can be therapeutically targeted to enhance the therapeutic activity of T-DM1 in HER2-positive breast cancer. If successful, this will establish data to support a clinical trial of T-DM1 with an mTOR inhibitor to overcome T-DM1 resistance.
Unfolded protein response in myeloproliferative neoplasms
This research focuses on patients with essential thrombocythaemia and primary myelofibrosis, two chronic but incurable blood cancers. We will test bone marrow samples from patients with these disorders to determine the types of cell survival mechanisms called Unfolded Protein Response (UPR) these cancers recruit to help them thrive. The presence of the UPR will be correlated with disease type and driver mutations. Then, small molecules will be chosen to inhibit the UPR in culture with an idea to restrain cancer cell growth. Our results will provide proof-of-concept evidence that drugs that inhibit UPR can help control disease progression in patients.
Exploring the emerging roles of the of Δ133p53 isoform as an epigenetic regulator in cancer
The tumour suppressor protein p53 is key in preventing cancer. In contrast variants of p53, called p53 isoforms, specifically Δ133p53 isoforms, have tumour promoting capabilities.Cancers with high levels of one or more Δ133p53 isoforms have poor prognosis, pro-tumour inflammation and are resistant to treatment. Cancer cell lines expressing each of the three Δ133p53 variants were enriched in cancer-promoting genes and genes associated with accessibility to DNA.Here we propose to assess DNA accessibility in cell lines expressing Δ133p53 isoforms. This will allow us to determine the mechanisms by which Δ133p53 isoforms control gene expression in cancer.
Recruitment and migration of T cells in colorectal cancer: implications for patient outcome
The immune response in colorectal cancer affects patient outcome. The different types of immune cells that are found within the tumour can have varying functions, some of which will support tumour growth, and some that will inhibit tumour growth. Key in determining the effects of these infiltrating immune cells is understanding what effect they have on the neighbouring cells. Our proposal will analyse the interactions between individual cells in the tumour and link these interactions to patient outcome.
Mapping malignancies in LAM: a case study
Lymphangioleiomyomatosis (LAM) is a rare cancer which almost exclusively effects women during their childbearing years. The disease manifests following the invasion of smooth muscle-like cells, progressing towards total lung destruction. There are currently no curative treatments for LAM, leaving lung transplantation as the last resort. Our relationship with one of New Zealand’s few LAM patients and their oncologist uniquely positions us to perform a case study, seeking to identify genetic and epigenetic underpinnings of this patient’s multi-tumour condition. We aim to determine new markers for LAM that can be used to develop targeted therapies – something all LAM patients desperately need.
Increasing patient survival from blood cancers by preventing bone marrow transplant rejection
Each day six New Zealanders are diagnosed with cancers such as leukaemia, lymphoma or myeloma. Stem cell transplantation can be a curative therapy, but in 15-20% of cases the patient’s immune system recognises donor cells as ‘foreign’ and the graft is rejected with fatal consequences. The cells responsible for early rejection use a protein called perforin to kill transplanted cells. We propose to block this process by employing a small molecule inhibitor of perforin activity, to preserve the graft and reduce incidence of failure. This therapy would address an urgent unmet need for patients receiving partially mismatched stem cell transplants.
New Zealand critical appraisal workshop for oncology trainees
The aim of this workshop is to help early career researchers and clinicians make sense of research reports by developing and explaining questions to consider when reading and reviewing cancer specific reports. This will enable participants to determine how dependable and useful the research is. Teaching includes lectures about different types of trials (the most common types) and short exercises using typical examples. The goals are to train early career researchers and clinicians in understanding research publications, enabling them to interpret their findings correctly, and apply them to clinical practice or in formulating research ideas.
Cancer Research Trust NZ palliative care breakfast lecture series.
Since 2004 Hospice NZ has been providing the Cancer Research Trust Palliative Care Lecture Series to health professionals across New Zealand.
Each month we average over 380 people listening to the lecture via audioconference. Topics cover a range of clinical issues such as cancer therapies, rehabilitation, Māori Models of Palliative Care and grief and bereavement support.
Thanks to funding from the Cancer Research Trust the lecture series is delivered without charge to participants.
To attend AACR Annual meeting 2020 (AACR: American Association for Cancer Research), April 24 - 29th, 2020, San Diego, USA
To attend the Advanced European Bioethics Course: Suffering, Death and Palliative Care, Radbound University, Nijmegan, The Netherlands
To attend the 1st World NEY conference, Barcelona, Spain March 2020.
To attend Keystone Symposia on Molecular and Cellular Biology, Advances is Cancer Immunotherapy. Whistler, British Columbia, Canada. March 2020