Targeting a Defective DNA Repair Pathway in Acute Myeloid Leukaemia
Closing Date: 07 February 2020
This study will test a potential new strategy for treating the devastating blood cancer, acute myeloid leukaemia (AML). In exciting preliminary studies we have identified a molecular pathway that is over-activated in poor response AML patients. We have shown that inhibiting this pathway with new pharmaceuticals kills AML cells, and that these drugs work in synergy with standard AML therapies. We will now test the efficacy of this new treatment strategy in pre-clinical studies, and investigate the molecular mechanisms by which this pathway contributes to leukaemia.
Acute myeloid leukaemia (AML) is the most common acute leukaemia and has a dismal 5yr survival rate of 24%. Using a phosphoproteomic screen of primary AML patient blasts, we have identified over-activation of the error-prone, non-homologous end joining (NHEJ) DNA repair pathway in poor prognosis AML patients. This pathway is driven by the DNA-dependent protein kinase (DNA-PK), and DNA-PK inhibitors have recently entered clinical trials for solid tumours. We have found that single agent DNA-PK inhibition induces apoptosis in AML cells. Most strikingly, DNA-PK inhibition synergised with kinase inhibitors or DNA damaging chemotherapies in AML. This project will now take advantage of our lead in the field; AML expertise and unique access to DNA-PK inhibitors in clinical trial; together with our established AML cell lines, patient derived xenografts and primary patient samples, to test the hypothesis that DNA-PK activation is a key driver of specific molecular subtypes of AML, and that combined inhibition of DNA-PK is a therapeutic strategy for AML.
- Determine the mechanisms by which activated DNA-PK contributes to AML.
- Identify the mechanisms mediating the synergy between DNA-PKi’s and tyrosine kinase inhibitors.
- Test the preclinical in vivo efficacy of DNA-PKi’s alone and in combination.
- Determine which molecular subtypes of AML are the best candidates for clinical trials with DNA-PK inhibitor therapy.
The student will be trained in a range of laboratory techniques, including but not limited to, mammalian cell culture, isolation of human leukaemia cells, cell proliferation and cell death assays, flow cytometry, retroviral transductions; biochemical assays e.g. enzyme assays, western blotting, mass spectrometry, proteomics, HPLC, immunofluorescence; molecular biology e.g. cloning, PCR, next-gen sequencing; animal studies e.g. cell line and patient derived mouse xenografts of human AML cells and preclinical drug testing. You will be supervised by a team with expertise in all of these areas, and will be part of a dynamic team with a passion to develop better therapies for cancer patients.
PhD Scholarship details
Funding: $28,092 per annum (2020 rate) indexed annually. For a PhD candidate, the living allowance scholarship is for 3.5 years and the tuition fee scholarship is for four years.
Supervisor: Associate Professor Nikki Verrills
Available to: Domestic students
A passion and drive for cancer cell biology. A strong work ethic with the ability to work independently and as part of a dynamic team. A passion to learn and develop new laboratory techniques and research approaches. The ability to meet the minimum eligibility criteria for admission.
Interested applicants should send an email expressing their interest along with scanned copies of their academic transcripts, CV, a brief statement of their research interests and a proposal that specifically links them to the research project.
Please send the email expressing interest to Nikki.Verrills@newcastle.edu.au by 5pm on 07 February 2020.
Applications Close 07 February 2020
|Contact||Associate Professor Nikki Verrills|
|Phone||+61 2 4921 5619|
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