Metabolism-Focused Preclinical Development of Therapies for Acute Myeloid Leukaemia

Suitable for Honours and PhD students.

BACKGROUND

Acute myeloid leukaemia (AML) is an aggressive and lethal blood cancer with a 5-year overall survival of less than 45% for patients younger than 60 years of age, or less than 10% for older patients. In Australia, about 1,000 patients are newly diagnosed with AML each year, and about 60,000 new AML patients per year are estimated for the developed world in total. Most patients initially respond to chemotherapy but ultimately relapse and die from disease. Relapse is mediated by leukaemia stem cells (LSCs) that initiate, maintain and serially propagate AML. The development of therapeutic strategies to target leukaemia stem cells is therefore a promising approach and key priority.

We have previously identified a specific vulnerability of LSCs to genetic telomerase inhibition, and subsequently performed comprehensive, randomised, Phase II – like preclinical trials of imetelstat in AML patient-derived xenograft (PDX) models. Using extensive mutational, transcriptional and lipidomic profiling techniques in combination with functional genetics (genome-wide CRISPR/Cas9 knockout screens), we have identified molecular driver candidates for resistance and response to imetelstat therapy, and discovered lipopagy-induced ferroptosis as unexpected mechanism of action of imetelstat in AML.

AIM

The aim of this project (Honours component) is to better characterise imetelstat-mediated lipophagy-induced ferroptosis in AML. These findings will reveal critical insight into the mechanism of action of imetelstat, facilitating the development of effective combination therapies and selection of AML patient subgroups that will respond best to this treatment. This Honours project is not limited to but will involve cell culture techniques, molecular biology, immunoblotting, metabolomics and flow cytometry.

The project suitable for a PhD student will aim to (1) define metabolic biomarkers of resistance and response to imetelstat, (2) identify metabolic vulnerabilities of therapy-resistant AMLs, and (3) evaluate the effectiveness of sequential combination therapies that target putative metabolic vulnerabilities of AML cells to effectively combat AML relapse. This PhD project involves a breadth of wet and dry lab techniques, prior experience with small rodent work is highly desired but not essential.

SELECTED PUBLICATIONS

Bruedigam C, Porter AH, Song A, Vroeg In de Wei G, Stoll T, Straube J, Cooper L, Cheng G, Kahl VFS, Sobinoff AP, Ling VY, Jebaraj BMC, Janardhanan Y, Haldar R, Bray LJ, Bullinger L, Heidel FH, Kennedy GA, Hill MM, Pickett HA, Abdel-Wahab O, Hartel G, Lane SW. Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia. Nature Cancer 2023.

Waksal JA, Bruedigam C, Komrokji RS, Jamieson CHM, Mascarenhas JO. Telomerase-targeted therapies in myeloid malignancies. Blood Advances 2023.

Bruedigam C, Bagger FO, Heidel FH, Paine Kuhn C, Guignes S, Song A, Austin R, Vu T, Lee E, Riyat S, Moore AS, Lock RB, Bullinger L, Hill GR, Armstrong SA, Williams DA, Lane SW. Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy. Cell Stem Cell 2014.