Disease relapse is a major barrier to long-term remission in AML and is attributed to the presence of measurable residual disease (MRD). MRD assessment is established for prognostication and therapeutic guidance in AML, but only a handful of MRD markers are currently recognized for this purpose. We aim to validate the prognostic impact of novel MRD markers and assays and gain further insight into what drives resistance in these MRD cells using single cell technologies. Additionally, we have established a world first multi-domain, adaptive platform trial, ALLG AMLM26: INTERCEPT, which aims to facilitate the proof-of-concept development of new therapies and combinations for patients with increasing MRD in AML according to the MRD biomarker present.

Wei Lab | WEHI

Q: Employing novel technologies to improve clinical activity of targeted therapies in AML

Patients with TP53 aberrations or FLT3-ITD+ AML have a particularly high risk for relapse and resistance to therapy. This project uses innovative proteomic and biochemical techniques to analyse protein expression and activity in these high-risk subgroups of AML. This project aims to identify changes in immune signatures that may indicate which patients are likely to fail treatment and provide a list of potential new therapeutic targets. Analysis of serial patient samples culminating in treatment failure will also allow for identification of proteins most relevant to the drug resistant phenotype in addition to any changes that could be leveraged to improve patient outcomes.

About the lab

Our laboratory is focussed on identifying more effective therapies to treat patients with acute myeloid leukaemia (AML).

AML is a rapidly lethal blood cancer that is fatal within weeks if left untreated. Our laboratory team has established a range of pre-clinical models to study new therapies and combinations for translation into the clinic. We have multiple collaborations with industry partners and much of our work is linked to clinical trials led by clinician research members of the team. A major focus of our laboratory is to target pro-survival pathways in AML and to find more effective strategies to overcome TP53 mutant disease.

Our mission

Our mission is to develop clinical trials that will deliver more effective therapies to patients with AML through discovery, innovation and translation.

Impact

Our team has guided pre-clinical and clinical research resulting in regulatory approval of new drugs including oral azacitidine as maintenance therapy in AML (NEJM 2020) and venetoclax (JCO 2019 and Blood 2020). We designed pre-clinical studies that supported the first clinical trial combining venetoclax with intensive chemotherapy (Leukemia 2018 and J of Clin Oncol 2020). This study paved the way for venetoclax to be tested in younger patients by groups around the world.

Our lab conducted biomarkers studies guiding use of venetoclax in AML using patient samples from clinical trials (Blood 2020) in collaboration with MD Anderson, Roberts and Majewski from WEHI and identified the importance of TP53 mutation in venetoclax failure (Blood 2021) in collaboration with Huang, Kelly and Roberts lat WEHI and the role of BAX variants in venetoclax resistance (Blood 2022) in collaboration with the Huang, Roberts and Adams. We pioneered the combination of BH3-mimetics to target both BCL-2 and MCL1 (Leukemia 2019) in collaboration with Lessene and Servier. This work led to a first in human trial (NCT03672695).