Optimising azacytidine (AZA) responsiveness in MDS, CMML and AML
Professor John Pimanda, University of New South Wales
Funding period: 2020-2021
Although MDS can manifest in children and young adults, it is predominantly a cancer of the elderly and its incidence increases progressively with age. Although bone marrow transplantation can be curative, most patients are too fragile and are not eligible for transplants.
The most effective drug (azacitidine) works in only half of MDS and associated AML patients who commence treatment. Azacitidine is administered as a daily injection for a week every month and is continued indefinitely until relapse, discontinue treatment or die of unrelated causes. Currently, there is no reliable mechanism of predicting which patients will or will not respond to treatment.
As such all eligible patients undergo six months of injections despite only half these patients ever demonstrating a drug response. Furthermore, response is not durable and half of those who respond will progress on treatment within the first two years.
All in all, there is an urgent need to risk stratify patients early to those that are likely to respond and those that are unlikely to respond and to implement evidence-based alternatives for this latter group of patients.
This comprehensive program is aimed at changing the current paradigm of MDS/AML patient management by predicting and optimising azacitidine responsiveness.
Over the past decade, we have developed a framework to risk stratify patients and have identified treatment alternatives for potential and proven azacitidine non-responders. During this project, we will use samples from an on-going clinical trial to evaluate treatment alternatives for patients predicted to respond poorly to azacitidine.
To discover new drugs that improve azacitidine efficacy, we will use a novel chemical-genome screen using a MDS cell line to first identify specific genes that when activated or inhibited make MDS cells more sensitive to azacitidine. We will then use this information to identify molecular pathways that are amenable to pharmacological manipulation to achieve the same effect.
We will then test the efficacy of drug combinations in enhancing azacitidine activity using a panel of AML cell lines and a library of azacitidine non-responder MDS cells from patients sourced from a clinical trial. In parallel, we will use azacitidine non-responder MDS cells from patients to generate a library of xenografts (mice carrying human cells) to perform pre-clinical testing in preparation for a future clinical trial.