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Molecular determinants of sensitivity to novel AKR1C3-activated prodrugs in paediatric leukaemia


Centre for Childhood Cancer Research

Prof Richard Lock , Dr Cara Toscan Applications accepted all year round Competition Funded PhD Project (Students Worldwide)

About the Project

Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy and remains one of the most common causes of death from disease in children. Paediatric ALL can be broadly divided into B-lineage (B-ALL) and T-lineage (T-ALL). Disease-free and overall survival are comparable between children with B-ALL and T-ALL when treated on contemporary risk-adapted regimens, however the outcome is particularly poor for children with T-ALL following relapse.

We have previously shown that T-ALL expresses significantly higher levels of aldo-keto reductase family 1 member 3 (AKR1C3) compared with B-ALL, albeit by currently unknown mechanisms. These findings contributed to the AKR1C3-activated prodrug, OBI-3424, being granted Orphan Drug Designation by the US Federal Drug Administration in 2018 and to an impending clinical trial in relapsed/refractory T-ALL in the USA. Our initial testing of the next generation AKR1C3-activated prodrug, SN36008, has shown a greater degree of specificity for AKR1C3 compared with OBI-3424. Moreover, we have identified two active downstream AKR1C3 enhancer regions in T-ALL, but not B-ALL cells.

This research project will improve our understanding of the mechanisms regulating AKR1C3 gene expression in paediatric ALL and facilitate further development of the novel AKR1C3-activated prodrug SN36008 for patients with T-ALL.

Aims:

1. Define the mechanism of AKR1C3 gene regulation in T-ALL versus B-ALL.

Understanding the mechanism of AKR1C3 gene regulation in T-ALL will identify opportunities for novel drug combinations to enhance the efficacy of AKR1C3-activated prodrugs.

2. Define the determinants of response to AKR1C3-activated prodrugs.

Understanding the determinants of SN36008 sensitivity and resistance will inform combination drug treatment decisions.

3. Test the in vivo efficacy of SN36008 alone and in combination with standard-of-care drugs. Preclinical testing of SN36008 alone and in rational and empirical drug combination efficacy experiments will inform future clinical trials of SN36008.

Techniques:

This research project incorporates both discovery science and preclinical studies and will involve molecular biology, epigenetics, genomics and in vivo preclinical testing in our patient-derived xenograft model of paediatric ALL. 


Funding Notes

All students at the Institute must fulfil the requirements for enrolment at UNSW Australia to undertake their PhD with us as well as obtain a scholarship that will cover both your living expenses and tuition fees. Scholarship and entry requirements can be found on the UNSW Graduate Research School website.

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