Our lab is interested in biological processes that contribute to drug resistance in myeloid leukaemias, with particular focus on leukaemic stem cells (LSCs).
Chronic myeloid leukaemia (CML) is caused by a reciprocal chromosomal translocation within a haemopoietic stem cell. This leads to transcription of BCR-ABL, a constitutively active tyrosine kinase that is necessary to induce CML. The development of the tyrosine kinase inhibitor (TKI) imatinib significantly improved the life expectancy of CML patients; however, we have shown that disease persistence is caused by the remarkable ability of CML LSCs to survive, despite complete BCR-ABL inhibition mediated by TKI treatment1,2.
Acute myeloid leukaemia (AML) is a more heterogeneous, involving different disease-causing genetic mutations. First line treatment for AML patients consists of chemotherapy, aiming at inducing remission. Generally, five-year survival rate in AML remains at a dismal 20%. Activating internal tandem duplication mutations in FLT3 (FLT3-ITD), detected in about 20% of AML, represents driver mutations and a valid therapeutic target in AMLFLT-ITD. However, although new FLT3 inhibitors have begun to show promising clinical activity it is unlikely that they will have durable effects as single agents
In recent years there has been resurgence in interest in autophagy, energy metabolism and mitochondria function as a possible area for development of novel anti-cancer agents. We recently developed improved protocols for autophagy and metabolic assays in rare LSCs and highlighted mitochondrial oxidative phosphorylation (OXPHOS) as a metabolic dependency in CML LSCs3. Primitive AML cells have also been shown to depend on increased mitochondrial respiration4,5. We will therefore further investigate mitochondrial metabolism and through validation of drug-repurposing screen, identify new clinically applicable drugs that inhibit OXPHOS in CML, and in AML where improved therapy options with acceptable toxicities are urgently needed.
Our working hypothesis is that autophagy and deregulated mitochondrial metabolism in LSCs renders them sensitive to inhibition of the ULK1 autophagy complex and pathways that sustain mitochondrial OXPHOS. Our first aim is to use complementary functional and omic approaches to further assess the dependency of CML/AML LSCs to recycle or oxidise major mitochondrial fuels (objective 1). Our second aim is to test ULK1 inhibitors6 and FDA-approved OXPHOS inhibitors (which we have recently identified through drug-repurposing screening), in combination with TKI treatment, for eradication of CML and AMLFLT3-ITD/TKD LSCs (objective 2).
This project will therefore promote identification of a core fuel pathway signature of CML/AML LSCs and a set of new potentially selective LSC-specific metabolic drug targets (objective 1). The student will also use state-of-the-art in vitro and in vivo models to test clinically relevant drugs, which will in the longer term, facilitate the translation of our findings into the clinic, with the overall aim for CML and AML LSC eradication.