Activation of the HIF pathway as a therapeutic strategy in acute myeloid leukaemia

Acute myeloid leukaemia (AML) is an aggressive blood cancer which prevents the production of normal, healthy blood cells and can therefore lead to severe anaemia, infections and bleeding. There are many different types of AML, but most have a very poor prognosis. AML most commonly affects older adults, but can occur in all age groups. It is usually treated with chemotherapy which kills most cancer cells, but the leukaemia stem cells (LSCs) from which these originate are often resistant. LSCs can restart production of the cancer cells which means that AML usually returns, or relapses. Furthermore, the older, less fit patients who constitute most cases are often unable to tolerate chemotherapy treatment. As a result, the prognosis is usually poor. Patients therefore urgently need new treatments that are tolerable yet capable of destroying LSCs to prevent relapse and lead to a long-lasting cure. This project aims to develop a new treatment for AML which could tackle this unmet need and improve patient survival. Our team’s previous work suggests that activating a set of chemical processes called the hypoxia-inducible factor, or HIF, pathway, represents a promising strategy for killing AML cells, including LSCs. The HIF pathway is usually activated by cells in the body to cope with low oxygen levels and they switch a variety of different genes on and off. When oxygen levels are normal, the HIF pathway is inactivated by proteins called prolyl hydroxylase (PHD) and factor inhibiting HIF (FIH). Our team have developed a new drug, IOX5, that stops PHD from inactivating the HIF pathway. This drug was given to mice with AML and both improved their survival rate and killed LSCs, suggesting that it has the potential to prevent AML coming back. Additionally, it proved to be even more effective at killing leukaemia cells when given with venetoclax, an existing AML treatment often given to patients who are unfit for chemotherapy. These early results are promising, but to find out whether this potential treatment strategy works in humans with AML, clinical trials are needed. However, we need to answer several questions relating to HIF pathway activation before these can be planned. These represent the aims of this project, which are as follows: We need to understand against which AML types IOX5 and venetoclax work best, so we will test them against a variety of different human samples. We will determine whether stopping FIH in addition to PHD, which should reduce inactivation of the HIF pathway, also increases treatment effectiveness. We have a drug, DM-NOFD, which achieves this and early tests indicated that it enhances the effects of IOX5 and venetoclax. We will therefore test this triple combination on human samples to discover if it works better. We will investigate the way in which the HIF pathway targets AML, which may help us to identify potential side effects which could occur in a clinical trial and new treatment targets. We will determine the effects of these treatments on the production of normal blood cells, which is often inhibited by the therapies currently used and limits their tolerability. By improving understanding of HIF pathway activation and how it can best be utilised to treat AML, we hope to bring these treatments closer to clinical trial and potentially improve the cure rate for patients with this devastating disease.