Developing novel synergistic drug combinations with venetoclax in acute myeloid leukaemia

Abstract

Acute myeloid leukaemia (AML) is a malignancy of the blood and bone marrow characterised by the accumulation of immature myeloid cells. AML affects children and adults of all ages and is associated with poor survival outcomes. Intensive chemotherapy has remained the gold standard treatment for AML for the last 50 years. Until recently, patients who were elderly or otherwise unfit for intensive chemotherapy had limited options for treatment and were primarily given best supportive care including pain relief and hospice care. In recent years several targeted therapeutics have been developed to specifically target oncogenic pathways in AML. In 2017 venetoclax, the first-in-class BCL-2 inhibitor, was granted FDA approval in combination with a hypomethylating agent for the treatment of unfit patients with AML. The remarkable efficacy of venetoclax and improved patient survival outcomes quickly made venetoclax an attractive option for unfit patients. However, recent clinical trial data suggest that although venetoclax and azacytidine promote prolonged survival, patient relapse and drug resistance are still very common. This study aimed to develop novel synergistic drug combinations with venetoclax to overcome mechanisms of venetoclax-resistance. A panel of eight AML cell lines were exposed to venetoclax for 72 hours and each cell line had a unique sensitivity profile. THP-1 and OCI-AML3 cell lines were identified as venetoclax-resistant at the highest concentration tested (5 μM). The THP-1 cell line was selected as the venetoclax-resistant model for a high-capacity drug screen which tested 1,971 compounds as single agents. A total of 306 compounds demonstrated efficacy as they induced >50% reductions in cell viability and were identified as hits. Subsequently, 180 of the top hits were tested in combination with venetoclax in THP-1 cells in a combination drug screen. The combination drug screen identified several novel combinations. The most synergistic and effective compound in combination with venetoclax in venetoclax-resistant cell lines was the Hsp90 inhibitor, ganetespib, which may overcome venetoclax resistance via downstream dysregulation of oncogenic and drug resistance pathways in the THP-1 and OCI-AML3 cell lines.

Thesis is embargoed until 31st May 2026.

Date of Award	May 2024
Original language	English
Supervisor	Kyle Matchett (Supervisor) & David Gibson (Supervisor)