Strategic combinations to overcome therapeutic resistance and relapse in acute myeloid leukemia
Jenny Wang
PhDThe University of Sydney
Project Term: July 1, 2023 - June 30, 2026
Acute myeloid leukemia (AML) is the most fatal type of leukemia and has a high rate of relapse following current therapies. We have recently uncovered that RSPO3-LGR4 pathway is a key regulator of leukemia-initiating cell activity and is exclusively activated in relapsed and refractory AML. Our project aims to investigate the mechanistic link between the pathway activation and therapy resistance, and design combination therapies that would overcome resistance and improve the treatment of relapsed leukemia.
Acute myeloid leukemia (AML) is an aggressive hematological malignancy and remains the leading cause of leukemia death globally. Chemotherapy is the primary treatment option for AML but unfortunately only cures a minority of patients. Despite intensive efforts to improve outcomes, the 5-year overall survival rate for AML is still less than 30%. Relapse is the main cause of therapeutic failure and occurs in approximately two-thirds of AML patients who have achieved remission after standard therapy. Treatment of relapsed and refractory AML has been clinically challenging, with poor response rates and low chance for cure. Treatment failure and relapse are commonly caused by drug resistance. In this regard, understanding resistance mechanisms, uncovering therapeutic targets to reverse resistance, and developing combination therapies to limit or prevent relapse have become a central focus in the field. We have recently identified RSPO3-LGR4 as a key stemness pathway, which mediates the interaction of leukemia-initiating cells with the microenvironment to promote tumor progression and therapeutic resistance. RSPO3-LGR4 pathway is only activated in patients with relapsed and refractory AML who have a poor prognosis, but not in those with favorable outcomes. Pharmacological disruption of RSPO3-LGR4 interaction by an anti-RSPO3 antibody effectively eliminates leukemia-initiating cells and consequently reduces tumor burden in preclinical models derived from AML patients who have previously developed resistance to chemotherapy. This project seeks to investigate the mechanistic link between the pathway activation and therapeutic resistance, and to understand resistance mechanisms that bypass the drug targets to maintain leukemic cell survival. We will use patient omics and genetic profiling, patient-derived preclinical models, genome-editing and functional analysis of therapeutic targets to investigate molecular mechanisms driving resistance to anti-RSPO3 treatment in individual patients with AML. The knowledge gained will be leveraged with our drug discovery strategy to design personalized combination therapies that would circumvent resistance and inform future decisions in clinical trials of anti-RSPO3 antibody to improve the treatment of relapsed and refractory leukemia.