WEHI Wednesday Seminar hosted by Professor Andrew Roberts
 

Dr Yin Yuan
PhD Student – Roberts & Wei Laboratories, Blood Cells and Blood Cancer division, WEHI
(this is a PhD Completion seminar)
 

STING agonists in acute myeloid leukaemia

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

Acute myeloid leukaemia (AML) is a highly aggressive blood cancer arising from the clonal expansion of haematopoietic progenitor cells in the bone marrow, with consequent failure of normal haematopoiesis. Unfortunately, the prognosis for patients diagnosed with AML is very poor, with an estimated 5-year survival of only 28%. The development of new targeted therapies, such as the BCL-2 inhibitor venetoclax, has improved the care for patients with AML. However, resistance remains a major problem, and one of the key challenges is mutations in the tumour suppressor gene TP53. Patients with this subtype of AML face a dismal prognosis, with a lack of effective treatment options due to the reliance of all current therapies on intact TP53 function. Thus, novel therapies that have TP53 independent mechanisms of action are urgently required.

The canonical role of the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway is to generate type 1 interferon production in response to cytosolic double-stranded DNA. Thus, drugs that activate STING have been developed and studied for their anti-cancer potential as a form of immunotherapy. We have found, however, that STING agonists have unique cell-intrinsic anti-tumour effects in AML. In my PhD, I have demonstrated using primary patient samples that AML cells have high levels of STING expression and are exquisitely sensitive to both STING agonist induced killing and cell cycle arrest. Importantly, these processes still occurred in TP53 abnormal cells. We confirmed the efficacy of clinically relevant STING agonist compounds, alone and in combination with venetoclax, using TP53 wildtype and defective cell line and patient derived xenografts. We are now using the preclinical data and biological insights generated to inform the rational design of a phase I clinical trial for STING agonists in relapsed/refractory AML.

All welcome!