Survival rates of infants suffering from acute lymphoblastic leukaemia (ALL) characterised by a rearrangement of the MLL/KMT2A gene (MLL-r ALL) remain below 50% and many survivors suffer from detrimental long-term health issues due to side-effects of conventional chemotherapeutic treatment. New targeted therapeutics with a higher level of cancer-specificity are thus urgently needed to develop more effective and safer treatment schemes.
One of the recent success stories for targeted therapies has been the development and progression of BCL-2 inhibitors (e.g. Venetoclax) into the clinic for haematological malignancies. Based on its success in a range of adult haematopoietic cancers, Venetoclax is currently in clinical trial for refractory/relapsed paediatric malignancies. However, despite its success, inherent or acquired resistance to Venetoclax occurs due to dependency of the cancer cells on other prosurvival BCL-2 family proteins MCL1 and BCL-XL, which has resulted in a push towards the development of specific inhibitors for these molecules. Decades of intense research have recently led to the generation of the first specific small molecule inhibitors of MCL1 which are now being advanced into clinical trials for adult haematological malignancies.
In view of the particularly dismal outcome for infants with MLL-r ALL, our research is focused on identifying novel targeted agents for this disease through the testing of candidate compounds in our state-of-the-art, fully molecularly annotated patient-derived xenograft (PDX) models for infant ALL that are internationally unique and recognised as the gold standard preclinical models for this disease. Based on the hypothesis that MCL1 is a major contributing factor in the survival and therapy resistance of infant MLL-r ALL, the aim of this project is to elucidate the clinical potential of targeted MCL1 inhibition for infant MLL-r leukaemia by investigating the preclinical efficacy of a novel, specific MCL1 inhibitor, S63845 in our in vitro and in vivo models of the disease.
Started: 1 April 2019
Ending: 31 March 2021
