Cancer Institute Seminar Series

Hosted by Dr Marc Mansour

Cellular pathways that are important for haematopoietic development are processes that are often subverted in malignant cells. Accordingly, development of healthy immature progenitor cells and cancer cells often share certain properties, such as rapid proliferation, migration and active angiogenesis. Margs’ PhD studies have focused on the role of two proteins, HECTD1 and MCL-1, in normal blood cell development and in haematopoietic malignancies. Using mouse models whereby HECTD1 is lost only in blood cells, she was able to show that this E3 ligase is crucial for normal haematopoietic stem and progenitor cell function. Of note, the loss of HECTD1 causes a delay in tumour onset in a model of acute myeloid leukaemia. Understanding the fundamental biology of HECTD1 could lead to the identification of novel therapeutic targets.

In addition, Margs has worked on generating a novel humanised MCL-1 mouse model for more accurate testing of MCL-1 inhibitors in pre-clinical models. Using this model in conjunction with the Eµ-Myc mouse lymphoma model, she showed that a therapeutic window could be reached with MCL-1 inhibitors with more than 60% of mice achieving long-term tumour-free survival after treatment with tolerable doses of the MCL-1 inhibitor designed by Servier. Importantly, combining low doses of the MCL-1 inhibitor with a low dose of cyclophosphamide led to almost 100% tumour-free survival of mice. These findings in lymphoma models, and the utility of the humanised MCL-1 mouse model to examine the efficacy of MCL-1 inhibitors in other cancer types, will be helpful for informing future clinical trials as MCL-1 inhibitors enter the clinic.
 

A light lunch will be served after the seminar. 

This seminar has been sponsored in part by the Biomedical Research Centre and Cancer Research UK.