Gemma Kelly - Projects

Gemma Kelly - Projects

Researcher: 
Dr Gemma Kelly

Projects

Last modified: 
Thu, 11/07/2019 - 2:08pm

Identifying potential resistance factors to BH3 mimetic drugs targeting MCL-1 for cancer therapy

BH3 mimetic drugs aim to trigger cell death for cancer therapy through inhibiting cellular pro-survival proteins of the BCL-2 family.

In earlier work we found that expression of the pro-survival protein MCL-1 was required for the continued growth of MYC-driven lymphomas. We have been working with the pharmaceutical company Servier to test novel BH3 mimetic drugs targeting MCL-1 for cancer therapy and related drugs entered clinical trials in 2018.

We are currently seeking to identify factors that could confer resistance, either primary or acquired, to these MCL-1 targeting drugs with the aim to find strategies that could overcome resistance.   

Project resources

Team members: Dr Sarah Diepstraten and Ms Catherine Chang

Investigating mutant p53 in cancer

Approximately 50 per cent of human cancers harbor mutations in the tumour suppressor p53 that result in reduced sensitivity to many conventional chemotherapeutics and a poor prognosis for the patients. We seek to understand how exactly these mutations in p53 contribute to the growth of cancer cells, in particular we are interested to know if there are neomorphic gain-of-function effects of mutant p53. Additionally, we aim to determine if mutant p53 contributes to the growth of established tumours, thereby identifying it as a therapeutic target. For these experiments we have generated novel and sophisticated pre-clinical models of mutant p53 cancers.

Project resources

Team members: Ms Elizabeth Lieschke and Dr Zilu Wang, PhD students co-supervised by Dr Gemma Kelly and Professor Andreas Strasser

Investigating the role of the Epstein-Barr virus in lymphomas

Approximately 200,000 cancers annually are associated with the Epstein-Barr virus (EBV). We are researching the role of EBV in two types of lymphoma – Burkitt’s lymphoma (an aggressive B cell lymphoma), and T/NK cell lymphoma.

In a subset of Burkitt’s lymphomas, EBV expresses a viral homologue of the cellular pro-survival BCL-2 proteins, called BHRF1. We seek to understand how BHRF1 interacts with the cellular apoptotic machinery to block cancer cell death. In the setting of EBV-associated T/NK cell lymphomas we aim to understand how viral proteins contribute to tumour growth and to find alternative therapeutic options since these patients currently have a very poor prognosis.

Team members: Mr Nenad Sejic and Ms Catherine Chang and also a collaboration with the group of Dr Claire Shannon-Lowe at The University of Birmingham

Is there therapeutic potential in targeting the BCL-2 pro-survival proteins BCL-W and BFL-1/A1 for cancer therapy?

BH3 mimetic drugs targeting the pro-survival protein BCL-2 have shown efficacy in the clinic for the treatment of patients with chronic lymphocytic leukemia (CLL).

More recently, BH3 mimetics targeting the related BCL-2 family protein, MCL-1, have shown promise for the treatment of certain blood cancers in pre-clinical models and entered clinical trials for these cancers in 2018.

Two of the other BCL-2 pro-survival proteins, BCL-W and BFL-1/A1, are by comparison relatively understudied. We are using genetically engineered pre-clinical lymphoma models and CRISPR/Cas9 genome editing of blood cancer cells to determine if drugs targeting BCL-W and BFL-1/A1 would have therapeutic potential.

Team members: Dr Sarah Diepstraten, working in collaboration with the groups of Professor Andreas Strasser and Associate Professor Marco Herold