Our Program uses molecular genetic technology and small-molecule drug screening approaches to improve the diagnosis and treatment of children with cancer. To identify new pharmaceutical agents that target cancer-associated genes, we use high-throughput screening of small-molecule chemical libraries.
We have identified several small-molecule inhibitors of these targets in infants with leukaemia, and in childhood neuroblastoma. Both these groups of children have particularly poor survival rates compared with children with other tumour types. The development of inhibitors of defined molecular targets—such as the MLL (Mixed Lineage Leukaemia) oncoprotein and MYCN-associated proteins—provides the opportunity to devise therapies that are more specific in their action, are effective at low concentrations, and have an irreversible effect on cancer cells. We focus on developing clinically-relevant chemical small molecules that specifically inhibit leukaemia cells with an abnormal MLL gene as well as on characterising novel genes and co-factors involved in MYCN-driven neuroblastoma.
Leukaemia accounts for the greatest number of deaths from childhood cancer overall. Particularly poor survival rates are found in infants, whose leukaemias commonly display abnormalities of the MLL gene (MLLr-ALL).
We have established a pipeline for the discovery, characterisation and development of novel agents for MLLr-ALL, including high-throughput screening; cellular and molecular characterisation in a large and diverse panel of leukaemia cell lines; in vivo testing in paediatric leukaemia patient-derived xenograft (PDX) models; and efficacy testing of potential new drugs in combination with the leukaemia drugs currently in use. Several projects are ongoing, reflecting the various approaches taken. These include:
i) Characterisation of the mechanism of action of novel MLL-specific molecules identified by High-Throughput Screening
ii) Targeting the DNA structure in childhood ALL using CBL0137, a quinacrine-related DNA-binding compound that acts by targeting a complex known as FACT (Facilitates Chromatin Transcription)
iii) Blocking production of NAD using the small molecule compound OT-82, an exciting new anti-cancer drug extremely potent in PDX models of MLLr-ALL and other high-risk ALL
iv) Re-purposing drugs for MLL therapy, using a chemical library of bioactive molecules.
Many patients with neuroblastoma present with widely disseminated disease at diagnosis, and the prognosis for such patients is dismal. Several prognostic markers have been identified for this disease and one of the most powerful is MYCN oncogene amplification, demonstrated in 25–30% of primary untreated neuroblastomas. We have sought to identify pathways downstream of MYCN that are required for neuroblastoma initiation and maintenance, as these represent potential candidates for therapeutic intervention.
We have undertaken a large ENU-mutagenesis screen using N-ethyl-N-nitrosourea (ENU), a compound that causes heritable mutations in DNA. As a result of this screen, we generated a founder line showing Mendelian inheritance of a specific mutation that prevented neuroblastoma formation. A combination of gene mapping and next-generation sequencing was used to identify the gene, which had a loss-of-function mutation. Although this gene has never previously been shown to have a role in neuroblastoma, our research shows that it has a critical role in the initiation and development of this disease. These studies have the potential to elucidate an entirely novel approach to the treatment and, ultimately, prevention of this refractory childhood malignancy.
ATP-binding cassette (ABC) transporters are a large family of transmembrane proteins. It is now known that certain members of this family have roles in cancer biology. In a study of ovarian cancer, we found that expression levels of the cholesterol transporter ABCA1 vary between the subtypes of ovarian cancer and that its aberrant expression is associated with poor clinical outcome. Our goal is to conduct mechanistic studies into the action of ABCA1 in ovarian cancer, using 3D and 2D cell culture models and in vivo PDX models, towards the goal of identifying potential avenues for molecular targeted therapy.
Our research to date has shown that modulating the expression of ABCA1 in ovarian cancer cells in vitro decreases their malignancy, as measured by growth ability, migratory activity and ability to form three-dimensional tumour-like structures. This suggests that the cholesterol transporter ABCA1 plays a significant role in the biology of this disease. The findings are being extended to an in vivo model of ovarian cancer, using an inducible system to knock down ABCA1.
Some of the most aggressive neuroblastoma cells have increased rates of protein synthesis compared to normal, non-cancerous cells. Highly efficient protein synthesis provides the essential building blocks for unlimited cancer cell growth, particularly when the cancer is driven by the MYC or MYCN oncogenes. The dependency of MYCN-driven neuroblastoma cells on fast rates of protein synthesis makes them vulnerable to agents that disrupt protein synthesis.
We have shown that ABCE1 is a critical factor supporting protein synthesis in neuroblastoma cells. Reducing the level of ABCE1 protein in neuroblastoma cells drastically slows the rate of protein synthesis and consequently disables the growth and spread of neuroblastoma tumours. Interestingly, reducing the level of ABCE1 in non-cancerous, normal cells does not affect their growth, predicting no adverse side effects to patients.
Our goal is to find novel approaches to disrupt ABCE1 and hence disrupt protein synthesis to impair neuroblastoma progression. This involves generating chemical inhibitors to ABCE1. If successful, these drugs will be the first class of therapeutics that kills cancer cells by blocking ABCE1. Since many cancers depend on MYC genes for their protein synthesis, therapeutics targeting ABCE1 might benefit a large number of patients, not only those with neuroblastoma.
Group LeaderProfessor Murray Norris
SENIOR SCIENTIST AND PROJECT LEADER
SENIOR RESEARCH OFFICER
Dr Klaartje Somers
Dr Chengyuan Xue
Dr Ruby Pandher
Dr Emanuele Valli
Dr Jayne Murray
Dr Firoozeh Salehzadeh
Dr Jixuan Gao
Dr Mawar Karsa
Dr Jayne Murray
SENIOR RESEARCH ASSISTANT