This new series of webinars, called Future Leaders in Convergence Science, brought to you by the Cancer Research UK Convergence Science Centre at Imperial College London and The Institute of Cancer Research, will give a platform to our PhD students to present their research, and share their experience of navigating between disciplines and finding their scientific identity as convergence researchers.

Please join us online on Tuesday 16th July, from 15.00-16.00 for this 4th edition:

 

Hosted by Professor Oscar Ces, Head of the Department of Chemistry, Imperial College London. With talks from:

 

Sadiya Quazi – Department of Chemistry (Professor Matthew Fuchter) & Department of Surgery & Cancer (Dr Anke Nijhuis & Professor Hector Keun), Imperial College London, and Division of Clinical Studies, The Institute of Cancer Research (Professor Louis Chesler).

 

“Development of novel dual-target agents to treat neuroblastoma that combine selective protein degradation with synergistic inhibition”

 

Neuroblastoma, a severe childhood nerve cancer, often leads to poor prognosis and high relapse rates. Indisulam, an aryl sulfonamide, degrades the RNA splicing factor RBM39, causing cell death through aberrant RNA splicing. Alectinib, an ALK inhibitor, is effective against neuroblastoma, especially in relapsed tumors with ALK mutations. Our preliminary data show a synergistic effect when combining alectinib with indisulam. This study aims to develop a dual-target agent that combines alectinib and indisulam, hypothesizing enhanced treatment efficacy through simultaneous RBM39 degradation and ALK inhibition. Additionally, alectinib inhibits serine–arginine protein kinase 1 (SRPK1), involved in RNA splicing. Docking calculations guided the design of the dual-target agent, predicting strong binding to ALK, SRPK1, and RBM39. Synthesis of the agent is nearing completion, with ongoing purification efforts. The designed agent shows promise as a novel therapy by disrupting critical splicing mechanisms through the synergistic action of indisulam and alectinib. Future work will test the compound's activity and optimize its potency. This research presents a promising approach to neuroblastoma treatment, potentially improving patient outcomes with more effective therapies.

 

&

 

James Zhang – Department of Chemistry, Imperial College London (Professor Ed Tate), and Division of Clinical Studies, The Institute of Cancer Research (Professor Louis Chesler).

“Investigating the mechanism of action of NMT inhibitors in MYCN-amplified neuroblastoma.”

 

Myristoylation is the covalent attachment of a C14:0 fatty acid, myristate, onto the N-terminal glycine on >200 proteins. Catalysed by N-myristoyltransferases (NMTs), the modification is important for protein function and localisation, and in particular regulates protein localisation dynamically. Neuroblastoma is a leading cause of childhood cancer and MYCN amplification, present in 25% of neuroblastomas, is associated with treatment resistance and poor prognosis. Recently, it has been found that NMT inhibitors are effective in MYC-deregulated cancers. In this project, I show that NMT inhibitors are effective in MYCN-amplified neuroblastomas as well, and identify loss of respiratory complex I and oxidative phosphorylation in high MYCN contexts specifically as a contributing factor to NMTi-induced cell death. 

 

Please note: This webinar is exclusively available to colleagues from the Institute of Cancer Research, the Royal Marsden, Imperial and Imperial College Healthcare. Do not forward to colleagues outside of these organisations.