Identification and characterisation of novel compounds for potential application in the immunotherapeutic treatment of leukaemia

BCR-Abl is an essential driver mutation in many leukaemias. While front-line treatments of these BCR-Abl+ leukaemias rely on aggressive chemotherapy and targeted therapies, patient survival remains unsatisfactory and highlights the need for new therapeutic options. Recently, using high-throughput, competition-based screening, our lab discovered a handful of compounds that can induce the rapid degradation of c-myc, a favourable target often considered ‘undruggable’. c-myc is a critical transcription factor of the BCR-Abl pathway, essential for cancer cell proliferation and survival. Moreover, c-myc also regulates the expression of several immune-suppressing receptors, such as PDL1, important for cancer cell evasion from the immune system and as such, inhibition of c-myc activity could offer promising immunotherapeutic activity.

Goal

The goal of this research is to understand the mechanism in which c-myc regulates immune-suppressing receptors in leukaemia and how this system can be disrupted using small molecules. Compounds that can trigger c-myc degradation have the potential not only to promote anti-cancer immune response, but may also prove effective in many ‘myc-addicted’ cancers, i.e. those cancers were c-myc is an essential oncogene required for survival and progression. We aim to determine to what extent these compounds can deregulate PDL1, and indeed other immune-suppressing receptors, and how this will realistically correlate to improve immune recognition. Crucially, we are looking to establish the target of these compounds and better understand how the pathway in which c-myc is regulated in these cancers. Finally, via further screening of analogous compounds, we aim to identify a scaffold in which further immunotherapeutic drugs in this class can be designed.

 

What we offer the student

  • Experience working in compound screening on cultured leukaemia cells.
  • Experience in drug discovery, mechanism of action and cellular pharmacology.
  • Experience in molecular biology and biochemistry methods: Western blotting, FACS, cloning, microscopy.
  • Working closely in drug design, structural rendering and commercialisation.
  • Training in transferrable skills: presentations, writing, project planning
  • You get to be part of an international research team with researchers at different stages of their careers
  • Frequent opportunities to get input on your data (weekly lab meetings) and to get updated on the most recent advances in our field of interest (“journal club” presentations)
  • We have an ambitious environment where team members share their expertise to help each other get better!

Our research group

The Cancer Molecular Medicine research group is led by Jorrit Enserink and consists of 12 members from 7 different countries. One of our research areas is leukaemia and the development of new therapies for AML patients, where we have established a personalised medicine drug screening platform. The group is a young and dynamic environment and has long experience in supervision of Masters and PhD students. Our group is part of the Department for Molecular Cell Biology at the Institute for Cancer Research (Radiumhospitalet) where we share facilities, reagents and expertise with other groups in both our department and around the hospital.

Supervisors:

Day-to-day:                Richard Crispin

Group Leader:            Jorrit Enserink

Published Mar. 22, 2018 10:26 AM - Last modified Apr. 19, 2018 8:13 AM

Supervisor(s)

Scope (credits)

60