Phosphoproteomic profiling for novel target identification in childhood sarcomas

Sarcomas are a diverse group of rare, highly aggressive tumours of the connective tissue that disproportionally affect the young. Despite aggressive treatments, survival is limited (~20% in advanced setting) and side-effects frequently occur, stressing the unmet need to identify novel, tumour-specific treatments. Pinpointing clinically actionable targets is however extremely challenging in these tumours. Widely used genomics interrogations reported very few targetable defects.

Tumour genomics are however only one piece of the puzzle, and the picture they paint is incomplete. As the actual oncogenic effect of a gene is carried out at the protein level, where it needs to be “switched on” (phosphorylated), it seems only logical to investigate deregulation directly on this level.

Here, we have an excellent opportunity for a PhD/honours student to study the complete phosphorylation patterns (pTyr/pSer/pThr) of key effector molecules (kinases) in a diverse set of sarcoma cell lines, PDX models and unique patient samples, with the ultimate aim to identify novel, clinically actionable targets for young sarcoma patients. The student will work closely with the ZERO Childhood Cancer program (ZERO), a national clinical trial aimed at identifying targeted treatments for high-risk paediatric cancer patients (including sarcoma). The student will use a variety of molecular methodologies, including Mass-Spectrometry and targeted phosphoproteomic assays (Kinome Profiler/Western Blot/Immunohistochemistry). Functional relevance of identified targets will be validated using in vitro (drug screens/siRNA/CRISPR) and in vivo (drug efficacy) sarcoma models; exact techniques depend on honours/PhD level.

Results have the potential to have an immediate clinical impact on sarcoma patients in ZERO.