In the field of oncology, more than 250 drugs are currently available and over 700 are in late-stage development. Despite major advances in targeted therapies, one of the greatest challenges remains to select the right drug for the right patient at the right time. Clinicians are missing diagnostic tools to predict which patients will respond favourably to which therapy.
Most targeted cancer therapeutics inhibit molecules that are involved in regulatory pathways within cells. A key method used to predict drug response is called gene expression profiling. It involves sequencing the entirety of messenger RNA (mRNA) - the transcriptome - following administration of a drug to find out which genes are switched on. However, these methods cannot discern drug-induced, newly formed mRNA from “background” mRNA, or they require large amounts of cells and are cumbersome to handle.
A new project supported by an ERC Proof of Concept Grant seeks to overcome these limitations. Following an ERC Starting Grant awarded in 2013, IMP Group Leader Johannes Zuber aims to develop a fast, simple and accurate method to profile direct transcriptional drug responses in primary tumour cells. He will build on a method called SLAMseq that was invented in the lab of Stefan Ameres (IMBA) and further developed in collaboration with the Zuber lab. SLAMseq can uncover and quantify newly transcribed mRNA by detecting the incorporation of an artificial nucleotide. Due to its unique features, such as low input cell numbers and short treatment-to-sample time, SLAMseq is ideally suited to measure direct drug effects on gene transcription with unprecedented precision in primary tumour cells.
Following pioneering studies in cultured cancer cells, which have been published last year in the journal Science, the project “Diagnostic drug response-profiling using SLAMseq”, short SLAM-Dx, aims to further develop SLAMseq as a method for profiling drug responses directly in freshly isolated tumour cells. “If we succeed”, says Johannes Zuber, “SLAM-Dx will pioneer a revolutionary method for monitoring drug responses directly in patient cells, which would open fascinating opportunities for drug development and personalised medicine in a variety of disease areas”.
About Johannes Zuber
Johannes Zuber, born 1974 in Dresden, completed his medical studies and a doctoral thesis in molecular cancer research at Berlin’s Charité Medical School in 2003. Two years later, Zuber moved to the US to join Scott Lowe's lab at Cold Spring Harbor Laboratory, where he developed innovative genetic models to study targeted therapies in leukemia. In 2011, he started his own lab as a Group Leader at the IMP, focussing on identifying and understanding cancer dependencies. Johannes Zuber’s research was supported by an ERC Starting Grant in 2013. In 2014 he was elected into EMBO’s Young Investigator Investigator Programme (YIP) and in 2016, he was awarded the German Cancer Prize.
ERC Proof of Concept Grants
The ERC’s Proof of Concept Grant is an add-on grant on offer to Principal investigators who already benefit from an ERC main research grant and whose proposals draw substantially on their ERC funded research. Proof of Concept Grants aim to maximise the value of the excellent research that the ERC funds, by funding further work to verify the innovation potential of ideas arising from ERC funded projects. The objective is to enable ERC-funded ideas to be brought to a pre-demonstration stage where potential commercialisation or societal opportunities have been identified.