My name is Hadley Sheppard, and I am an incoming Postdoctoral Fellow joining Professor Paul Workman’s Signal Transduction and Molecular Pharmacology (STMP) Team at the Institute of Cancer Research (ICR), London. Dr. Workman’s group is based in the Cancer Research UK Cancer Therapeutics Unit at ICR and has extensive experience in many areas of cancer drug discovery – from identification of drug targets, to discovery of novel cancer drugs, and their progression to clinical trials in cancer patients.
I recently finished my post-graduate PhD in the lab of Dr. Charles Lin at Baylor College of Medicine. My PhD thesis was actually focused on chordoma research and I have been collaborating with the Chordoma Foundation since the beginning of my graduate work in 2017. I am very passionate about my work in chordoma; not only do I find our work very impactful as it can potentially better the lives of affected patients, but chordoma also serves as an excellent system to study transcriptional dependencies in cancer. Chordoma is similar to many other cancers in being dependent on an oncogenic transcription factor (TF) that drives gene expression required for the cancer to develop and progress. My post-graduate work centered on understanding the role of brachyury, the oncogenic transcription factor found in all chordomas, and its potential as a drug target. I’m very excited to join the STMP team and work closely with David Drewry and Opher Gileadi’s groups, under the support of both the Chordoma Foundation and the Mark Foundation for Cancer Research, as we now move towards directly drugging brachyury.
The Drewry, Gileadi, and Workman teams have come together to form a multidisciplinary group with the overall objective of drugging brachyury. Dr. Gileadi and his team bring expertise in structural biology, Dr. Drewry and his team expertise in medicinal chemistry, and finally we in the Workman group bring expertise in molecular pharmacology and chemical biology.
Given this, my primary role in this collaborative project — under the mentorship of Dr. Workman and Dr. Paul Clarke, group leader in the Workman lab — will be to validate and characterize compounds targeting brachyury in intact chordoma cells. As you may have read in the previous chordoma open lab notebook posts, Dr. Gileadi and his team have been able to crystalize brachyury’s DNA binding domain in complex with small molecule fragments. These small fragments tell us about regions of brachyury that could potentially be targeted with a drug.
Importantly, these fragments also provide a starting point for developing a brachyury-targeting drug. Dr. Drewry and his team are now working on chemically modifying these small molecules to improve their characteristics and, at this stage especially, their potency in inhibiting brachyury function. While it has been possible to measure certain characteristics of these small molecules in biochemical assays, the next critical step will be to test the best small molecules in intact chordoma cancer cells. This will include validation of brachyury binding and also inhibition of brachyury function through a suite of cellular assays whose development was initiated during my PhD. With the knowledge that we gain from these assays in the Workman lab, we will be able to better inform Dr. Drewry and Dr. Gileadi’s teams so that we can continue to optimize our brachyury-targeting small-molecules.
For those interested in further reading on fragment-based drug discovery and its clinical successes, I highly recommend the following review:
Structure-based drug design: aiming for a perfect fit.
van Montfort RLM, Workman P. Structure-based drug design: aiming for a perfect fit. Essays Biochem. 2017;61(5):431‐437. Published 2017 Nov 8. doi:10.1042/EBC20170052
That is all I have for today – I will be following up on our progress in future blog posts!