Holy Grail: RNA Polymerase II dysregulation a target for blood cancer therapies

Can you describe the aim of your research in 15 words? 

To understand transcriptional (dys)regulation in the hopes of finding new treatment options in cancer.

Tell us more: 

Transcriptional dysregulation is a hallmark of cancer and fuels aggressive growth and therapy resistance, but also exposes a weakness, as transcriptionally “addicted” cancer cells are exquisitely sensitive to therapeutic targeting of core-transcriptional components.

This transcriptional dysregulation is particularly prominent in mixed-lineage leukaemia (MLL)-rearranged leukaemias. My lab uses state-of-the-art technologies, such as genome-wide CRISPR-Cas9 screening approaches and advanced genomics methods such as nascent RNA-sequencing and transient transcriptome sequencing, to discover novel fundamental regulatory mechanisms that control RNA Polymerase II (RNAPII)-mediated transcription, identify how these may be dysregulated in cancer and find critical transcriptional dependencies herein.

The goal is to identify novel small molecule inhibitors through a drug discovery program that can be utilised to selectively abrogate oncogenic transcription. Ultimately this could lead to new drug treatments for hard-to-treat cancers such as acute myeloid leukaemia (AML).

What have you discovered so far? 

My work has uncovered novel regulatory mechanisms that control the RNAPII transcription cycle, which are altered in cancer and can be targeted therapeutically.

The transcription cycle is a unidirectional process that is regulated by cyclin-dependent kinases (CDKs) and their cognate cyclins at distinct checkpoints and phases such as Initiation, Pausing, Elongation, Termination and Recycling.

My work has revealed that CDK12 and CDK13 are critical during the elongation phase and that this process can be targeted in AML.

My more recent work describes the discovery of a submodule of the integrator complex, comprising INTS6, INTS8 and the phosphatase PP2A, which functionally antagonises CDK9 at the pause-release checkpoint and can be targeted therapeutically in solid and haematopoietic malignancies.

How long before your work affects patient care?

My lab’s work is focussed on the identification of critical vulnerabilities in cancers, particularly in blood cancers which are characterised by transcriptional dysregulation. Once identified, my lab will perform small molecule drug screens to identify novel inhibitors, which can subsequently be tested in vitro and in vivo. Ultimately, I hope one or more of these compounds can make it into clinical trials. This is a long-term process that can take many years, however I am confident my passion and commitment to creating better treatment options for cancer patients will be up for the challenge.

You recently won a fellowship with the Snow Medical Research Foundation — can you tell me a bit more about how that came about and what it means for your research?

I was recently chosen as one of three researchers in Australia to receive a Snow Fellowship and received $8 million to further this research project of mine. It takes years for a research idea to progress to a stage where it can have real-life implications for people. This Fellowship will give me the security and confidence I need to create these meaningful outcomes. Only six years ago I came to Australia for my postdoctoral studies and was able to benefit from the excellent research environment to do impactful science. Australia really is a place where we can compete on an international stage and the Snow Fellowship helps attract top scientists from around the world by offering the support needed to pursue big and bold research aims that will have a transformative impact.

What aspect of your research excites you the most?

I love that science is all about teamwork. You get together, brainstorm about the best ways to tackle a scientific question and then work towards a shared goal.

What’s your Holy Grail — the one thing you’d like to achieve in your research career?

It is my dream to make ground-breaking, fundamental scientific discoveries that can lead to completely novel therapeutics and improve patient outcomes. I hope to do this by creating a lab that unites the brightest minds from across the globe to pursue their scientific dreams in Australia.

What is your biggest research hurdle?

I do not see too many hurdles. Time management is always a challenge.

Who has inspired you in work or life? 

I am inspired by scientists like Frederick Sanger and Richard Feynman; creative minds that had a big impact on science, but also trained and inspired the next generation of scientists.

I also embody this passion for passing my knowledge onto the next generation. It would be a dream come true to one day see my work featured in a scientific textbook that is used to educate upcoming bright and bold thinkers.

What new hobby have you picked up during COVID? 

Perhaps not an entirely new hobby, but during all the lockdowns I started to do more elaborate cooking at home. It is a little bit like doing an experiment, add the right ingredients, follow the protocol, and enjoy the result.

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