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Transcription is a tightly regulated process, where chemical modifications initiate the duplication of genetic material. This epigenetic process is often dysregulated in cancer, but it can be targeted with small molecule inhibitors. A better understanding of the molecular mechanisms underpinning disease will ultimately help develop better drugs.

Q: Can you tell us about DNA transcription?

Panagis Filippakopoulos: DNA transcription is a very complicated process that involves many segregation factors that come to duplicate the genetic information, in order to generate the tools necessary for cell survival. This process is initiated by chemical modifications; chemical signals that are somehow interpreted by evolutionary conserved modules that segregate the machinery at specific locations, where transcription will be carried out. This process is often dysregulated in cancer.

Q: What is the focus of your research group?

PF: We are interested in understanding how the assembly of the transcriptional machinery is initiated by the read-out process: the recognition of chemical modifications by evolutionary conserved effective modules. Among other things, we generate small molecule inhibitors that are used to block this interaction, in order to study what happens when the process is disrupted (like in cancer or in other diseases). Using these tools, we can understand how a normal cell functions and also understand how it is perturbed in disease.

Q: Can you give us an example?

PF: We are interested in a rare but extremely aggressive tumour-type, called the NUT mid-line carcinoma which involves a genetic fusion of a protein that is normally expressed in the testes. Somehow, this fusion results in the expression of the protein in the mediastinum (the central compartments of the thoracic cavity in the chest).

It is very aggressive: it is deadly. We do not understand the molecular mechanism but what we do know is that it hijacks this process of read-out, taking advantage of the transcriptional machinery, and sequestering it to propagate and enhance tumour growth.

The important thing is that they can be targeted by small molecular inhibitors. The problem with NUT mid-line carcinoma is that there is no easy detection, so in principle, there have been no cases in the UK: it's only been detected in the US.

What we are interested in is understanding the molecular basis of the malignancy, in order to define the biomarkers, so that we are able to detect the disease, and eventually, cure it.

Q: What are the most important lines of research that have developed in the last 5-10 years?

PF: There are many significant things that have happened.

The most exciting for us is the fact that the recognition process of the chemical interpretation of signals can be directly inhibited by small molecular inhibitors. This has already been translated to the clinic, at least in an attempt to cure this rare tumour type, the NUT mid-line carcinoma. But it has also paved road to look into the deregulation of this signal read-out process in general, and define mechanisms in other diseases. Probably the most important aspect of this is that in the last five years, there have been 12 clinical trials have been initiated using such chemical tools.

Q: Why does your line of research matter and why should we fund it?

PF: What we do is considered basic research, but in principle, it allows us to understand and define the molecular mechanisms underpinning disease. By doing so, we define the biomarkers necessary for detection, but we also help understand how we can make drugs safer, more effective and more selective, avoiding cross-reactivities and off-target effects. Our research is often translational to the clinic.

Q: So this is how you feel it fits into translational medicine within the department?

PF: Absolutely. I think that medicine goes hand in hand with basic research: one helps the other. We are embedded in a department where we have access to clinical material, samples, expertise, ideas and opinions. We help define the molecular mechanisms underpinning disease and also find biomarkers that can help better understand how to target disease in the clinic, generating key tools that can be used eventually to lead compounds into translation directly into the clinic.

Panagis Filippakopoulos

Epigenetic signalling

Professor Panagis Filippakopoulos is interested in the molecular mechanisms of transcription, where the formation of non-covalent protein complexes is mediated by post-translational modifications. Dysfunction in this epigenetic signalling process is linked to disease, particularly cancer.

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