Genome instability can be exploited for cancer therapy

Share :
Published: 29 Jan 2016
Views: 2847
Rating:
Save
Prof Steve Jackson - University of Cambridge, Cambridge, UK

Prof Jackson talks to ecancertv at the PI3K-Like Protein Kinases meeting about how genome instability can be exploited for cancer therapy.

 

PI3K-Like Protein Kinases

Genome instability can be exploited for cancer therapy

Prof Steve Jackson - University of Cambridge, Cambridge, UK


Can you elaborate on your work with genome instability?

Of course the genome refers to the genetic information contained in the DNA in each of our cells and it’s been clear for a long time that this DNA contains the information that tells our cells to do what they do and do it in the right way. Of course, a normal cell will operate under normal conditions in the right kinds of way – it will divide when it’s supposed to divide, it will grow when it’s supposed to grow and it will stop growing when it should stop growing. Like other sources of information the genetic information in DNA can also occasionally be damaged and change; we call those changes mutations. So mutations are very intimately associated with cancer and virtually every full-blown cancer has a range of different mutations which have deregulated various genes. Those genes normally would control cell proliferation; if that gene gets damaged the cell will, for example, divide when it shouldn’t, it will invade when it shouldn’t etc.

So it’s clear that cancer arises through the accumulation of mutations, damage to the DNA, and of course that means that the genome is unstable in cancer cells. That is one of the hallmarks of cancer, that they have genome instability.

How can genome instability be exploited for cancer therapy?

Maybe it seems a bit counter-intuitive to start with because of course genome instability causes cancer. But the issue is that when you look at a cancer cell, a full blown cancer, in a full blown cancer, that genome instability can actually be an Achilles heel that can be used in certain circumstances to selectively kill the cancer cell but not normal cells in the body. There are various ways that can be brought about. For example, if a cancer cell has an unstable genome that probably means that the average cancer cell is sustaining more DNA damage than normal cells. So cancer cells are often very reliant on DNA repair pathways. So if you can inhibit those DNA repair pathways, for example, you often have a much stronger effect on cancer cells than normal cells. It’s also how radiotherapy and chemotherapy in many cases actually work quite well as cancer therapies. If a cancer cell is already sustaining quite a bit of DNA damage adding extra DNA damage can have a greater effect on the cancer cell than the normal cell.

One other area, and this has recently come to the fore, is to basically harness genetic defects in a cancer cell. Another example where the genome instability of a cancer cell can be exploited is using a principle called synthetic lethality. It turns out that many tumours actually lose certain DNA repair mechanisms during the evolution of the cancer. So when you look at the full-blown cancer, that cancer cell has normally got defects in DNA repair pathways where, of course, the normal cells in the body have normal DNA repair. So it turns out that in many circumstances a cancer cell that has lost one DNA repair system is very reliant on other systems of DNA repair that are working as back-ups. So it has become clear through working model organisms, yeast, simple model organisms and now human cells and human cancers, that if you can develop drugs targeting those other DNA repair pathways you’re taking away these back-up pathways that the cancer cell is really reliant on. But there’s much less effect on normal cells because they have all the full complement of DNA repair systems. So it’s now clear that this way of targeting cancer cells, taking advantage of their DNA repair deficiencies through targeting other pathways is being utilised in the clinic and I think there are many exciting opportunities yet to explore.

Can you give us an example of one of the drugs that you have brought to the clinic?

I was fortunate enough to be in a position that I could set up a company in the late 1990s, a company called KuDOs and KuDOs developed small molecule drugs against various DNA repair proteins. The idea was to use those in combination with radiotherapy and chemotherapy but also to try and utilise this synthetic lethality principle, targeting the Achilles heels of certain cancers. So the company, which was acquired by AstraZeneca a few years ago, developed a number of compounds that are now in the clinic but one of these, a compound called olaparib which targets the DNA repair enzyme called PARP, has recently been approved for treating ovarian cancer and it’s in late stage trials for various other cancers including pancreatic and prostate cancer.

In brief, what the PARP inhibitor does, what olaparib does, is to inhibit the PARP enzyme and that has not much of an effect in normal cells because they have other ways of repairing DNA damage but PARP inhibitors are very, very toxic to certain cancers that are defective in a DNA repair pathway called homologous recombination. In many cases the cancer cells lack that pathway because they have mutations in a gene called BRCA1 or a gene called BRCA2. So we know that people with inherited mutations or acquired mutations in BRCA1 or BRCA2 often end up with ovarian cancer, breast cancers and other cancers and it’s now clear that drugs like olaparib selectively kill those cells but not the normal cells of the patient by this synthetic lethality mechanism.

Do you think PI3 kinases could potentially be druggable targets?

There’s a lot of potential there. First of all these proteins that we’re talking about are protein kinases and there are many drugs already marketed in other areas that are targeting protein kinases. So the good thing is these are druggable targets. Indeed, various companies and academics, companies such as KuDOs, have developed small molecule drugs that can inhibit enzymes such as ATM, DNA-PK, ATR and other PI3 kinase family members. The challenge now is to find ways in the clinic to use those to find which patients will respond best, which tumours will respond best. In some cases that may be taking advantage of synthetic lethality opportunities, which the biology is very strong for this group of enzymes, but also seeing how these compounds could be used in combination with other anti-cancer therapies.

I should also point out that there is also potential in other areas of medicine outside of oncology for targeting these enzymes as well.

Are defects in DNA repair associated with cancer?

It is now clear that defects in DNA repair and associated mechanisms are not just associated with cancer, they’re linked to cardiovascular disease to some degree, certainly neurological diseases and neurodegenerative diseases. So there are raising levels of excitement that some of these programmes that were initiated in the realm of oncology, cancer, may actually have utility in other areas, in other clinical areas.

What are you currently working on in your lab?

My lab, as we have done for many years, now we’re focussing on the fundamental mechanisms of DNA repair and associated DNA damage signalling. We’re obviously trying to understand the basic details of this. We’re looking at protein kinases but we’re also increasingly looking at other enzymes and these include enzymes in a system called ubiquitylation. This is another way of regulating protein functions and we’re excited by the biology but we’re also excited that ubiquitylation factors in many cases are also potential drug targets that one day could be new cancer treatments.