NCRI Cancer Conference 2009: Finding the ideal cancer drug

Professor Gerard Evan

The 2009 conference ended on a high note with an inspirational talk from Professor Gerard Evan, who has recently been appointed Sir William Dunn Professor of Biochemistry at the University of Cambridge, where he’ll continue his cutting-edge work on studying cancer cells to find targets for new treatments.

In his talk, Professor Evan took the audience back to basics, pointing out that cancer cells “share certain common elements”. As he pointed out, despite the well-documented differences between people’s cancers, there are also similarities.

“If you could target those, you can target all cancers”, he added – leading neatly to the question “if you could target anything in a cancer cell, where would be the best place to target?”

He said the ideal cancer drug needed several properties –

• it should kill cancer cells,
• it should have minimal side effects and
• it should hit essential targets within the cell.

By ‘essential targets’, Professor Evans means molecules or processes which can’t be bypassed, replaced or re-made – which is what cancer cells often do when they develop resistance to cancer drugs. The target should also be common to as many cancers as possible.

But does this ideal target exist?

Accelerators and brakes

Cancer develops because of a series of faults in key genes in a cell. Under normal circumstances, whether a cell grows and divides or not depends on a delicate balance between the activities of various genes in its nucleus.

Some of these genes (oncogenes) can encourage the cell to divide, while others (tumours suppressors) act as a ‘brake’ on uncontrolled growth.

The traditional view is that cancer develops when a cell develops genetic damage that both over-activates oncogenes and prevents tumour suppressors working properly. In other words, a cancer cell needs to take its foot of the brake and press the accelerator.

But Professor Evan thinks of this process in a slightly different way – and for him, timing is crucial. He proposes that some of these faulty genes play an important role right at the beginning of a cancer’s development, and others play a part later on, by helping cancer cells continue to grow once they’ve developed.

And so this begs the question, in what order do genes get damaged in cancer? And flipping this on its head, which genes should we try to target with drugs to stop the cancer growing?

Using advanced genetic techniques to manipulate cancer cells in mice, Professor Evan is beginning to answer these questions.

He has been working with mice that are genetically altered so particular tumour suppressor genes and oncogenes can be switched on and off.

This is cutting-edge research, and allows Professor Evan’s team to carry out the sort of studies that would have been impossible only a few years ago.

The amazing thing about his work is that it looks at what happens if you turn certain genes on – or off – at different stages of tumour development. He can begin to see which ones are needed to maintain tumour growth and which may just have been needed to kick the whole process off, but are no longer important. And he has had some dramatic results.

Repairing the ‘guardian of the genome’

First, Professor Evans spoke about a tumour suppressor gene called p53. As we’ve written about before, p53 plays a vital role in preventing cancer (and was discovered by Cancer Research UK’s chief scientist Professor Sir David Lane). One of its key roles is to detect genetic damage in cells, and apply the brakes to cell growth  – giving the cell a chance to repair the genetic faults. And if there is too much damage for the cell to fix, p53 can trigger the cell to die.

This ensures that a cell is unable to grow when it has genetic faults which could lead to cancer development. p53 is so important that scientists think it is damaged or not working properly in almost all cells in which cancer develops.

So p53 looks like it could be an attractive target. The question is whether faulty p53 is important for the early stages of tumour development or whether it is necessary to maintain tumour development. Using state-of-the-art genetic tools, Professor Evans is able to restore normal p53 activity and see the effect this has on tumours.

Looking in tumours that are driven by a faulty oncogene called Myc (which we’ll talk more about later), the results looked initially very promising. Restoring normal p53 activity triggered rapid death in the tumour cells, showing that p53 inactivity is needed for continued tumour growth.

But eventually the cancers came back. This time however restoring p53 had no effect. In other words the cancer cells had evolved and were now ‘p53 resistant’. Professor Evans believes that, during the experiment, any p53 resistant cells in the initial tumour would have had a survival advantage once normal p53 activity was restored. These cells would remain and could grow into new tumours.

This doesn’t mean that p53 might not be a good treatment target. But it does mean that scientists still have a way to go before they can properly understand how to target it effectively in patients.

Taking the Myc

Professor Evans then turned his attention to an oncogene called Myc. Myc normally helps cells to divide – but it is overactive in many cancers, driving their uncontrolled division. And Myc’s role is essential and can’t be bypassed or duplicated by other genes. So it satisfies many of Professor Evan’s requirements as a target for the ‘perfect’ cancer drug.

However, Myc has largely been discounted as a target for cancer drugs, because its precise molecular nature makes it incredibly hard to reach – it is essentially considered ‘undruggable’. So very little research has been carried out into what would happen if it could be deactivated.

Professor Evan’s work involved mice, whose lung tumour growth was driven by a potent oncogene called KRAS – which is commonly overactive in tumours. Again, using state-of-the-art genetic tools, he was able to switch other specific genes on or off.

Myc plays an important role in the growth of normal cells, so permanently switching it it off could cause serious problems. But Professor Evans found that if Myc is briefly turned off, tumour cells are almost literally wiped out. In fact switching off Myc for just four weeks led to almost complete recovery, and the mice were generally healthy and had very few side effects.

When Myc was turned back on, any cancer cells still present started growing again. But the researchers were able to turn Myc off again to contain the disease with no serious or permanent side effects.

The next steps

Some notes of caution are needed. First, this work was done in a lab, so we need to find out if blocking Myc has the same effect in human cancers.

Secondly, Professor Evan stopped Myc working using complex genetic engineering techniques rather than by using drugs – and, as we mentioned above, it’s proven difficult to design drugs to target Myc.

But Professor Evan is optimistic, saying he feels “new technologies would solve this soon”. And his work, using a genetic approach, has gone a huge way to showing that Myc is a worthwhile candidate upon which to focus drug development research.

Research into cancer is uncovering increasing complexity in almost every aspect of tumour cell growth and development. By getting back to basics Professor Evan has pinpointed key features which could help selectively target and kill cancer cells, without damaging normal cells.

A drug which could one day be made to safely and reversibly block Myc in people is an exciting cancer treatment possibility.

We may not be there yet, but it’s certainly an avenue of research which left the conference delegates feeling like a significant step had been made towards beating cancer.

Laura

References:

Martins, C., Brownswigart, L., & Evan, G. (2006). Modeling the Therapeutic Efficacy of p53 Restoration in Tumors Cell, 127 (7), 1323-1334 DOI: 10.1016/j.cell.2006.12.007

Soucek, L., Whitfield, J., Martins, C., Finch, A., Murphy, D., Sodir, N., Karnezis, A., Swigart, L., Nasi, S., & Evan, G. (2008). Modelling Myc inhibition as a cancer therapy Nature, 455 (7213), 679-683 DOI: 10.1038/nature07260