p53 and cancer research: an interview with Professor Sir David Lane, Scientific Director of the Ludwig Institute for Cancer Research

Published on July 22, 2013 at 10:03 AM · 1 Comment

Interview conducted by , BA Hons (Cantab)

Sir David Lane ARTICLE IMAGE

You have recently been appointed as the new Scientific Director of the Ludwig Institute for Cancer Research. Can you share with us why you decided to join Ludwig?

I’m really delighted to join the Ludwig Institute as its Scientific Director. I’ve gotten to know Ludwig very well as a member of its Scientific Advisory Committee and also of the Board. I know what a tremendous opportunity it offers in terms of fostering breakthrough cancer research.

As a largely independently funded, international network of scientists with a 40-year legacy of pioneering cancer discoveries, Ludwig has a unique ability to carry its research all the way from the laboratory to the clinic. It’s an exciting time to join the Ludwig community and to help maximize the potential of its discoveries.

How do you plan to integrate into Ludwig and help advance its cancer research programs?

I have held a number of scientific and leadership positions, and each of them has provided me with a different set of skills and insights. Also, through my work as a member of Ludwig’s Scientific Advisory Committee and of its Board, I have a good sense of the organization and its people, but undoubtedly there’s more I need to learn.

I want to ensure that I become well acquainted with all the scientists and their research focus. As a scientist myself, I feel I can really understand what people are doing and why they’re doing it.

I also plan to focus on collaboration – helping people interact with each other because much of the best science comes from unexpected interactions. I want to foster an atmosphere where people feel really happy to work with each other and where they know they’ll be supported.

You are probably best known for your discovery of the p53 tumor suppressor protein in 1979. Please can you give a brief introduction to p53, and explain why p53 is often called “the guardian of the genome”.

P53 is a tumor suppressor gene. The gene encodes for a protein that monitors the state of the cell. If something goes wrong, it stops the cell from dividing or causes the cell to commit suicide.

I call it the “guardian of the genome” as it is the molecule that seems to keep cells normal. It is one of our big defenses against cancer.

In rare human families that inherit a defect in p53 gene function, we see that family members develop cancer much more frequently than normal, showing how important p53 is for most of us in preventing cancer.

Bring us back in time to your discovery and your “Aha!” moment. What was that like, and what carried you forward?

I had just started my post-doctoral fellowship in the laboratories of the Imperial Cancer Research Fund in the UK. We were working on a virus that could cause cells in culture to start to multiple uncontrollably, much like cancer cells. It was a very small virus, called SV40, and it only made a single protein, a so-called large T protein.

Surprisingly that one protein expressed in a cell was enough to cause it to behave like a cancer cell. It became clear from that moment that SV40 must interact in some very subtle and complicated way with the host cell to make it change its behavior.

I then used immunological methods to “go fishing” so that I could figure out what was going on intra-cellularly to interact with the T antigen. Turns out that the culprit was the p53 protein.

In this instance, the p53 protein was inactivated by the viral T protein. Something like this happens in human cervical and some oral cancers where the HPV virus associated with these cancers makes the viral E6 protein that also binds to and inactivates p53.

When you talk about the frequency, how many people could be affected by the absence of p53?

We think there are about 22 million people in the world today living with cancer and about half of those will have a mutation in the p53 gene – a genetic defect that can be determined from DNA sequencing.

In the other half of people with cancers, we believe they have something wrong with the pathway. My feeling is that nearly every tumor has an affected or moderated p53 pathway.

You mentioned that p53 is mutated or faulty in around 50 percent of human cancers. How do cells multiply recklessly in human cancers where p53 is not mutated?

When p53 is not itself mutated like, for example, in melanoma or some forms of Acute Myeloid Leukemia, we think the pathway to p53 is damaged or inhibited, so p53 does not get the right signal to be activated and stop the cancer from growing.

How close do you think we are to being able to restore p53’s function in cancer patients? Do you think this alone will cure cancer in these patients, or will the restoration need to be combined with other therapeutics?

We’re looking at ways to turn p53 into a target for drug therapy. We have two major areas that we’re exploring. One is a way to turn the p53 response on in the 50 percent of human tumors where the gene is still intact.

There are already some molecules in clinical trials coming from that area of research. These early clinical trials are encouraging, and many major pharmaceutical companies are now working on this target, which we first helped to define as “druggable” over 16 years ago.

The second area we’re focused on is trying to target those tumors where p53 gene function is lost. We’re currently investigating a variety of different approaches there – one, and perhaps the most challenging, is trying to get the mutant protein to work again.

This work is not yet ready for clinical trials. We are still slaving away at the bench really, though one early molecule that works this way is being tried in a very small group of patients in Sweden.

Please can you outline your current laboratory investigations that are underway?

As noted earlier, my work continues to focus on p53. Recently, we’ve made a breakthrough in terms of a new chemical entity called a stapled peptide. We believe it will be a third class of potential drug targets. There are small molecules and antibodies, and maybe small peptides will be the third class.

Additionally, we’re beginning to understand much more deeply how the p53 pathway works – and that fits in with many other aspects of research underway at Ludwig. It’s this mapping of the signalling pathways within cancer cells that offers cancer researchers tremendous opportunities for new interventions.

What do you think is the next frontier, generally, in cancer research?

I think there are two areas that look like they’re going to be hugely important in the fight against cancer. One is immunology.

For a long time, we couldn’t be certain that human beings really made a significant anti-tumor response. Now however, we know, thanks in fact to research by Ludwig scientists, that they do.

And we’ve made important headway toward immunological interventions that have reversed advanced melanomas, for example. But we need to continue our research efforts to expand the population that can benefit from these treatments and extend their efficacy.

The second frontier is detection and prevention of cancer. Our current cancer treatments focus on treating cancer once it has developed and, more often than not, once it has metastasized to other sites in the body.

Ideally you want to catch cancer early on or to prevent it entirely. Today we are seeing tremendous advances in both detection and prevention.

In terms of prevention, we already have one intervention, the HPV vaccine, which can vaccinate girls and boys against contracting HPV, the virus that can lead to the development of cervical cancer in women and oral, penile and anal cancers in men.

Research by Ludwig scientists in Brazil showed that the virus exhibits long-term infection in men, findings that helped secure the recommendation that boys receive the HPV vaccine as well.

We are also seeing tremendous advances in detection. New blood tests allow us to look at DNA in the blood and determine whether and what type of tumor is present, for example. This is another area of research on which Ludwig scientists are focused.

Where can readers find more information?

www.licr.org

About Professor Sir David Lane

Sir David Lane BIG IMAGEProfessor Sir David Lane, an internationally recognized and respected cancer researcher widely known for his discovery of the p53 tumor suppressor protein, is the Scientific Director of the Ludwig Institute for Cancer Research. He leads the Institute’s global cancer research effort, expanding interaction among Ludwig’s network and representing its science and scientists to the broader cancer community.

Professor Lane has directed scientific programs at Imperial College, ICRF Laboratories at Clare Hall and helped to establish the Cancer Research Campaign (CRC) laboratories at the University of Dundee in Dundee, Scotland.

With support from the University of Dundee and CRC, he founded Cyclacel Pharmaceuticals, where he helped to identify several oncology drug candidates currently under clinical development.

Along with his role as the Ludwig Institute’s Scientific Director, Professor Lane holds a dual appointment as the Chief Scientist of Singapore’s Agency for Science, Technology and Research (A*STAR).

His contributions to cancer research have been widely recognized. He was knighted by Queen Elizabeth II in 2000 and most recently received the 2012 Cancer Research UK Lifetime Achievement Prize.

Professor Lane is a member of European Molecular Biology Organization (EMBO) and a Fellow of the Royal Society, the UK’s premier scientific academy. He is the author or co-author of more than 350 publications in international peer-reviewed journals.

Professor Lane earned his PhD degree in immunology from the University College in London. He began his post-doctoral research in the laboratories of the Imperial Cancer Research Fund and the Cold Spring Harbor Laboratory in New York.

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