New Targets for Cancer Drugs

06 November 2011

Interview with

Madhusudan Srinivasan, University of Nottingham

Kat -   I'm joined by Madhusudan Srinivasan.  He's Clinical Associate Professor in Medical Oncology at the University of Nottingham and he'll be presenting a paper at the NCRI Conference this week about a new target for cancer drugs, and that's blocking the DNA repair mechanism.  Good evening.  Thanks for coming on the show.

Madhusudan -   Thanks, Kat.

Kat -   So let's start by going a bit back to basics, why do cells need to repair damage to their DNA?  How do they get damaged and why do they repair?

Madhusudan -   Well that's a very important question, Kat.  If you look at aDNA Helix normal cell, we all know DNA is the building block of life.  Sequencing the DNA makes genes.  Genes make proteins, but the problem is, in normal cells, the cells are constantly producing damaging agents.  These are called oxygen free radicals.  These free radicals can actually damage the DNA.  If they damage their DNA, the genes can get corrupted and that can make abnormal proteins.  In order to avoid this situation, what normal cells do is they're constantly scanning the DNA.  We call this scanning the genome to maintain stability of the DNA and DNA repair pathways are critical for maintaining this genomic stability.

Kat -   So there's damage to DNA created by just the processes going on in cells, but presumably also from other things like cigarette smoke or ultraviolet light from the sun, things that we know damage DNA and cause cancer.

Madhusudan -   Absolutely, right.  So what I spoke to you about was endogenous DNA damaging agents and you have exogenous DNA damaging agents, and the most important ones are environmental agents - smoking is a main culprit.  There are environmental toxins such as lead, industrial toxins.  Now these hydrocarbons as we call them can actually directly damage DNA.  And when the damage to DNA happens, the bases get corrupted and that leads to what's called mutations and it is the mutations that drive the cancerous phenotype.

Kat -   So we've got this DNA repair going on, that when we get damaged then we can get cancer.  But also, what's gone wrong with the DNA repair in cancer cells because DNA repair is also a bit messed up in some types of cancer, isn't it?

Madhusudan -   That's right.  In fact, the relationship between DNA repair and cancer is quite complex.  On the one hand, suboptimal DNA repair can actually increase the risk of cancer.  It can lead to a cancerous phenotype.  On the other hand, certain tumours actually upregulate DNA repair and when they upregulate DNA repair, what they do is it gives them a selective survival advantage and it also makes them resistant to certain treatments that we use in the clinic.

Kat -   So things like radiotherapy that damage DNA and cancer cells and make them die, they would become resistant to that kind of treatment?

Madhusudan -   That's correct.  It's radiation therapy and also, several chemotherapeutic agents that we use in the clinic.

Kat -   So, some of the drugs that you would treat them, they actually become resistant because they're repairing the damage that's being aimed at them to kill them.

Madhusudan -   Absolutely, right.  Yeah.

Kat -   So, talk a little bit about your research.  So you're studying a particular repair pathway in cancer cells and in healthy cells as well.  Tell me a little bit about that and what's going on with that.

Madhusudan -   Okay, so mammalian cells that's human cancer cells have several DNA repair pathways.  We know there are at least 6 different DNA repair pathways in man.  One of the DNA repair  in that is called base excision repair and this particular pathway is absolutely essential for maintaining the correct bases in your DNA.

Kat -   So the letters. The specific letters of the instructions.

Madhusudan -   Absolutely.  So they are absolutely essential to maintain the letter, keep the script going.  Okay, so that's the base excision repair.  Now this base excision repair was discovered about 20 to 30 years ago and over the last decade or so, we know a lot about base excision repair - what are proteins involved in based excision repair, how the process is coordinated.  One of the proteins that my lab has focused on is a protein called human AP endonuclease.   It's also called APE1.  This particular protein is very essential for base excision repair and the work in our laboratory, which has been going on for the past five to six years, is trying to understand what this protein does in normal cells, what this protein does in cancer cells, and how can we exploit them for cancer treatment in patients.

Kat -   So here at the conference, you're presenting some really exciting data where you've been trying to block this particular protein that's involved in this DNA repair and what do you see when you block this?

Madhusudan -   What we are trying to do in the laboratory is first understand what's happening to this particular protein in tumours and what we see is APE1 is frequently over expressed in tumours.

Kat -   So it's working too hard.

Madhusudan -   And also, the tumour cells are over expressing it so that they can try and circumvent other damages and continue to survive and lead to resistance to treatments.  So that's one thing that we've understood from studies in human tumours.  Then what we've gone on to do is, now that we know that this protein is very essential for cancer cells, we've actually established a drug discovery program to try and block this particular protein.  So we isolated what's called a small molecule inhibitors of APE1.

Kat -   These are little tiny drugs.

Madhusudan -   Little tiny drugs, compounds to be precise that block the functioning of APE1.  The next stage in our research has been to try and exploit novel treatment strategies to try and define which group of patients would actually benefit from APE1 inhibitors.  And that's what we are presenting tomorrow and I'm really excited about that because this new field in cancer called stratified medicine and personalised cancer medicine, where we can actually look at tumour biology and then tell our patients in the clinic that this is the treatment that you're going to have. 

Kat, one of the problems that I face in the clinic when I see a patient is, before I start the treatment, there is no way in which I could know whether chemotherapy is going to work or radiotherapy is going to work or not.  For the first time in the last three years, we actually have tools where we can actually predict who might be able to respond to treatment, and who may not be able to respond to treatment.  This is in its very early phase and over the next 5 to 10 years, we are going to see a huge explosion in this personalised cancer treatment.  And the research that we are presenting tomorrow is exactly in personalised cancer treatment approach where looking at tumour biology, we can actually target our APE1 inhibitors for treatment.

Kat -   So what particular types of patients or types of cancers might these drugs be suitable for?

Madhusudan -   So when you look at personalised cancer treatment, we believe that APE1 inhibitors are particularly going to be beneficial in breast cancer, in ovarian cancer, in pancreatic cancers.  A proportion of these tumours, up to 10 to 20% of these tumours, are deficient in a particular gene called the BRCA genes.  And what we know is, if we can identify those tumours, studies in our laboratories have suggested that APE1 inhibitors are likely to be particularly sensitive to those tumours.

Kat -   So you could do a test for a person with that type of cancer and say, "Okay, you have a fault in this BRCA gene and then you might benefit from this type of therapy."  How close are we to actually testing these drugs in clinical trials?

Madhusudan -   That's a very, very important question and as you know, drug discovery is a long drawn expensive process and the stage we are at the moment is what's called a hit to lead conversion.

Kat -   So it's very early still.

Madhusudan -   It's very early, but potentially very exciting.  So, I think our medium term to long term strategy is usually get a pharmaceutical partner and try and drive this research program for patient benefit.

Kat -   So at the moment this is just still in the lab.  You're trying to find the best kind of things to take forward to develop into a drug.

Madhusudan -   We're fine-tuning the structures of the compounds so that we can decide which one to take forward, so you're quite right.

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