Functional characterisation of therapeutic targets through comparative pharmacology

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Published: 22 Dec 2015
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Dr Igor Vivanco - Institute Of Cancer Research, London, UK

Dr Vivanco talks to ecancer at the 3rd EurocanPlatform Translational Research Course about how researchers are trying to determine the basic mechanism of how targeted drugs elicit the response they have in cancer cells. He also discusses comparative pharmacology: the detailed comparison and characterization of multiple selective pharmacological agents of a defined target with distinct mechanisms of action.

He describes how they’re currently trying to work on a number of Phase I clinical trials and learn why most trials tend to fail, as well as his work on the response to EGFR inhibitors in EGFR-mutant glioblastoma.

 

3rd EurocanPlatform Translational Research Course

Functional characterisation of therapeutic targets through comparative pharmacology

Dr Igor Vivanco - Institute Of Cancer Research, London, UK


There are two different messages that I want people to take home. One of them is that many times we treat patients with some drugs that have been developed for the treatment of a specific type of cancer and we don’t really understand what these drugs are doing to the tumour cells. We have some level of understanding between the genetics of the cell that can predict the effectiveness of these drugs but we don’t really understand the basic mechanism of how these drugs are eliciting the desired response, in this case the death of the cancer cell. So that’s one of the messages that I want people to take and I’m going to discuss a couple of examples of my previous work that deal with this issue.

The other message that I want them to take home is one that you can use drugs to actually understand function and there are a lot of times that people forget that not every drug is created equal. So we have a number of different drugs that were made to target the same protein and yet they work in different ways. By understanding the differences between these compounds you can actually tease out some of the nuances of how these proteins work. So using these chemical probes could be very, very useful to understand the function of these proteins.

What significance does this have for clinical practice?

I work very closely with the neuro-oncology unit at the Royal Marsden Hospital and one of the things that we’re trying to do is we’re trying to do a number of very small phase I clinical trials and what we try to do there is we try to enrol just a small number of patients but do as much molecular analysis as possible, such that we can understand why a trial fails or why it works. Just historically speaking, probably greater than 90% of all clinical trials are failures and one of the biggest problems and a big waste of money is that we just never bother to learn why the trials fail in the first place. So what we’re trying to do with this approach is just trying to see whether we should change something about the trial that might make it work the next time around or just abandon that specific target and move on and try to find something different. So that’s one of the things that we try to do with the research that we do in my lab.

For a number of years I’ve been interested in targeting the epidermal growth factor receptor in glioblastoma, which is the most aggressive form of primary brain cancer. The reason for going after this particular protein is that it’s deregulated in about half of glioblastomas. So being able to deliver a therapeutic that specifically inactivates this protein would, at least in theory, take care of half of that disease. Now the problem is that this is an obvious thing to do and people have tried to do this for a number of years. Most of the trials that have looked at EGFR, epidermal growth factor receptor, inhibitors have failed. So here’s an example of the work that I did in the past that deals exactly with what I said earlier, that we did a clinical trial with a small number of people and where we measured things like drug concentration in the tumour of these patients that received this treatment, we looked at whether the target was being inactivated and how potently it was being inactivated. Then we did some in vitro studies to try to predict what kinds of concentrations of drug, for example, can make these cells die and see if we’re achieving those levels. What level of targeting activation do we need to achieve to elicit a biological response and are we achieving that level of inactivation in tumours that receive these therapies? So from this exercise one of the things that we learned was, for example, that even though we can get drug into the tumours we don’t get enough drug to suppress the target to the level that we need it in order for the drug to kill cells. So it’s these nuances that a lot of times are critical for the success of a therapeutic drug.

What are the next steps?

Right now we are in the process, this is the big plan, we’re in the process of creating a multi-institutional consortium between the Institute of Cancer Research, the Royal Marsden Hospital, which is already our partner, our clinical partner, St George’s Hospital in London where a lot of the neurosurgeries are done, the National Institute of Neoplastic Diseases in Peru, I’m originally from Peru and so I have links there, and we are negotiating some additional interaction with the Cambridge Cancer Centre. So we want to bring everyone together and bring together different expertise from each one of these institutes and this includes neurosurgery, neuropathology, medical oncology, cancer biology, computational biology, evolutionary cancer biology and then bring all of these expertise. The point of this is to first of all identify new therapeutic targets, evaluate them in vitro and in vivo pre-clinically but very fast then promote these very small phase I clinical trials and do this analysis where we look at why the trial failed. Most likely it will, if it doesn’t great. Then try to see if we can redo the trial in a different way that might give us a better chance of success. This is an iterative process where we take tissue out, we analyse it, we see what went wrong and then we do the trial again. And at the same time we’re continuously looking for additional targets so that’s basically the big plan for the future.

Besides money, what obstacles have you faced?

One of the big obstacles that I’ve been fortunate enough not to face directly yet, but I know that there will be some of these bumps along this road, is that a lot of times it’s very difficult to bring all these different expertise together and have them work together. I was talking to some people, I won’t name the institution, but they were telling me how the medical oncologists have a very hard time working with the neurosurgeons. It sounds silly but it’s a reality, it’s a reality that we have to deal with. As I said, fortunately, up until now at least, we have not had that problem and we’ve been able to bring together all these people and we haven’t seen the emergence of any alpha personalities or anything like that. So I think the project is moving along very smoothly. I can’t predict what other obstacles we might find but that’s the main one, we might have overcome that already.

What will be the eventual benefit of this work?

We might come up with a new therapy for glioblastoma. Glioblastoma is, as I said, the most aggressive form of brain cancer. Right now the prognosis is very poor, the median overall survival of these patients is about 14 months, most of these patients are dead after two years of diagnosis despite aggressive treatment which is a combination of surgery, chemo and radiation therapy. So having the opportunity to provide an alternative to that that might extend the life, even if it’s just for a few months, but with enhanced quality of life, that’s the goal right now.

What is your take home message?

Sometimes people get discouraged because of all the money issues that you say we shouldn’t talk about but they exist. We just need to keep doing it, first of all, and the other thing is we need to work together. It sounds like a cliché but it’s very real. Team science is a big message at our institution and the world is globally moving in that direction, there’s a lot of these big consortia, big groups. That’s the way to deal with these problems which are massive. The individual labs are no longer able to deal with all the aspects of such a complicated disease.