WIN Symposium 2013
Battling therapeutic resistance
Dr Gerald Batist - McGill University, Montreal, Canada
My name is Gerald Batist, I’m Professor of Oncology at McGill University and the Director of the Segal Cancer Center as well as the McGill Center for Translational Research in Cancer.
Which, as you were just saying, has developed… can you give us a little background?
Yes, this was sort of what we have now, it began really in the university trying to focus on how we can translate fundamental things from the laboratory, discoveries from the laboratory, into things that would be clinically meaningful. Of course it attracted a lot of clinician scientists like myself who work in laboratories and at the same time take care of patients and do clinical research. It evolved over the years and got stronger and we started to realise that we needed to touch more people and reach out to the clinicians themselves and all of their patients. So we developed a network around that, first around the centre we developed a cancer centre called the Segal Cancer Center and then a network around Quebec which involves many, many centres. Our particular focus is on what, in fact, kills the majority of patients who die of cancer and that is therapeutic resistance. Tumours become resistant to treatment, even if they have spectacular responses once they have metastatic disease the tumour inevitably comes back. So we’ve developed a series, we’ve developed expertise in the course of doing a series of studies of the treatment of metastatic tumours where we biopsy at the initiation of treatment and then when the patients become clinically resistant. We’re doing molecular analyses of the tumours after versus before in order to understand mechanisms of resistance with the aim of prolonging the benefits of treatment.
But at the same time we’re starting to… we can help at all to understand that these are new targets, mechanisms of resistance, and we’re understanding a little bit more about how tumours grow and the various pathways waiting in the wings to be activated for a tumour to overcome therapy. And we’re learning things about heterogeneity, so some tumours in the same organ, some nodules will grow and some will shrink. So all of that is becoming the biological quest that we’re working on. And now we’re expanding that to try to bank as many, include as many patients as possible so we can really understand. And to have as many patients profiled in this sense so that we can find eligible patients for these very small subgroups of patients. In general now our thinking is evolving to the point where it’s quite provocative, I would say, but increasingly in favour and that is that randomised clinical trials of unselected patients don’t make any sense to us anymore. In fact, I would say that it’s not an appropriate default, the status quo is not ethically acceptable. For decades we’ve treated patients often with toxic treatment, certainly with expensive treatments, knowing that the majority of them will not benefit. And we haven’t even done the science to find the minority that do benefit and be able to identify them again. So we won’t do that anymore and we’re working with one of the WINTHER centres to really try to focus on each patient. We know what makes tumours respond, it’s an effective drug. We don’t need multi- hundreds or thousands of patients to see a real benefit. And we’ve been talking a lot with pharma, with our regulatory agency in Canada, mostly with patient advocates who really have the largest voice, strongest voice, in the room, to change the rules and think of ways of doing this in a much more accelerated way.
You talked about heterogeneity and resistance, is the resistance due to the tumour evolving, changing its mutations when it becomes a metastasis?
It’s a biological question that hasn’t been answered. Are we selecting, just killing a population that’s sensitive to what we’re using and therefore selecting out tumours that were already there before that are resistant or is it actually a modification in the tumour? Probably both are happening. But I think this takes us to the next level of genomic directed therapies. All of the studies worldwide have been one genomic variation, one drug, often out of context; just because a BRAF mutation in melanoma responds to a BRAF inhibitor in melanoma doesn’t mean it does, even the same mutation doesn’t respond in colorectal cancer and indeed it doesn’t and we understand why. Now the reason it doesn’t often in cancer is exactly the same mechanism why ultimately in melanoma the tumours relapse, so acquired resistance is often the same as or analogous to the same pathway or a similar mechanism to intrinsic resistance. So that’s our focus, really, to understand how we might combine things to anticipate resistance, combine drugs or give them in sequence or cycle them. But I think we’re early days in that.
One of the things the clinical oncologist now has to become more familiar with the basic science and targeted therapies. Has your centre helped to allow this communication between the basics?
In fact the word translational research is really quite important because it’s a word about language, really, translation. We have thought a lot about it and found ourselves over the years scratching our heads trying to help these two camps understand one another, fundamental scientists and clinicians. Our environment is very healthy in that regard and it helps a lot. But as we’re getting into now molecular medicine the configuration of the therapeutic team is changing as well. We need interventional radiologists, we need them to be able to biopsy in a certain way and we’ve discovered that an interventional radiologist in one hospital is the best person to teach his same kind, if you will, in another hospital. I can’t instruct another radiologist in how to do a biopsy, but there are different kinds of biopsies. Likewise we need a molecular pathologist to look at a specimen and tell us about the quality content of tumour. So the entire process of the team composition, therapeutic team, tumour boards now have to involve molecular information. So we all have to evolve along with the science, absolutely.
You have recently published, or it will be published shortly, a paper in Nature on biopsy driven…
It’s in Nature Reviews in Clinical Oncology and it’s a discussion and a review of all of these different aspects that are involved; the challenges and some suggestions in resolving the evolution of the entire system to be able to do this in an appropriate way. And the challenges are ethical as well, asking people for biopsies of their tumours, even if the biopsy is not going to guide therapy but if you’re looking, say, for mechanisms of resistance. We have studied this and discovered that the patients all will go along with it; the real problem is their physicians, they’re a little bit stuck in the past. So we are identifying the obstructions and the way forward and the paper describes the sort of panoply of challenges that are involved and how we’ve tried to deal with some of them.
