The quest for improved cancer treatments
Updated: Oct 5, 2022
A/Prof Michael Hay presents an overview of cancer research happening right here in Auckland. From the laboratory bench through to clinical trials, hear directly from a leader in the field.
Watch the video above or read the transcript here.
Advances in Cancer Therapy: Targeting the tumour microenvironment
Thank you very much everybody for coming my name is Michael Hay. I’d like to talk to you about some work that has been ongoing in the Auckland Cancer Society Research Centre and which has been generously supported by Auckland Medical Research Foundation as well so I just would like to start with a brief overview of cancer.
10-year cancer survival rates (1972-2011)
Here is a representation of cancer survival in New Zealand and the rates of cancer survival and you can see that across the many diseases there are very very different circumstances and outcomes.
The point I’d like to make today is that across all cancers from of over a 40-year period from around 1972-ish through the current day the rates of long-term cancer survival over ten years have improved from around one in four to well over fifty percent.
That's a remarkable and steady gain that can be attributable to multiple causes not least of all improved screening and detection, improved treatments, improved follow-up and a wide variety of impacts. I think that's a very positive thing but obviously there's still a lot to do across the whole range of improvements that can be made for patients and for people who are diagnosed with cancer.
Hallmarks of cancer
Our area of expertise is drug development and we are looking at cancer as a disease and across all of those multiple diseases and you can think about almost up to 200 separate diseases which we can identify some commonalities. If I look at this chart and sort of try and break it down for you cancers are typified by a loss of control and that control is around how they receive messages to grow, how they evade the mechanisms that normal cells use to control growth, that they become active and engage in invasion through surrounding tissues and can also move out of the site of origin and metastasize to distant sites.
They become essentially immortal and they have certainly can resist all the signals that would normally tell a cell to die in an appropriate context and they also recruit their own blood supply to create an environment that they can survive in.
There are some more recently defined features that are also typical of many cancers: they deregulate their cellular metabolism to cope with the environment in which they find themselves so often they're finding that because of their rapid growth and because of the poor blood supply they often are short of nutrients.
Cancer is a moving target
They can adapt their metabolism so they're essentially invisible to the immune surveillance that is constantly on in action in our bodies. They are often inflamed and that promotes further malignancy and one of the underlying features is in fact the genomic instability that leads to more mutation and the evolution of cancers. It's a moving target and here is a cartoon that just demonstrates that from a single mutation there will be an evolution that might be as many as 30 generations before a cancer is detectable.
So over this period of time the cancer is growing in a stressful environment adapting to that and changing and it's going to eventually be detected somewhere in this region in the meantime or thereafter it has metastasized and has gone on and will keep growing unless treated in some way.
You can think about this in terms of an evolutionary pressure. The environment drives evolution and that also encourages diversity that can respond to that environment. If we look at this diagram which is just following the time of starting from a single cell with a chromosomal problem or mutation you can see that it acquires more drivers if you like of this cancer. Some of these die out, some of these clades or clones don't survive, and others will survive.
So whilst most of the cancer is represented here from a common ancestor there are other evolutionary groups of cancer cells. so they're not all the same so you have heterogeneous genius genetic background and I think it's best example exemplified if you look at say -- I’m sure many of you have looked into ancestry and tried to do some family tree tracking. if you were to say well do Zara and Prince Harry represent their distant ancestor Queen Victoria you might go well there's a connection but they're quite different people, and they will respond quite differently to their circumstances. I think that's a convenient metaphor to consider the heterogeneity that you'll see within a tumour.
The tumour microenvironment
Also there's this micro environment. cancer cell cancer tumours are not simply groups of cells of all the same evolution. there's cancer cells, there's the normal cells that support this, so endothelial cells, fibroblasts, all sorts of other cells immune cells that are all mixed intimately in this relationship. we try and capture that in this cartoon: it's an environment, it's genetically flexible, it's very disorganized and it's invisible to the immune system.
You can see that because of the poor blood supply and the strong demand for oxygen and nutrients, there will be gradients of these nutrients and there is a term called hypoxia which really just means lack of oxygen. so these cells are under stress and they respond they will respond to that stress and also in terms of drug delivery this is not a particularly well served environment for drugs to move into from the bloodstream.
Understanding Tumours: Cancers as Weeds
I’m sure many of you are gardeners and if you just think about your garden which you've tended carefully and you have all your plants growing appropriately and you've got the irrigation system going. well your tumour microenvironment looks more like this: the irrigation system is broken the weeds are invading and they're growing. you can still see there's somewhere in there there's some roses and there's some other various plants but they're being strangled and lost.
Complex ecology of many types of cells
Carcinoma cells + endothelial cells, fibroblasts, immune cells, + extracellular matrix molecules
Creates environment for tumour growth
Genetically flexible and adaptable
A highly disorganised architecture
Invisible to the immune system
So that is kind of the a good metaphor for what might be happening in the tumour micro environment so this lack of oxygen the tumour hypoxia is a consequence of trying to grow the tumour, and trying to recruit and attract blood vessels to supply it with nutrients. Whereas a normal bloodstream has a distinct architecture that allows for diffusion of oxygen and nutrients the chaotic architecture you can see here and also over here leads to these hypoxic cells. They're all usually at some distance from the blood vessel because sometimes these blood vessels just constrict because of pressure within the tumour or they leak and therefore the flows of oxygen are not particularly good.
You can see here compared to normal tissue where you have this nice architecture where you have an artery leading down through an arterial into a capillary and out to a vein. here we've got all this very lots of dead ends lots of loops lots of short processes that really go nowhere. you can see how inefficient that might be so that is one of the problems of the tumour micro environment that we have spent probably three decades trying to understand and trying to work out what its impact is.
The four pillars of cancer treatment
Certainly when we come and look at the pillars of cancer treatment surgery chemotherapy radiation and now more laterally immunotherapy you can see that in fact the micro-environmental factors the heterogeneity of those tumour cells. the fact that you're in a hypoxic environment which is stressful and it's acting as an evolutionary stress can defeat each of these modalities.
If we think about in terms of which of these are used most often, surgery is in fact the most successful treatment for cancers and it often is because they are discrete they are often very easily accessible. this is followed by radiotherapy again is used very often and chemotherapy less often. more often than not these are all combined into a schedule of treatment but it just gives you some sense of the distribution of therapy with intent to cure.
The data I have here is a little old and it hasn't really taken account of the tremendous impact that immunotherapy is currently making on cancer treatment. Just thinking about some of the various modalities of treatment the new generation of targeted cancer therapies are in fact incredibly precise and they can have some dramatic effects.
You can see here this is a patient who's metastatic melanoma with advanced disease. the cancer is driven predominantly by a mutation in one of one of those oncogenic mutations that drive the cancer growth. You can see treatment with a targeted treatment that stops that particular pathway of growth leads to this remarkable remission and you can see what a tremendous benefit that has achieved in that period of time.
Unfortunately it's the tumour heterogeneity will actually defeat many of these agents. unfortunately and this patient obviously relapses because some elements of that tumour are not responsive to this incredibly precise therapy. You can see that occurring although the treatment does provide an advantage in blue over the standard of care and green most patients are not seeing long-term benefit.
Game changer: Immunotherapy and dramatic recent improvements
There is a subset for whom this treatment is working but again you can see the challenge with just applying that particular targeted therapy immunotherapy is changing the game dramatically.
This cartoon here is just meant to represent the idea that tumour cells do present antigens which could be recognized by the immune surveillance system and detected as foreign and that they then can go on and prime the soldiers if you like who go around and sort out the problems in your body.
These T cells can be activated but there is a very well defined handshake system that stops the T cells running out of control, running amok. So many T-cells find themselves inactivated the use of some of these immune checkpoint blockade inhibitors such as ipilimumab can bind and disrupt that particular handshake and allow another handshake that activates the T cell, allows it to go out throughout the body and identify these particular tumour cells and get rid of them.
Indeed you can see here that in we're looking at again metastatic melanoma and you can see that for patients with advanced disease who are treated with alone there is a proportion of patients that will achieve long-term survival, essentially long-term disease control without symptoms,
When we look at another one of these immune checkpoint inhibitors called Nivolumab which affects a different handshake you can see that there is again significant benefit. And when we combine the two you can see that approximately four in ten patients will achieve a long-term survival
That is a dramatic effect that is a tremendously different effect from five years ago when these there were very few options for these patients. Immunotherapy is a tremendous game changer.
Radiotherapy: a cost-effective treatment
Radiotherapy is also used very widely.
More than half the patients who have cancer will receive radiotherapy and of those the majority will be treated with curative intent either alone or in combination with other modalities of treatment.
Increase in precision drive increases in survival
It has the advantage it can be used across many different tumour types and there are a variety of different technologies that can deliver this. It's also pretty economical in terms of its fraction of the cancer budget it's relatively low so it is a good therapy. It has particular application and indeed much of the advances in the last 20 odd years have been driven by improved technology has given improved treatment responses.
We can see here in 2003 this is for patient data probably from last century but just radiotherapy alone is achieving local region control in head and neck cancer patients. whereas if you add in chemotherapy either afterwards or concurrently you can achieve increasing control and that very much maps to survival as well.
So that is quite effective with 75 odd percent of patients responding positively to the treatment and over the last 20 years the technology has increased the ability to deliver that radiation to the tumour sparing normal tissue which is very important, whether the pancreas, lung, neuroendocrine or other tissue.
In head and neck cancer it has improved dramatically and the survival rates have actually increased as well just incrementally but steadily going upwards so that again is a very positive trend looking forward.
Combination therapy: targeting mechanisms of resistance
Further advances in cancer treatment are going to be driven by combinations of these therapy modalities. You can see in this cartoon the various sorts of classical chemotherapy and genomically targeted or therapies all provide improvement or can or some degree of protection from cancer but are not necessarily long-term solutions.
The real game changer is seen in immune checkpoint therapy.
It really will be a positive outcome for a certain proportion of patients but not all patients and again how do we move the green line up to the red line. We will need to focus on the mechanisms of resistance such as hypoxia and genetic heterogeneity and also the DNA repair mechanisms that lead to these highly mutated diseases that have lost control
Hypoxia as a therapeutic target
So I’d like to now focus on some work that we've been doing over literally three decades in our laboratories trying to use hypoxia as a therapeutic target. It is pretty unique to tumours most other locations in your body are reasonably well oxygenated.
We can see here in thin green, these are areas of hypoxia that we've stained, imaged and they've sort of formed these circles around what are you probably can't see blood vessels in the centre and well oxygenated tissue surrounding them. then as you go out along the periphery you can see this tissue many tumour types have hypoxia but it's very variable .
You can see from these this is a degree of hypoxia across a whole range of different diseases and you can just see the huge variation there but it is a therapeutic target. we can see here some data from Denmark where looking back at patients who received radiotherapy alone and who for whom the tumours could be stratified into being more or less hypoxic. You can see that the least hypoxic tumours or the patients with those less hypoxic tumours fare better than those with hypoxic tumours and that was a consequence of the failure to control the tumour within the radiotherapy field most often times. And again the hypoxia tumours were less controllable and that could be manipulated therapeutically.
You can see here when you separate the two groups of patients and you can treat them with a relatively simple agent nimorazole which works against anaerobic bacteria but like metronidazole you can see that for patients that don't have hypoxic tumours it has no benefit but for those patients for whom their tumours they have a significant hypoxic fraction the nimorazole acts to redeem or to make that radiotherapy more effective.
That has a dramatic effect.
Unfortunately this drug is only licensed for use in Denmark and has been so for the last 15 or so years it is under review in Europe to be included with radiotherapy regimens.
Tumour Selective Drug Delivery
Our take on this is to look at that and go yes we and we have developed drugs that can be used in the same manner and targeting and killing hypoxic cells but is also to look at those hypoxic cells which are treatment resistant is a very specific location, a postal address, to which you can send a drug. This is deactivated, a thing we call a pro drug/prodrug. It's non-toxic, non-effective when it diffuses into the tumour where it's activated by enzymes in the absence of oxygen and releases an active metabolite which could be something like a cytotoxin which goes and kills the cells and surrounding cells.
Tumour Selective Drugs: Hypoxia activated prodrugs
Or it could be one of these exquisitely targeted molecular agents that have been developed more recently and this cartoon just shows you what we're trying to achieve. Over here the blood vessel surrounded by tumour cells and the pro drug diffuses out through into this hypoxic zone, it's activated and then returns back and can kill or inhibit the growth of the surrounding cells.
I just want to showcase some work from two very talented investigators in our laboratories, Associate Professors Adam Patterson and Jeff Smale who've taken a very targeted agent that targets one of those growth signals which is driven through the epidermal growth factor receptor. This is a receptor that sits on the cell wall and has a site outside which then can recognize proteins that can come and stimulate that and set off a signal in cascade.
It has this intracellular domain where it has an active site which the drug has been designed to just fit in there. Here's a better example of how that signalling pathway works so the receptor out here can be bound by a molecule that stimulates this growth pathway and whether through an oversupply of the stimulation or an over-expression of the receptor or a mutation that leaves it permanently on.
This drives growth through this signal pathway. If you inhibit that intracellular domain, you inhibit the function, and you have the signal and the cell which is essentially addicted to the signalling pathway will then certainly stop growing and most probably die.
Here's another cartoon just demonstrating how that might work. You can see that the drug diffuses out of the blood system to these hypoxic cells where it's activated and then it can then start to drag the tumour with the released molecularly targeted inhibitor. it can then diffuse from this zone so we've killed that treatment resistant portion of the tumour. it can also diffuse and start to target more of the cells with it throughout the whole tumour.
You can see here a picture of this again just showing areas of hypoxia that we have been staining within a tumour and you can see that it's not through the whole tissue and here Adam and Jeff have mapped the activation of the drug from the pro drug with the red being the highest concentration. You can see that there it has diffused through much of the tumour from those areas of high concentration now.
Tarloxotinib as it's called has been taken into phase one clinical trial firstly in the USA and also in two sites in Auckland and that's been led in New Zealand by two of the researchers from the Auckland Cancer Society Research Centre, Associate Professor Mike Jameson down in Hamilton and Professor Mark Mckeage in Auckland.
It's also gone on to phase two clinical trials. we're still currently in trial looking at its ability to work with a particular subset of non-small cell lung cancers that are driven by these mutations in that signalling pathway and also in recurrent or metastatic squamous cell carcinomas of the head and neck or of the skin. These studies are currently limited to these types of cancer, but future work may look at cervical, pancreatic or bowel cancers at different stages.
Whilst those are ongoing, what Adam and Jeff have been able to do is to bring it back home to New Zealand and with Dr Andrew McCann from Auckland City Hospital they are hoping next year to start what we call a window of opportunity study to look at the combination of this drug with a form of radiation in head and neck patients prior to them receiving the surgery they would normally receive.
So this gives us the researchers an opportunity to see how the drug works in combination with radiotherapy. It is an active drug and the preliminary analysis of the phase two trials are showing at least some partial responses in patients. This is when it's just given alone and so it is certainly working on mechanism within these patients. You can see the sorts of effects that are being achieved with this patient who has this pleural effusion and tumour mass. After approximately 12 or 12 doses of the drug that has been cleared so this is ongoing research and there's no definitive answers as to the efficacy of the drug at this stage but it is a very positive signal.
Drugs from the ACSRC
I’d just like to – having looked closely at a little bit of research from the centre – step back a little bit and just talk about our centre overall and what we're trying to achieve.
One of the big things that we are trying to do is to impact patients with new cancer therapies. We've had a measure of success over many years and we can go back to Bruce Kane who developed amsacrine in the 1970s and it was finally approved in 1983. That also spun out a series of other DNA binding drugs if we go back far enough of course the structure of DNA had just been described, cancer was really only known of as a disease that was constantly replicating, and DNA was part of that so targeting DNA was the target to choose.
So a flurry of clinical activity from the Centre lead to one approval
We're also looking at immune stimulants and a drug here called DMXAA was worked all the way through to phase three clinical trial in Europe and New Zealand with Novartis but was ultimately unsuccessful. Further work with the DNA binding drug has actually led to a rather novel application where it's used to sterilize blood cells and remove viruses.
There's been a big body of work around these targeted agents--we call them kinase inhibitors that target those signalling pathways I mentioned. And indeed work with Pfizer over several decades has led finally to the registration of one of these agents. It's available in the us but not currently in New Zealand and another agent has been segued sideways into companion animal therapy
We have a very strong TB program which has led to clinical activity; another program with immune stimulants has also been licensed into clinical trial and again we have this strong area where we're targeting hypoxia as a therapy.
Commercialisation of research
I’ve mentioned the progress with tarloxotinib but there is another agent and there is another whole program of work following in behind this with the next generation of agents have we done this and again I’m just trying to sort of point to the fact that it is very challenging to go from preclinical research into clinical research. We've been able to utilise the university’s commercialization arm but we've had to be agile and quick thinking.
We've worked with international charities we've worked with big pharmaceutical companies where we've partnered with them and that's been very much a learning curve. We've taken advantage of their wealth and knowledge and been able to advance our ideas very successfully. We've licensed it out to a range of commercial companies from big pharma such as Novartis to tiny small companies that had been set up around the world and again that has led to successful access to clinical trials.
We've even set up our own start-up companies in New Zealand and then let them head off to overseas taking the drugs with them in an effort to try and raise the money to conduct these trials and I hope today just to convince you that in fact academic laboratories have a very important role to play.
The important role of academic laboratories
Our mission statement is to improve outcomes for cancer patients in New Zealand and globally and we do this by understanding the mechanisms of disease and resistance to treatment. Our job is to try and translate these new ideas into drugs into the clinic and also train the workforce while we're at it and so there's some opportunities that an academic lab has we often have longer time frames. We don't try and compete head to head with the big boys, if you will. There are niches we need to occupy and these ideas aren't necessarily the main thing in front of you.
We've been very productive and perhaps the one thing that's missing is how are we developing drugs in New Zealand for New Zealanders. Inevitably taking our drugs offshore means we lose some of the development approach some of the local flavour and context and also the ability to actually move these into use in New Zealand and that's a big challenge for us.
I’d just like to finish by taking this opportunity to thank the AMRF and to thank you the donors and supporters of the AMRF over I think it's 25 or 26 years. The AMRF has very generously funded a lot of research in our laboratories particularly early career researchers and I think if I add this up and convert it to today's dollars it's over three million dollars’ worth of research has been funded in our centre so we're extremely grateful
I think that we've done a reasonable job in trying to convert that into great things. It's often it's not necessarily the quantum of money: it's the fact that small portions of money can be very effective as glue that holds together bigger programs that we can leverage and take forward to develop drugs which will cost tens of millions of dollars to develop but it is in fact very important glue so thank you very much.
I’d like to thank you for your patience and attendance but also for your generosity and support. Thank you.
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