The Hallmarks of Cancer: implications for cancer

(applause) – Well, good morning, well, thank you It’s really a great honor to be here to kick off this conference It was an inspirational beginning and then, I guess, we’re starting off to look at the big picture before we drill down into the intricacies and complexities and frustrations of individual forms of human cancer And I guess, I’m trusting that maybe all of you haven’t read the reviews that were just described ’cause otherwise, I shouldn’t be giving this talk, but I’m gonna summarize for those of you have not or are not intimately familiar with this concept The concept and then talk about, well, why does this matter? Why might it matter? Why might it be important for cancer medicine? Okay, so, hang on, how does the pointer work? Oh, I see, okay Okay, so yeah, so I want to, basically, start with just the notion, which you’re so familiar with, of the conundrum of cancer, which is really, this is not one disease, it’s hundreds of diseases of tumor types and subtypes I’m having trouble here (laughing) This is why I wanted to use my computer, (laughing) okay – See it – Pardon me? – You could use the screen down there to see what you’re speaking to – Oh, okay, yeah – But you’ll need to be at the microphone – Okay, yeah, so I can’t see the screens here, all right So anyway, basically, cancer’s a disease of incredible complexity at all levels, genetic, histological, pathological, prognostic, therapeutic and so this is really daunting for those of you who suffer from cancer or treat cancer and then the question arose of whether we can rationalize this complexity or their common principles underlying this daunting diversity And so the notion is and the hypothesis upon which this concept is based, is really the disparate cancers share fundamental qualities and that this daunting complexity really reflects the fact that cancer cells have to overcome multiple checks and barriers that are embedded in our bodies to prevent the aberrant proliferation of cells And so the notion is that in different tissues, there are roadblocks and barriers that are used by the organism to prevent expansive cell proliferation, unauthorized proliferation, but that these barriers vary from organ to organ, depending on the purpose of that organ and whether it has cells itself, for you, or not And so that led to this concept, The Hallmarks of Cancer, which, again, we published And this is the schematic of it that there’s a series of acquired capabilities that collectively enable the development of this aberrant organ, an outlaw organ, which we call tumors or cancer So what are the hallmarks of cancer? Well, essentially, we define these as acquired functional capabilities that allow tumors to do things that collectively enable their proliferation So their active capabilities, they do things that normal cells should not, but, typically, they do them chronically rather than as carefully orchestrated actions ’cause, again, cancer cells are not inventors, what they do is corrupt and co-opt normal processes and functions of cells in our bodies And so I’m gonna walk you through what we think are arguably some distinctive capabilities, it’s like disassembling an automobile engine, that there are differing parts to that engine that enable it to function And so we look at tumors very much in the same way And so the first hallmark is really embedded in the whole fundamental basis of a proliferative disease and that’s the capability to sustain proliferation, or the signals that drive cells to divide continuously And much like with an automobile engine, driving a car, not only is there an accelerator to move things forward, but there are a series of cellular brakes or barriers

that normally limit proliferation and we call these growth suppressors And essentially, what we see in successful tumors, is that they evade these suppressors, these capabilities that are normally supposed to stop cell proliferation Now, the third hallmark is another one, it’s a so-called form of assisted cell suicide, that there are triggers in all cells that will cause them to die if they’re so instructed In particular, if they show signs of aberrancy or dysfunction and there’s been a lot of historic work done here at WEHI in studying the role of cell death and evading cell death in cancer and it’s actually led to new therapy Venetoclax, which is really historic development And what we know is that cells, by varying mechanisms, learn how to resist this protective mechanism of program cell death and there are many manifestations of it, many mechanisms, but it seems to be a general principle that most cancers, most cancer cells and most tumors have found a way to evade this protective mechanism of program cell death Now, another check and balance is embedded in our chromosomes, which are linear and every time a cell divides, the chromosomes get a little shorter because of the nature by which the DNA is copied And a million organisms have created a system for counting the number of cell divisions that have been undergone And after a certain number of those cell divisions has passed, the cells cease to be able to continue growing And the most common mechanism for this is, again, triggering cell death or the cessation of cell proliferation, but cancers learn how to evade this by turning on a mechanism that’s used in germ cells and in stem cells of the body to preserve the end of telomeres to allow a replicative immortality in stem cells And this is an enzyme called telomerase And so most tumors evade this barrier to continuing proliferation by turning on telomerase or another mechanism that allows them to have replicative immortality And so these are, I think you can appreciate, are each distinctive characteristics from one another that collectively allow cells to proliferate indefinitely The fifth hallmark takes us outside of the cancer cell itself because these cells arise in organs and what we appreciate and John mentioned this, is that tumors, also, to grow, need to have access to a blood vasculature, as do all cells and all tissues of our body And as a tumor mass grows, it’ll run out of its ability to receive oxygen and nutrients from distant blood vessels, which actually will cause them to die unless they develop access to a vasculature So this is the notion, the most prominent mechanism of this is to induce angiogenesis It’s a normal physiological mechanism, normally it’s transient, tumors turn it on and keep it on So the notion of inducing angiogenesis or are acquiring access to vessels through other mechanisms, so as to be able to be supplied with oxygen and nutrients, but we generically call this the induction of angiogenesis The sixth hallmark is the one that underlies most of cancer lethality It’s the most perplexing, the most complex biologically and that’s the ability to activate invasion and metastasis because if tumors were just lumps of cells, it would be very easy to surgically excised them, but when they become invasive and migratory, then, as you can appreciate, it’s very hard to seek them out And then again, this mechanism has many manifestations, the teleology of it is less obvious, the ones I just described to you, it’s obvious that if you’re a cancer, you’re a proliferate disease, you have to have signals to proliferate, you have to avoid the brakes, avoid cell death,

get access to oxygen, but why do you wanna become invasive and metastatic? Well, for one thing, we think that this also is another way of getting access to vasculature, that you can both induce new blood vessels, but you can also invade and co-opt normal tissue vessels, either locally or in distant sites, if you have this migratory capability, but it’s still a perplexing capability The seventh hallmark, when we first wrote this in 2000, this was an emerging concept, but in this preceding decade became clear that the other thing that cancer cells do is change their metabolism, the way acquire energy and utilize energy because their goal is to really assemble all the building blocks to produce a new cell And so they corrupt and reprogram cellular energetics and metabolism to favor the expansive growth of cancer cells Another fascinating area And again, we think this is basically, again, a separable capability from the ones that I’ve just described And then the eighth is really one that, it was already been mentioned because it’s a foundation of a whole new pillar of cancer therapy and that is that we now appreciate that cancer cells learn how to evade immune destruction and that varying times during the development of tumors and differing organs, the immune system becomes aware of and attempts to attack incipient cancers, but the other cancer cells develop a number of mechanisms to evade immune destruction And so again, this is a really discrete capability of staying under the radar of this whole immune system, which is supposed to help protect the organism And so what we see in different tumors are, again, through different mechanisms, different strategies, is that they have acquired the ability to fly under the radar of the immune system So basically, I hope you can realize are really distinctive qualities and so when we think, for many cancers, that these are all contributing to the manifestation of the disease and so that’s the hypothesis that these eight hallmarks are sufficient to generate a lethal cancer And so an ancillary question is, well, how are these cancers acquired? And there are at least two, what we defined as enabling characteristics that contribute to the acquisition of these eight capabilities And the one that’s been evident for decades is a genome instability in mutation that our cells have, obviously, DNA of the chromosomes which instructs their behavior and what we see in cancer cells is that the reason they’re so insidious is that they lose their genomic integrity, they become mutable and adaptable And one of the reasons that they resist therapy is that they can change, they can change in a form of darwinian evolution, that if they’re subjected to a selective pressure, either from the attempts of the organism to attack it or from drugs, they can mutate and adapt to become resistant to enable their proliferation And this has been evident now and it’s clear with the whole world now of the ability to sequence the entirety of the human genome that we can audit in great depth the alterations that happen in the human genome, in the context of tumor development, tumor progression and adaptation to therapy And indeed, we think that this instability in mutational alterations is one of the mechanisms that produces these eight hallmarks The other one, really came into focus, again, in the last decade or so And that is the notion of tumor promoting inflammation Now, I just suggested that the immune system was attempting to protect the organism against cancer by attacking tumors, but we now appreciate that there’s another branch of the immune system, the so-called innate immune system, that’s, for example, involved in wound healing, that actually insidiously contributes to tumor growth and progression And the reason for this is an old saying of observation

made by surgeons and that is that tumors are wounds that don’t heal And so wound healing involves many of the hallmarks I just described, and during wound healing, there is transitory proliferation, there’s transitory invasion, there’s transitory angiogenesis, key point, it’s transitory So in a wound if it’s proper wound healing, these processes, these hallmarks are transitorily induced and then switched off, but what we see in tumors is that cells of the wound healing innate immune system populate tumors and contribute to a variety of these hallmarks So these seem to be two major mechanism, mutation and inflammation are two ways in which developing tumors acquire these capabilities And that really leads in to another concept, is that even though we talk a lot about the cancer cells and tumors, the historical reductionist view is that all we need to be concerned about is these mutant cancer cells that are populating a tumor, but the reality is, the tumors are not bags of cancer cells, they’re really outlaw organs and that there’s a heterotypic collection of cells that are really contributing to the manifestation of the disease And so, obviously, the foundation of cancer, the reason that it’s so hard to treat, of course, are the cancer cells that are mutated and, therefore, have evaded a lot of these checks and balances and, therefore, are very, very hard to eradicate, but in addition to that, there’s populations of stem cells, which, again, help to sustain disease, even in the face of effective therapies, but beyond the cancer cells, there’s a series of normal cells that are recruited into the tumor to contribute to it And one of them is obvious from what I just described, are the endothelial cells that form the tumor vasculature and produce the blood supply that helps feed the growing tumor There’s also a support cell called a pericyte that helps maintain the functionality of the vasculature so it actually allows blood flow and oxygen and glucose to get to these cancer cells There’s also a series of fibroblastic cells called cancer associated fibroblast, which were once thought to be benign, but are now appreciated to, again, contribute to a number of the acquired capabilities that I just described And then there are these tumor promoting inflammatory cells of the innate immune system, that are normally involved in infection-fighting and wound healing, but which are variably contributing to hallmark capabilities And so basically, multiple normal cell types are recruited to become components of tumors and they help to provide these hallmark capabilities And indeed, of the eight hallmarks that I’ve showed you, there’s data in differing tumor types, not necessarily general, but there’s data in a variety of experimental systems that suggests that at some point during the ontogeny of a tumor from its inception to its full-blown malignancy, these heterotypic cells, the angiogenic vascular cells, cancer associated fibroblast and tumor promoting inflammatory cells can demonstrably contribute to all of the hallmark capabilities, except for this one of enabling replicative immortality So really important take-home lesson here is that it’s not just the cancer cells, but rather this is really an outlaw organ where these normal cells have been recruited and contribute to the manifestation of the disease So basically, yeah, this was a collaboration with Bob Weinberg, professor at MIT, its inception actually happened many years ago in Hawaii So that’s the concept and as mentioned, it’s a tad a surprising resonance When we first started talking about this, we thought, “Well, this is kind of interesting “and maybe we should try to publish it,” but we really didn’t have any vision that this was gonna resonate through time So it’s really been a remarkable response to what we thought was an interesting thought that we should put up as a trial balloon So what I wanna do now, given the breadth of this conference, is talk a little bit about the applications to cancer medicine because, so this is an interesting concept and okay, but the question is really, is this applicable

to the goal of more effectively treating human cancer? And I’ll tell you at the onset, this is a work in progress and there is no answer, but I wanna lay out the proposition that maybe this concept could be applicable to more effectively treating human cancer because what is interesting is that all of these capabilities and the enabling characteristics of which there are 10 and some, have been targeted with so-called targeted therapies And so we have an armamentarium of drugs that target each of these hallmarks And so that’s come about through both academic and pharmaceutical research So this is quite interesting, these are just examples here, but there’s a broad spectrum of drugs that are known now to target one or another of these of these hallmarks And so then, if the hallmarks are important and we have hallmark targeting drugs, well, why aren’t things working better than they are? So here’s an instructive example, one that’s known to many of you, so what happens when we target the proliferative hallmark and in this case, in metastatic melanoma? Because about half of melanomas have a mutation in a gene called BRAF, which drives proliferative signaling and there are drugs that have been developed that target both this BRAF oncogene, as well as downstream effectors of the signal that it transmits And so, for example, there are therapies now, as many of you know, for treating metastatic melanoma that involve inhibitors, or kinase inhibitors, of this BRAF oncogene that are used with and without a downstream effector, called MEK And metastatic melanoma, 10 years ago, I mean, was an invariably fatal disease I mean, in general, metastatic disease is very, very challenging to treat This class of drugs has the kind of responses that you would dream about as a patient or as a cancer doctor because here’s an image of a metastatic melanoma Oh, there I see some normal organs here, so radiographic different images of metastatic melanoma And when you treat with this drug, you melt away metastatic disease So again, this is a poster child for really what we want to see and what we dream about for cancer drugs, something that would melt away metastatic disease, this happens in a couple weeks in this particular patient And so this is really, really exciting, but the reality check is six months later, metastatic disease is back and it’s even more aggressive And so this really, I think crystallizes the point I was making earlier about the adaptability, the Darwinian evolution of cancer cells, that even though you eradicate 99% of those metastatic melanoma cells, there are stem cells, there are cells that evade, by one way or other, this drug and adapt and come back with a vengeance So this is the challenge that we face So the reality check is that targeting single hallmarks is often transitory followed by adaptive resistance and relapse And now, as many of you appreciate, it’s already been alluded to, there are now the immunotherapies that are targeting this acquired capability to evade immune destruction And one of those are so-called checkpoint inhibitors and those are producing dramatic responses and arguably cures in a subset of patients with metastatic melanoma, but it’s not curing all of them and in some cases, the disease is coming back So we have, even with immunotherapy, we have the reality that the adaptability of these cells is such that if you hit them with one target, if they can find a way around it, they will So that then leads to the thought, “Well, okay, well, “but we’ve got all this armamentarium, “so why don’t we just treat them all simultaneously?” But the problem is that this is gonna be too toxic and we’ve already got major issues with toxicity with many of these drugs So the thought that I’d like to raise is the notion of taking more of a battle space plan,

if you think about the way the evolution of conventional warfare, we no longer stand in long lines and march toward each other across the playing field, but rather you attack in very sophisticated ways, by air, by land and by sea And so I think that a future of cancer research is gonna be similarly sophisticated attacks on tumors, that attack different capabilities and differing sequences to outsmart the tumor And so, for example, you could imagine a future cancer therapy for melanoma where you treat with immunomodulators, for example, checkpoint inhibitors, perhaps you take out this tumor promoting inflammation, which parenthetically can also suppress the immune cells that kill tumors, the cytotoxic T cells, but then you could switch to drugs that target proliferative signaling or cell death, so that if you start hitting the tumor in so many ways, from so many different directions, maybe its ability to adapt will be limited because it just can’t deal with altering itself to become resistant to so many differing disruptions of the cancer machine And so I could envision a future where you would really have complex sequencing regimens, or along with early detection, identification of incipient adaptive resistance ’cause, again, the other thing we really need, through liquid biopsies, through better imaging, is the ability to see a recurrence before it’s symptomatic because then if you treat it with something, immunotherapy and you see that it’s starting to fail, you could come in with another treatment targeting proliferative signaling or targeting angiogenesis and metastasis And then if you see incipient resistance developing, you could switch back to something else And so I think this is an interesting concept for the future, of producing a series of treatments that perhaps can keep cancer at check or if not eliminating it And so I’ll just take you now, so the question is is there any testing of this hypothesis? So there’s now some clinical studies that are starting to come out in regard to this and I’m just gonna summarize these, they’re not definitive, but I will just summarize those, just as a clue into whether this hypothesis has any merit And so I’ve already mentioned that in metastatic melanoma that these oncogene driver inhibitors, the BRAF inhibitors, are clinically approved and have transitory efficacy, anti-PD-1, this checkpoint inhibitor, a Nobel Prize winning work It also has activity, in fact, dramatic activity in some patients, but it doesn’t work in all patients and it doesn’t last forever in all patients And so what about combining them? And so, for example, there was a recent publication that described the combination of these oncogenic signaling inhibitors with a checkpoint inhibitor and BRAF mutant melanoma And on stage, I’m not gonna show you the data, but basically, so they conclude that this drug has numerically longer progression-free survival and duration of response, but with a higher rate of adverse events, i.e. toxicity, suggest that it’s worth pursuing this combination So that’s one example, here’s another one that actually combines anti-angiogenic therapy with immune activating therapy And there’s a couple examples of this, again, a checkpoint inhibitor and angiogenesis inhibitor and this is in renal cell cancer and this combination had significantly longer overall survival and progression-free survival and a higher objective response rate than treatment with the clinically approved drugs submitted by itself So this, again, suggesting the combination is having benefit Here’s a second study, came out of Lancet Oncology, again, angiogenesis inhibitor combined with a checkpoint inhibitor, with endometrial cancer and, again, an objective response in a proportion of patients So these are all suggesting some combinations And here’s another one that targets, basically, conventional chemotherapy, which really hits activate cell death and actually causes can accentuate mutational instability, combining that with checkpoint inhibitors and this is a non-small-cell lung cancer And again, if you added the checkpoint inhibitor

onto standard chemotherapy, there was significantly longer overall survival So these are clues into the potential of combinations that are targeting these discrete hallmarks, but I have to say, the reality check is that these are clues, but they’re far from exciting I mean, they’re not transformative improvements in response and survival I mean, these were incremental improvements, but maybe they’re a first step And so I think, at this point, it’s encouraging, but I think that we’re still gonna have to think more about not only just combinations of drugs, but rather sequences of switching from one combination or targeting strategy to another, from immunotherapy to oncogenic drivers, to angiogenesis and metastasis, invasion of metastasis and so on, that I don’t think that these simple combinations that are being tested now are gonna be sufficient But that, again, is something for you all to think about, but really my goal here is to raise this notion that this may be part of our future if we’re really gonna make advances against some of these intractable cancers Now, and as you’ve appreciated, the Nobel Prize winning discovery of these checkpoint inhibitors, of CTLA-4 and PD-1, PD-L1, have really transformed oncology and they’re being tested in every form of human cancer They work well on about half of melanoma patients, 20% of lung cancer patients and we’ll hear, I think, a whole session on this later in the meeting and some real updates on what’s going on, but so there’s a lot of excitement about this, but as I mentioned, it’s not working for everybody And so now, the notion is, above and beyond the one I showed you, is that checkpoint inhibitors are being combined with drugs that target all of these other hallmarks And basically, there’s over 1,000 clinical trials going on with checkpoint inhibitors at the moment There’s a dozen or so checkpoint inhibitors that are clinically approved or in late clinical stage development and they’re being tested I mean, this, of course, is unreadable, but it’s, basically, just to make the point, they’re being tested in virtually every form of human cancer and in combination with almost every drug you can imagine And a lot of this is not logical, I have to say, I think it’s more just, “Why don’t we try this?” Or, “Why don’t we try that?” But I would hope that there will become to be a logic in the way that some of these things are combined And this was just another restatement of this, of just the drugs that are combinations, that are using checkpoint inhibitors, targeting proliferative signaling, tumor promoting inflammation, angiogenesis invasion of metastasis So this will be interesting as these play out, that in certain forms of human cancer, perhaps there will be instructive combinations, but I the next era is still going to be back to the notion of sequencing and layering, but I think that, right now, the jury’s out, but I just leave this for you all to think about, that maybe there will be transformative benefit if we do it in more sophisticated ways as we develop the knowledge and the capabilities to do that So I think there’s hope and time will tell, but at this point, this is an interesting possibility for you all to consider Now, I’ll just say a couple things in closing, just because, as John mentioned, 10 years ago, I moved from San Francisco to Lausanne and one of the reasons I moved there was a notion of trying to create, from the ground up, a new cancer center that would be innovative and really try to tackle some of these issues And so basically, we’re building a new multi-institutional cancer center based in Lausanne and Geneva So very similar, I think, to the VCCC, that involves multiple institutions In particular, we’ve got institutions with complementary expertise We’ve got a couple university hospitals in Lausanne and Geneva, along with their partner home universities that involve medical and clinical research, a big oncology service, major focus on immuno-oncology and a precision, or personalized, oncology network that spans Western Switzerland, so the doctors and community hospitals and private clinics can have their patients analyzed and be advised about the latest potential treatments

for a particular disease and for the particular characteristics of that patient’s tumor because we’re now appreciating that with that armamentarium of drugs I described, that if you know that your patient has a particular mutation in a gene that’s targetable, a so-called actionable mutation, then that could be used to treat that patient, but again, out in the community hospitals, that’s maybe not so obvious And so I think it’s probably something you’re all talking about as well, is the notion that in addition to the elite cancer centers, here and and and around the world, that we need to get the knowledge about how to best treat these patients out into the community So that’s going on, now, my institution, EPFL, Science and Technology, so we have a cancer research institute, but also, really cutting-edge bioengineering in alliance with the Ludwig Institute in immune engineering We’ve got a new branch of the Ludwig Institute that was previously and as you know, has had a major history in Melbourne We have a new branch of Lausanne that’s focusing on cancer immunotherapy research And we got a big focus on, as well, in bioinformatics, which is crucial to deal with all the big data that’s being generated in cancer Now, one of the things that I inspired was the construction of a new research building, it’s called the AGORA, it’s a Translational Cancer Research Building, which we think is gonna be the flagship of our multi-distributed, much like yours, distributed cancer center This is the building, it’s across the street from the cancer clinics And the idea is is to have thematic programs in the building where we bring together people who normally live on different campuses, on different floors, into proximity where they’ll be bumping into each other in real time And so we’ve got clinicians side by side with immuno bioengineers, geneticist, molecular biologist, radio biologists and bioinformaticians And the thought is that this proximity and thematic focus will, hopefully, expedite the development of new therapeutic strategies So that is, I think, again, something that, I’m excited to hear about what you’re all doing here, we’re excited about what we’re trying to do and make a difference as well And now, I was, again, asked to give a big picture talk and so I’m not really giving you a science talk today, but I would just end with two slides to saying that I’m also pretty excited about the science that my lab is doing I gave a talk, actually, on our unpublished work on glioblastoma at WEHI on Friday, but in addition, we’ve been working now, for some years, on an autocrine paracrine signaling pathway that drives invasion and metastasis And basically, this involves activation by secreted glutamate ligand of the neuronal NMDA receptor, which normally is involved in synaptic transmission So in neurons, basically, glutamate is released from presynaptic neurons and it stimulates the NMDA receptor on post-synaptic neurons to transmit the signal And there’s this protein that John mentioned called GCAP, which is an adaptor protein that contributes to that signal transmission And what we found is that a number of cancers hijack this signaling circuit to drive invasion and metastasis And so basically, we published, over in 2003 and 2008, two papers that describe the activation of the signaling pathway in both forms of pancreas cancer where, basically, the ligand is secreted, the receptors are expressed and the signaling happens, but it drives, not neuronal signaling, but the growth and invasion of pancreas cancer cells See that’s just described in these two papers on cell and cancer cell And in an attempt to try to generalize, they asked the question, “Well, is this involved “in other forms of human cancer than pancreas?” We did a bioinformatic analysis which suggested that it was activated in some forms of breast cancer And in fact, we’ve a long way to go in terms of establishing when and how this pathway is activated, but in particular, we’ve shown that it’s involved in the metastasis of breast cancer cells to the brain And so we got a paper coming out, actually in a couple days, that describes that the breast cancer cells migrate to the brain where they actually parasitize neurons for that glutamate in order to drive their growth in the brain So it’s a new concept and we don’t yet have any idea about how to therapeutically target it,

but I think it’s potentially an important part of the biology of the cancer and that the first step is knowledge, the second step is what we might do about it Okay, well, at that point, I’d like to then stop and thank you very much for your attention (applause) – [John] Will you answer a few questions? – If you want, it’s up to you – Yeah, we do Okay, thanks very much, Doug, what a superb way to start the meeting I was actually reading The Hallmarks of Cancer, again, over the weekend and it did never gets old and there’s always things in there that you can learn It’s so, so elegantly written, thank you So I guess, this is the moment we all now get to promote our own hallmark, Doug, you’ve probably dealt with this over the years, many times So I’ll open the talk up for questions We’re gonna have a few roving microphones I think we already have our first question on slide as well, but are there any questions to start off? Grant – [Grant] I’ll wait for the mic, yeah Brilliant, thank you, Doug So I have, rather than promoting my favorite hallmark, I’d like to ask you about, as a medical oncologist, perhaps some of the challenges in targeting some of the hallmarks There’s two, in particular, that I’d be interested in your comment on So one is cellular energetics I mean, is this really a targetable hallmark from the point of view of toxicity is one question? And then the other hallmark is targeting angiogenesis, it’s been, I know this is close to your heart having worked in that field for a long time, has it been disappointing and if so, why? – Well, yeah, so I’ll start with the second one ’cause that’s one that I have a lot of personal experience with As you mentioned, that we discovered this angiogenic switch in the collaboration with the late Judah Folkman who was an inspirational surgeon who had this concept that tumor growth was dependent on new blood vessel growth and inspired us all with the notion that if we could target the angiogenesis and stop it, that we could stop tumors dead in their tracks And so I was completely inspired by this vision and we did a lot of work on this and we did a lot of testing of angiogenesis inhibitors in some of the models of cancer that you described And what we and others discovered though, this gets back to the point I was making earlier, is that the tumors responded to the anti-angiogenic therapy, but then they develop became resistant And so much like resistance to mutations in BRAF, they develop resistance And originally, the idea was, well, maybe because the endothelial cells were normal, there wouldn’t be resistance, but the answer is that there’s resistance And interestingly, one of the things that needs to be adapted in the hallmarks concept is it’s not only inducing angiogenesis, it’s getting access to a vasculature And so what we and others have discovered is that if you shut off angiogenesis in tumors, they shrink, but then they come back, but what they do is they come back as being more invasive and more metastatic And so they start living off the land, that they grow invasively along normal blood vessels that does not require new blood vessel growth, but this gets back to the notion of multi-targeting And so now, there are studies going on looking to concomitantly inhibit invasion along with angiogenesis And so I think that has potential, that is another area that is under clinical and preclinical investigation But I think the other really fascinating thing is that with all of these therapies, we’re seeing resistance, but we can study, the resistors used to be viewed as a failure, right? You treat with your drug, stops working, that’s really miserable But now, by a analyzing the resistance, we can be informed about the biology of tumors And so again, in this case, what we see are these insidious ways of resisting anti-angiogenic therapy So I think that, yeah, so this is, again, reflective in that biology, but the question then would be, if you could really shut down invasion, metastasis and angiogenesis, would that then be more significant? And so that is what we envisage, but the proof of principle is still, there are clues, again, but nothing definitive With metabolism, yeah, there’s a lot, I mean, obviously, it’s a huge field of cancer research now,

trying to understand the metabolic alterations that happen in tumors and, yeah, the big question is, in all cases, with all cancer therapies, is the so-called therapeutic window How can you find vulnerabilities in tumors that can be hit without causing unacceptable toxicity And I think, yeah, the question there, I suspect there will be tumors where you will find that therapeutic window and that metabolic modulations will be impactful But, of course, then there’s the larger ones, we were talking about prevention, obesity, excess, Lou Cantley, a prominent scientist director of the Cornell Cancer Center in New York, really, his seminar, now, is sugar is the new tobacco And that sugar and the whole regulatory mechanism involving insulin and insulin-like growth factors, that we’re really killing ourselves with too much sugar And so this is a very interesting hypothesis and I think one that, really, we need to think about And obviously, one of the things that’s fueling cancer of many types is obesity So yeah, so there is a treatment maybe that could be used, right? Is if we could tackle obesity, that that could have a big impact, but in terms of therapeutic targeting and metabolism, yeah, I think it would be interesting to see – Okay, so maybe we’ll go to the Slido question, Doug It’s on the screen there if you wanna, I’ll read it out, but in case you want to follow it So the question is, Doug, do you think each cancer driver gene predominately drives a specific hallmark, or are they more promiscuous and context-dependent? – Oh, I think that, yeah I mean, certainly a number of these mutations appear to affect, some of them are rather pure, RAS and RAF are pretty pure drivers of proliferative signaling, other alteration seem to affect multiple hallmarks Because some of these things are concomitantly regulated, for example, in the course of wound healing or other homeostatic purposes Yeah, so the simplicity of the mutations may not be hallmark specific, some may, some may not – Do we have another question from the floor? Maybe, we’ll take one more – [Ricky] Hi, Doug, Ricky Johnstone from Peter Mac So the first Hallmarks of Cancer paper came out in 2000, the second in 2011, what’s going to come next? Are you going to have a 2020, 2021 edition and what do you think will make the list in the next iteration? – Well, yeah, that’s been a good discussion ’cause one of the points has been that the hallmarks should be fairly generic, applicable to, it doesn’t have to be all, but many forms of human cancer And the question is right, are there other, now, qualities and factors that we’re observing that could arguably be generic? Now, one of them that’s interesting is the microbiomes and that we now appreciate the intestinal microbiome, but also the microbiomes in the skin and the lungs and in many of the barrier surfaces of the body vary and that variation can modulate the immune system and influence (microphone banging) the development of cancer phenotypes So the microbiome is I think is an interesting concept Another one we’re playing around with is the notion of another cell type ’cause I mentioned the cell types which we think are, there’s been a number of other normal cells that are in different tumor types that are recruited osteoblasts and the like (electronic dinging) But we haven’t felt that they were generic, but an intriguing one, now, for those of you who’ve been studying this, is a special cell type, if you want to call it that and that’s a senescent cell So that, in addition to dying, many cells, particularly as we age, just become senescent, which is that they change substantially in their character, they don’t die, but they also don’t proliferate, but they change their characteristics in rather significant ways and some of those seem to, again, elicit tumor promoting inflammation and potentially, in other ways, support tumor growth

So there’s another sort of an idea, maybe senescent cells should be added to the roster of cells that are contributing to the development and progression of differing tumors But again, the question is how general is that? So we’re playing around with, some of these are some ideas that perhaps would make it in the third edition. (laughing) – [John] Thanks for asking that question, Ricky Do we proceed? – Yeah, sure – I might just change gears slightly and it was, firstly, very reassuring to see you present the model of the cancer center in Lausanne and it’s reassuring that the model we’re working on here is being recapitulated in other parts of the world I guess, you touched on and you gave explanations for why some of this beautiful biology isn’t quite translating into better outcomes and the biological underpinnings for that were nicely described, but I wonder whether there’s also a sort of philosophical, whether you have any thoughts on how we’re actually going about this, as a community, as an academic sector, for example, our funding agency here are undertaking a bit of a change in terms of how they wanna fund grants, their challenging our scientists to be more innovative and creative with our approaches I wonder if you wanted to comment on that and do we need to rethink the way we’re actually undertaking research? – Well, I don’t know, I think, well, it’s fair to say, it already came up, is we need more money for cancer research and hopefully, yeah, I think that one of the things I have heard here is that a lot of the researchers in the VCCC are perhaps resource limited in terms of their ability to really pursue their scientific hypotheses as quickly as possible And so I think that, obviously, I think both philanthropy and government, I think there should be more support ’cause we’re in such an expansive area But I also think that there needs to be a good blend of unfettered basic research along with translational research And we’re sort of in an area now, in many places, where governmental agencies are saying, “Well, we wanna see the return on investment “Let’s see things getting into the clinic.” But I think over and over, we’ve seen epic discoveries happening through unfettered basic research So I think we need to not lose sight of the importance of basic research, but I also think that we need to do more creative translational research and an area that I’ve argued more ’cause another area where government funding and actually pharmaceutical funding is limiting, is in the combinatorial trials that I’ve described, this is not, for example, many clinical trials are supported by pharmaceutical companies who are interested in getting their latest drug approved so they can make money on it ’cause that’s their business model, but a lot of the combinations that I’m alluding to involving all these combinations and potentially repurposing drugs and the like is another really interesting area, are not gonna be supported by pharma and I think we need support mechanisms for doing these innovative combinatorial clinical trials And I think that they should also be integrated to good preclinical models ’cause we can’t test all of these combinations in people And so my lab works a lot on preclinical models, but it’s hard to raise money to linked co-clinical and clinical trials And so, for example, we’re doing preclinical trials in glioblastoma, which we think, with repurpose drugs, that we think could be potentially impactful, but trying to get the money to do the clinical trials is not easy because pharma’s not interested These are generic repurpose drugs So I also think, in addition to basic research, we do need innovative funds for exploring combinatorial therapies and how we might pursue those, so I would argue strongly for that – [John] Thanks, thanks very much, Doug Look I think, I might close the session now, but I really want to thank all of our speakers The honorable Anthony Carbines, to Grant and to Olivia for sharing part of your journey What a great way to start the day And to Doug Hanahan, so please join me in thanking all the speakers and we’ll close for morning tea (applause)