 Thank you very much for inviting me for this talk on biology and resistance which I ought to accomplish in 15 minutes and that's quite a task actually. So I kind of focus on certain things which I think are important. So you've seen that slide probably over and over again within the past couple of years or so and basically what we see in the clinic quite often is that you expose a patient to a given drug and there will be response and over time it just awaits responsiveness and becomes resistance. And there's the other clinical scenario which is the lower one where you do not have response at all whatever you do that you too much just keeps on growing and kind of question I mean how do you assess that? I mean what is intrinsic resistance? Is that something that I mean it's quite clear if it's progressive disease it's intrinsic resistance but how do you measure? Is it three months time within six months time and I would even propose it can be done differently and that's something we've shown for ESMO and a quite different aspect and I would just draw your attention to tumor shrinkage in different categories and to the orange and red line in patients that have been exposed to tyrosine kinase inhibitors and I would argue if there is no tumor shrinkage I mean these are the ones that are truly non responsive and intrinsic resistant. So there's some work that looked into the tumor architecture and I think that really gets us to a point where you've heard a lot during the day about microenvironment and I think that's a another way to look at this because there seems to be some correlation in terms of how the tumor has been built up so whatever is blue on here are tumor nests and you can see that there's a resistant phenotype for VGF inhibition where the tumor nests are blue and the vessels which are green are surrounding these tumor nests and this is the resistant phenotype in the sensitive phenotype it's mixed up so the vessels are inside the tumor basically and that has been investigated in preclinical models and also in patient specimens actually so even though I think it may not be the solution for RCC it really takes us to the level of microenvironment which has been a topic during the day and I think is really the next step where you could just get to the next point of therapy and this is a rather complex scenario and I think myelot cells have been mentioned quite often today and it really is a mechanism of how to sustain endogenesis in this complex so macrophages are part of that and the M2M macrophages have been explored in terms of how they influence tumor growth and this is a nice model where tumor cells have been inoculated in mice and either with or without macrophages so this is the one only the tumor cells and here tumor cells plus macrophages and you see that there is an increase in tumor growth once you inoculate these two compartments and there's also an increase in endogenesis so really supporting the notion that macrophages do spur tumor growth and are important in that scenario on top of that I mean if you talk about microenvironment and stroma of course there's fibroblasts and there are numerous articles addressing this issue I think in terms of supporting endogenesis and I just brought you this one which is about autophagy an area that becomes more and more apparent in treatment of cancer where the autophagy of fibroblasts really is spurring or fueling the cancer cell with with ketones and lactates to really spur growth and it can be done or well LKB1 is in as a molecule that could manage fibroblast autophagy and has been interestingly studied here in this model where kinase there at LKB1 has been shown to decrease autophagy and therefore lead to delayed tumor growth in this model so in acquired resistance we do have a little bit different scenario where we do have a initial response to a TKI and then it's being resistant and that has been explored here in this study that you probably know it's from 2011 and in that scenario xenotransplant have been then at time of resistance transferred to another host and then re-exposed to the very same drug which is seraphonib in that case and it responded again and the gene signature that came along with resistance was reverted so that really gives you an idea that some of these resistant mechanisms may be transient at least and it goes along very well with the clinical data that we have so you've heard about third line therapy is it effective yes it is but in in terms of efficacy you will lose efficacy over time if you go from first to third line so apparently there's more than just this reversible type of resistance but there must be also other factors that kick in later in later lines of therapy and I think something we have to keep in mind and that could be one of the hurdles that we have seen with some of the current aspects in clinical trials is really I mean what are we measuring and if you look for serum and you can measure tons of cytokines that go up and down with different treatments and is it really what you see is what you get here is this is it the key driver that we measure in the bloodstream it is unlikely to be the case actually and that is an example from a lung carcinoma preoperative exposure to perzopinib in that scenario for only a brief period of time so this wasn't intended to look for remission but rather than go for biomarkers and what you see it's almost exclusive upregulation of PLGF throughout the course and this is this is unlikely to be related to a resistance it's just a biological response to the VGF receptor inhibition so for a while it has been thought that PLGF could overcome angiogenesis inhibition and it has been debated but eventually it becomes clear that PLGF is not the major driver of resistance to angiogenesis angiogenic genetic inhibitors and so therefore that that is one of the caveats that we face one once we measure just a certain biomarker and there's also more to that and there's again a preclinical model looking into resistance to VGF R2 inhibition which has been done here with an antibody and at time of tumor resistance it has been analyzed for certain cytokines and it appears that FGF and angiopoietin could be major drivers in resistance to VGF inhibition and as you know the angiopoietin study in combination with seraphonib has been negative and you just have seen the Davidinib data which also have for you here and it looks apparently that the expansion of of the TKI spectrum by addition of the FGF receptor does not really do the trick that we would like it to do actually so it's more complex than just looking at one simple parameter and then embarking on that with a medical therapy and just having the tremendous benefit so I think in the last part of my talk I would just talk briefly about enrichment design or how we could succeed in that scenario and for that purpose I chose a melanoma model with kid mutant melanomas which certainly is just a small subgroup in that scenario and it's about 5% that will harbor activating mutations in the kid gene but however once you treat those with imatinib it has tremendous effect the response rate is about 40% in these patients and I think what is nice about this publication is they looked into tumors at the time of disease progression and of course this is melanoma and this is more simple to get tumor biopsies done than in renal cell carcinoma but anyhow that's what they did in some index patients there were only a few of them and interesting they didn't find any secondary mutations that could drive the tumor that as a process of selection throughout the course of treatment with imatinib but instead they find some activity in the AKTM tour pathway and therefore they embarked on a second line treatment with Averolimos as an m2 inhibitor and again had major response in these tumors and I think this is really illustrates nicely how we really should do our clinical trials and there's no way we're going to succeed in later lines of therapy without having that tissue done at time of progression and knowing what's what's happening in the tumor or the stroma and instead of focusing of serum marker I think this is really where we should go for so does this translate somehow into RCC well yes it does there are some articles relating to m2 activity and poor outcome in renal cell carcinoma and this is one of them so as you see in here so phosphorylation of mTOR is associated with a poor prognosis in this in these patients and that's something that kind of translate to the data you've seen already so I mean Averolimos is not an option for first line that's clear I mean we don't do that it's not supported by these trials that we do but however in later lines of therapy as based on what you've seen in the melanoma setting I mean it could be that we do have a priming effect by using the VGF inhibitors initially inducing hypoxia in these tumors and altering them and therefore mTOR may play a better role in later lines of therapy than initially so with that I would like to conclude certainly VGF resistance is beyond the scope of a single driver mutations and the micro environment really adds another complexity a layer of complexity to this scenario but however this is where we really should aim for and I think selecting the right target population is really key for clinical trials to succeed and to have positive trials thank you