Posted by Jeff Berk, BOLT International;
So I survived my blog last night with no sarcasm, and I’m happy to report that I’m none the worse for wear. We’re all headed to Chicago for the next week. For ASCO, or deep dish pizza, or something like that. I hear they have lovely beaches in Chicago, but Rhambo closed them all because the townsfolk were coming down with “heat stroke”. Is that what they call it in Chicago when unruly flash mobs have the run of the place? Anyway, in honor of the Heller ruling, today’s cactus is Myrtillocactus geometrizans, here depicted in bloom. Research in Scottsdale AZ has shown conclusively that this flower has a dramatic disease modifying effect on “heat stroke”. Unfortunately, due to Chicago Health Care laws, only crooks, cops and Friends of Daley (but then I threepeat myself twice over) can access this therapy. You want to know something? Even though it’s 30 degrees hotter here in the desert than it is in Chicago, we don’t have any flash mobs. I mean “heat stroke”. Just sayin’.
I’m really partial to the development of metabolic agents for cancer. It seems intuitive to me that tumor cells don’t like to eat the same stuff as the rest of us. I have a couple of other favorite new platform technologies, but cellular starvation is way up that list. I’m sure that some of the compounds BOLT’s Oncology Thought Leaders talk about below are going to be updated this week, and the list of metabolic targets and ways to target them will be expanded at ASCO 2011. But for now, here are some things to think about in relation to metabolic disruption of pancreatic ductal adenocarcinoma:
- PET will measure glucose uptake in pancreatic tumors but this doesn’t convey any insight as to whether or not the tumors are primarily undergoing aerobic or anaerobic metabolism. Imaging of lactase could be (but is not currently being) used as a signature that the cells are at a high conversion of glucose to lactase; suggesting that there is anaerobic metabolism feeding these tumors.
“So you touched on PET as one of the diagnostics. I associate PET with glucose uptake. So once again I am asking this as a question and I am looking for your wisdom, but I think of the glucose uptake as a surrogate for aerobic metabolism and low glucose uptake I start to think about more anaerobic ways to feed these tumors. Is that valid? So there was a paper I believe last year in 2009 where they actually looked at PET scan and the standard uptake value and adjusted that to perfusion in them. It appears that a number of pancreatic cancers that actually have high glucose uptake if you adjust for perfusion, it actually is relatively high rather than what is currently known which is about 40 percent being positive, it could be as high as 70-80 percent. I look at it that mainly the PET scan itself would just give an index of perfusion but it cant measure perfusion directly. And it is not surprising that the cells will take up some amount of glucose. And I am not sure beyond that whether the glucose is an indicator of aerobic versus anaerobic metabolism. It is just glucose uptake. That is all we know about it. So how would you comment on the strategy of targeting anaerobic metabolism in pancreatic cancer? We are going to need to do quite a bit more work on that. So whether, and again this is not standard practice at all, but it is more in the experimental setting. People actually image, for example, lactase production in vivo in patients. And the question there is could that be a potential indicator of anaerobic metabolism? So a signature that the cells are at a high conversion of glucose to lactase, for example, and that is not being used. So again, people tend to use PET scan and I would say in an overreaching way and interpret it as anaerobic metabolism. All it tells you is that glucose hits the cells.
- Aminooxyacetate is an inhibitor of aspartate aminotransferase that has been used in preclinical models in various tumors. It presumably works by interrupting some level of glutamine metabolism. This was recently tested in pancreatic ductal adenocarcinoma xenografts and surprisingly had a pretty uniform response on these tumors. Other agents in the same models had more variable responses.
“We took this relatively, I would say, agnostic approach with different agents so we are running almost a dozen chemotherapeutic agents as well as about six to eight metabolic inhibitors. There are some metabolic inhibitors that appear to create, generate, a more uniform response among the xenografts. For example, aminooxyacetate. It is inhibitor of aspartate aminotransferase and it has been used in preclinical models in various tumors presumably interrupting some level of glutamine metabolism. So we were surprised that one actually had a pretty uniform response on tumors versus some other agents where you see some respond and others don’t respond. We don’t quite understand that yet, but we hope to understand that”.
AGS-1C4D4 (targets AGS-5; Agensys / Astellas)
- AGS-1C4D4 is a monoclonal that targets SLC44A4 (a.k.a. AGS-5). Preclinical data demonstrate that SLC44A4 (AGS-5) is expressed on more than 80 percent of samples derived from patients with pancreatic, prostate and gastric cancers. NCT00902291 is a Ph-II trial ongoing in PDAs comparing GEM +/- AGS-1C4D4. The primary endpoint is survival rate at 6-months.
“The AGS-1C4D4 trial is enrolled. Gemcitabine plus that agent, the enrollment in the trial is completed. We are waiting to see what the results show”.
ASG-5ME (targets AGS-5; Seattle Genetics / Agensys / Astellas)
- ASG-5ME is in Ph-I trials ASG-5ME ADC consists of a XenoMouse-derived fully human IgG2k monoclonal antibody that binds to SLC44A4 (AGS-5) with high affinity conjugated with the antimicrotubulin drug, monomethyl auristatin E (MMAE), via a conditionally labile valine-citrulline (vc) maleimidocaproyl linker. ASG-5ME induced long-term regressions in preclinical models of established pancreatic, prostate and colon cancers.
“These are great questions. You have obviously thought about it a lot. There is one more group of compounds. I wanted to be complete so just one more. It is no secret, but we started just a few days ago. It is Seattle Genetics (and Agensys, an affiliate of Astellas.) It is ASG-5ME and it is an antibody-drug conjugate. Seattle Genetics announced it. They didn’t announce our name as the institution doing it, but it is against a transport protein. It is pretty close to a GLUT-1 receptor so it is an anti-metabolomic. And what it is, is an antibody to that. I am worried about it getting into the tumor. But I can tell you there are a lot of strategies now with hyaluronidase and high dose steroids that we are trying to soften up the tumor. But if there is one thing that will get the transporter is this ASG-5ME. So it targets the transporter and it delivers a really incredibly cytotoxic agent, auristatin it is called. And they have got this conjugated for Hodgkin’s and it is a miracle drug in Hodgkin’s disease. Hodgkin’s is SGN-35. Yes. That was along the lines of what I was thinking about in terms of the monoclonal plus warhead. Yes, but I am just saying they don’t get it. That is what I worry about. So you are using this monoclonal plus warhead to target something that then is used to transport something into the tumor. Right. We think that it is going to be dynamite in combination. But I will also let you know that we are using hyaluronidase and other things that could make drugs like this really work. Is ASG-5ME a drug name or is that the target? No that is the drug name. That was a weird one. Who came up with that? I guess it was Seattle Genetics and Astellas owns the molecule. Yes, okay. They own the molecule and then the 5ME is the migrastatin E is the drug that is delivered”.
“Those supposedly will only target…I don’t think these targets are in the stroma. I think they are just in the cancer cell. But the problem that you may face, for example, the Astellas compound is an antibody, so it is going to be quite hard for these antibodies to get to the pancreas cancer. So there will have to be some sort of active transport? Or again, eradication of the stroma with something else”.
2-HG (2-hydroxyglutarate; Agios / Celgene)
- The mutated form of IDH1 produces a metabolite, 2-hydroxyglutarate (2HG), which may contribute to the formation and malignant progression of gliomas through altered metabolic activity. Unfortunately, IDH1 doesn’t raise 2-HG in pancreatic ductal carcinomas, so the research program has just started to resect pancreatic tumors in order to study their metabolomic characteristics.
“What do you think of 2HG? This was one of the metabolic approaches that was suggested for glioma. Yes, well 2HG antagonists are what people are looking at. That is Agios. That is the company that makes it. So alpha-ketoglutarate is what it is and you get mutations in those patients. Now is the issue for all of these still going to come back to the pancreatic tumor has to be transporting, we have talked about the transport of albumin but it has to be transporting from its external environment. Are there roots of transport that are upregulated that we see? We know that they take up a lot of glucose because they are positive of PET scan. But I will tell you a little inside information, which is not bad inside information, it has been published but kind of obscure ways, is that this IDH1 mutation which is common in patients with glioma where the 2HG goes up; it is very interesting that it doesn’t happen in pancreas cancer at all. It happens in leukemia, but we are probably the most disappointed people on the planet because it doesn’t play out in pancreas. It breaks down protein. We think that breaking down of protein creates ammonia, ammonia creates fibrosis, so we think that the early mutations are causing a lot of fibrosis by dumping ammonia in. The answer is that is why Agios was formed. That is why we got the grant and I am working with the best guy in the world in this area who is Craig. There is no question he has been the guy. He described these IDH1s, he is the first author on all this. He and Chi Dong who is at Hopkins, these are the two best people in the world and I just spent last week working with them. There is no lead yet in this area nor insight. But what we are doing is we are resecting patient’s cancers after doing PET scans and glutamine scans. Then we give the tumors to the Princeton team who are doing all the metabolomic products to figure out what is out of balance that we could actually say, oh that pathway is important in keeping that thing alive. It hasn’t been done. We know, as you have said, these are very hypoxic. The only cancers that are really, really hypoxic are head and neck and pancreas. It has been measured with probes, real low oxygen tension. That makes HIF-1 alpha go up. That drives aerobic glycolysis so it is trying to stay alive but how we cut off that fuel supply without cutting off glucose to the brain is the problem. We are real excited. We did our first patient ever in the world with a metabolomic profile of their tumor just down at Princeton last Thursday.
“I think the notion that many of these cancers may be fueled by consuming glutamine, instead of glucose, is an interesting hypothesis. And they are going to be agents that are trying to block the glutamine and amino acid uptake in the metabolism. The problem that I see in that field is that first it is early. And second, the drugs are not very good. These are drugs that have been around for many, many years. They are off-patent, and pharmaceutically they are not a very good molecules, they are not very specific. So if the concept is proven to be correct, I would anticipate there is going to be an interest to develop more inhibitors of those different enzymes and pyruvate kinase and these others that may be involved in the very complex metabolism of cancer cells. But certainly it is a very emerging area, yes”.
“Have you seen any metabolic approaches that seem particularly useful for pancreatic tumors? Yeah, I think there is definitely a lot of work going on in UPenn in terms of metabolic approaches; glucose depravation. The problem here is they have really not been able to go forward in the clinical setting in terms of I have seen this work now for five or six years suddenly where they have presented a lot of data and they have received a lot of attention but it has not gone in the clinic. So as a clinical investigator my skepticism is just based on that; that by this point you should have seen some phase I information, something there”.
- FX11 [3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid] is a small molecule that inhibits the reduction of glucose to lactate by lactate dehydrogenase A (LDHA). This causes oxidative stress and cell death. The molecule has been patented by Johns Hopkins.
“There was a guy at AACR I think is David L. Vander Jagt. Do you know him? I don’t. He gave a talk where he was talking about a small molecule inhibitor of LDHA and the molecule was FX11. My notes from this was that he said that in pancreatic cancer FX11 causes some slow down in tumor growth. It is not as good as what was seen in Burkett’s lymphoma. So the question I pose for you is LDHA what is the relevance of that? Again, in the metabolic pathway it has been shown to be upregulated. People are taking a look at that as possible I think by itself again the drug has to get in. It is the same old thing. You will hear me say there are a lot of good ideas but if we are not getting it in. It is one of the metabolomic enzymes that is definitely up and there are a lot of inhibitors of it being looked at. Agios has a big program in it, and others do, that try to make it more active. So it is a perfectly bona-fide target in the metabolomic way. But it doesn’t change the growth rate very much, almost to the point that you feel that there is no chance this is really going to go into people. So the strategy is being with any of these inhibitors is to put it together with a therapy we have. By itself it is unlikely. But people are taking many shots at the metabolomics”.