Drug Treatment Prevents Polyps In High-Risk Cancer PatientsA randomized clinical trail led by Huntsman Cancer Institute investigators finds that a combinatorial chemotherapy reduces precancerous polyps by 75 percent in patients at high-risk for cancer. This…
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April 19, 2016
Cancer
Clinical Trials
Health Sciences
Innovation Interviewer: Stopping cancer before it even starts. We'll talk about that next on The Scope. Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope. Interviewer: I'm talking with Doctor Deb Neklason, Huntsman Cancer Institute Investigator and Program Director of the Utah Genome Project. Dr. Neklason, congratulations on your recent JAMMA publication. What did the results of your clinical trials show? Dr. Neklason: This clinical trial showed that we were able to treat individuals that had a hereditary predisposition to gastrointestinal cancers. We were able to reduce the polyps in their small intestine with about a 75% response rate. Interviewer: 75%. I mean, that's a lot. Dr. Neklason: It was a huge response and they've never seen anything like that. Interviewer: And what is a polyp? Dr. Neklason: So the polyps are precancerous lesions that are their duodenum, which is part of the small intestine just after the stomach. These individuals have about a 10% to 12% risk of developing duodenal cancer. If we can find a way to actually drive these precancerous polyps away with a drug instead of having to go in and cut it out every time, it's just a huge proof of principle, a huge success. Interviewer: And do the people that took part in this trial have a certain type of colon cancer? Dr. Neklason: Yes, so this is a fairly rare genetic condition. It's about 1 in 10,000 individuals and it come about from a genetic change in a gene called the APC or adenomatous polyposis coli gene. These individuals develop hundreds to thousands of polyps in their colon. They have 100% risk of developing colon cancer if it's not managed clinically and by that they usually end up having a colectomy where their colon is removed and then reattached. That then eliminates most of that risk of colon cancer in those individuals, but then they still have the risk of other cancers, namely this duodenal cancer. That is very much an unmet need for these individuals. They run the risk of still developing cancer and you can't really take your small intestine out because it's essential for nutrition and digestion and you don't do very well without your small intestine. Interviewer: How did you arrive at this drug therapy? What made you choose this combination? Dr. Neklason: So the drug combination we used is Sulindac, which is a non-steroidal anti-inflammatory, kind of like aspirin or ibuprofen. It's used for arthritis but it inhibits a really important gene that's overexpressed in the colon tissue and the duodenal tissue, especially as they advance to become polyps and cancer. This drug, Sulindac, worked really well to drive regression of colon polyps but it didn't do anything to the duodenal polyps. The thought was that this COX-2 protein was expressed at much higher levels and they couldn't use that drug at high levels. Through our work here at Huntsman Cancer Institute and University of Utah we, as well as others throughout the country, started to pick apart the pathway that turns on this gene. We know that APC, the gene that's altered in these individuals, is important in driving up expression of that and we also discovered that there is a feedback from epidermal growth factor receptor, which is eGFR There's a lot of new drugs that have been developed against eGFR because this is overexpressed in a whole bunch of cancers. We choose to use a small molecule inhibitor of eGFR called erlotinib, and our thought was if we can hit two segments of the pathway with these two drugs, maybe we can have an effect in the duodenum, and indeed, we were successful with that. Interviewer: Do you have plans to track them further out? What are some of the next steps with this trial? Dr. Neklason: There are some really important end points that we need to figure out. One of the important questions that you alluded to is what happens when you take them off drug? Do the polyps come right back? Or we talk about the durability of the response. Is it repressed for maybe a year out and would the design need to be where you cycle them, put them on for six months, off for a year, on for six months, or what would it look like in that way? Probably even more important is to follow these individuals long-term and actually show a different clinical outcome. What I mean by that is do we prevent them from having to undergo surgery? People that are treated with the drug, do they undergo less surgeries than people that are on placebo? Or even do we prevent cancers in these individuals? Those end up being five, ten, fifteen year studies to be able get a good solid result that you understand. Interviewer: So here you are testing this potentially new drug therapy in clinical trials and these families who are stricken with colon cancer, and this is really where the whole project started. In a way this is kind of bringing work here at the University of Utah full circle. Dr. Neklason: This goes back to the late 1980s. There is a team of researchers, including my mentors, that discovered the APC gene. They have gone on the . . . Randy Burt, the clinician who managed these patients has just retired, but he is a legacy in and of himself for treating and managing people with familial adenomatous polyposis and other polyposis conditions. It's very exciting because we've identified the gene. Over the years we've studied how does the gene work. We've studied the patients, how does the disease progress in them? We're finally at a point where we can precisely understand what's going on in those cells and prevent the disease. This whole idea of precision medicine, we like to think of this as precision prevention. Interviewer: One of the interesting things that you actually mentioned is that the mutation that causes FAP, this inherited cancer, is in the APC gene and that gene is mutated in sporadic cancers as well. Do you think this therapy could have implications for other colon cancers too? Dr. Neklason: I think that what we call the proof of principle, I think the fact that we know that we can target these pathways with these drugs will enable us to make better design of treatments down the road. The APC gene is altered in a very early step of cancer progression. There are some really exciting analogies with colon cancer where it's known that aspirin, regular aspirin, can reduce the risk of colon cancer for people that are at pretty high risk, so that's a drug a little bit like Sulindac. It's quite possible that that knowledge can be used in the prevention and potentially even the treatment because the eGFR is known to be overexpressed in a lot of cancers, so just understanding how we can manipulate that pathway and as we understand cancers better, colon cancers, even lung cancers have a lot of eGFR expression, that just understanding that we can actually get the drug into the body where it needs to go, do what it needs to do, can be applied more broadly. Announcer: Interesting, informative and all in the name of better health. This is The Scope Health Sciences Radio. |
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Genomics Tool Aims to Take Guesswork Out of Infectious Disease DiagnosisA child comes into the emergency room in with fever, coughing, and chest pain. What’s causing her illness? A new type of test promises to take the guesswork out of making an accurate diagnosis…
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June 08, 2015
Health Sciences Interviewer: A patient comes in to the clinic with an infectious illness that the doctor can't quite put her finger on. What's causing it? We'll talk about a new way to find out, up next on The Scope. Announcer: Examining the latest research and telling you about the latest breakthroughs. The science and research show is on The Scope. Interviewer: I'm talking with Dr. Robert Schlaberg, an assistant professor of pathology at the University of Utah, and a medical director at ARUP Laboratories. Doctor Schlaberg, let's imagine this scenario - a child is brought in to the emergency room with symptoms of shortness of breath, fever and coughing. There can be a lot of causes for this type of illness. First of all, how do doctors typically diagnose a patient like this? Dr. Schlaberg: Yes, so a patient with suspected pneumonia, which this child may have, requires a battery of tests. So usually nasopharyngeal swab, an upper respiratory track specimen is collected through the nose from the child, and probably a blood sample will also be collected for culture, and then a large battery of tests is run on both of those samples. These tests generally work well if a common cause actually is responsible for this patient's disease. However, in about 20% or so of children, no cause is found with the standard approach. Interviewer: You've helped develop a tool called Taxonomer, how is it different? Dr. Schlaberg: So with the current approach, one has to know what a test is supposed to detect. So we call this a differential diagnosis. So the physician who sees the patient has to decide which bacteria or viruses to test for in this child. The tests we're developing aims to do away with this guess work and provide an answer or a way to detect any virus specter or fungus in a patient's sample. Interviewer: So you perform this test, what's the output? Dr. Schlaberg: The output is a list, or in this case a graphical representation of all microbes that are present in the patient's sample. Interviewer: And so how do you do that? Dr. Schlaberg: So we take the patient's sample and we extract RNA and/or DNA from the sample . . . Interviewer: And that's the genetic material? Dr. Schlaberg: That's the genetic material from the patient as well as from anything else that's in the specimen. Interviewer: So basically you're cataloging all the genetic material that's in a patient's sample? Dr. Schlaberg: Yes, exactly. Interviewer: So how do you go about figuring out . . . when you have this long list, how do you go about figuring out which one is the likely candidate cause for the disease? Dr. Schlaberg: So the easiest scenario is if there is a known pathogen, say influenza virus. If we find influenza virus in a patient who has symptoms that match influenza, then the general assumption is that that's the cause of the patient's symptoms. The same is true with current tests. Interviewer: But I guess the other important thing here which we alluded to earlier is that, there are many types of influenza viruses so knowing exactly which one could help tailor the treatment for that particular person? Dr. Schlaberg: Yes, it can, as the genetic information for, in this case influenza virus, is read out by this test and there are known changes in the genome, known mutations that can cause drug resistance. You can also, at the same time, determine if the standard therapy is likely to work or not based on those known mutations. Interviewer: So having this really accurate diagnosis can really maybe save time and money, and just wear and tear on the patient. Dr. Schlaberg: Yes, absolutely. Oftentimes the correct diagnosis is delayed by the need to test with multiple amounts of testing. If their first round of testing comes back negative, then the next most likely causes are tested for. This test offers the advantage that it's one stop shopping. It's a catch-all test that doesn't require follow up testing. Interviewer: How else do you think that this tool can be used? Dr. Schlaberg: One challenge and also great opportunity of using this testing methodology is to learn more about what other factors may influence the disease severity of a given patient, because we know that two patients who are infected with the exact same virus may present very differently. So the difference could be due to factors that lie with a patient such as genetic predispositions, but they could also be related to the nonpathogenic, normal bacteria that reside in these patients respiratory tract. So that's a very active field of investigation, how different pathogens interact with the normal bacteria, and how that can influence the disease severity. Interviewer: Interesting. Okay, so instead of just looking for the causative microorganism, you can look at the whole array of what's in there to understand whether that's influencing how the illness manifests itself? Dr. Schlaberg: Yes, absolutely, and all that information has been ignored previously. Interviewer: Okay, interesting. Dr. Schlaberg: The longer term goal is to put all of these layers of information together, and improve accuracy of the diagnosis, and better informed treatment decisions. Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio. |
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Return to Kindred: Family History + Genome Sequence = ProgressMark Yandell from the department of Human Genetics.
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