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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.

Interviewer: Genetic discovery is allowing a family to outlive their family history. 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 Deb Neklason. She's Program Director of the Utah Genome Project. Dr. Neklason, tell me about this family. What sets them apart from others?

Dr. Neklason: This family is a family that had a lot of colon cancer going on and a lot of people dying at young ages, in their 40s and 30s and 50s, and the family was very impacted by this. So the family was engaged in research to be able to try to piece together the genetics and the history and try to determine what was causing colon cancer in the family.

Interviewer: How did scientists go about discovering what was causing that disease?

Dr. Neklason: The clinicians and the researchers, geneticists at University of Utah worked very closely together on identifying individuals that seemed to have a clinical . . . they had a relative who had had colon cancer or they themselves had had multiple polyps. And they engaged these individuals in research, obtained a blood sample that they were able to look at the DNA, and tried to piece together some part of their genome that they are inheriting that is shared by all the people who are affected by either multiple polyps or have had colon cancer or a parent with colon cancer, and try to piece that together and rebuild that puzzle.

Very early on they identified a gene that's involved in a similar condition called familial adenomatous polyposis. These individuals have hundreds and thousands of precancerous polyps. And so they were able to associate it with this gene and then eventually over time to be able to sequence through and actually find the specific genetic change. And in fact, everybody who had had colon cancer or had multiple polyps did have this genetic variation.

Interviewer: Right. So as part of your journey in helping this family, you went back to patient zero. You did kind of investigative work to figure out where this variation came from. Why was that important?

Dr. Neklason: Well, that's really important because it demonstrates the breadth of the impact of this genetic variation. It's not just a little two or three generation family. We actually traced this back 14 generations to a Pilgrim couple that came to America in the 1640s, and it tells us there's a lot of families and a lot of individuals in this country that potentially have this genetic variation, and we're trying to still continue to piece together these families.

Interviewer: How many of those descendants do you know of have this genetic variation?

Dr. Neklason: We went through and very rigorously investigated three branches of the family that looked like they had more colon cancer than usual. Two of those three branches have the genetic variation, the mutation that leads to high colon cancer risk. And in those two branches we have identified, let me think, 186 individuals with the mutation, and 819 individuals who do not have that mutation, and we've been able to go back and provide that information along with genetic counseling and education to these individuals. A hundred and forty or so of them chose to pursue genetic testing and education and so they know the mutation. The remaining individuals, some of them are deceased.

Interviewer: That's the important part here is that there actually are preventative screening and preventative measures that these people can undergo to slow or stop the disease, right?

Dr. Neklason: There are, and that's definitely the amazing thing about it. We've been able to look at the family and the cancer rates in the family over the years and see what sort of impact did genetic testing have on this family. What sort of impact did it have on cancer prevention? And so we are able to look at cancer rates using the Utah population database that has the genealogies, and overlay the Utah cancer registry, cancer records on top of that. So all cancers diagnosed in the state are reported. When we went and looked at the numbers of cancers in the two affected branches, we found that when we initially engaged them in research, which was about from the mid-80s to the mid-90s, we saw that cancer rates dropped in half in the family.

Interviewer: Wow.

Dr. Neklason: Their incidence was about five times higher than the general population, and they dropped down to about two times higher than the general population by just knowing. That is in the absence of genetic testing, but knowing that they have something going on in their family. So that's the impact of communication and knowledge and education on these individuals. And then we see again after we started to do genetic testing and return results to the family, we see another drop, about 30%, in this family for cancer rates.

Interviewer: How are they made aware of this inherited condition and what the risk is to them?

Dr. Neklason: All of these individuals that I had mentioned we've done genetic testing on, about 180 of them that were mutation positive, we've enrolled them in research and their successive generations. So whenever the children turn 18 we give them the opportunity to enroll in research, and through that we're able to extend this knowledge and the information.

We also encourage the families to communicate with their family members and work with the parents to say, "Okay. You need to talk to your children about that. When they're at the age where they can make their own decisions, you need to look at pursuing genetic testing." And then if they don't carry the mutation then they don't need to undergo colonoscopy like past generations did until they're age 50, the average population risk. If they do carry the mutation then they need to start having colonoscopies in their early 20s and prevent and remove these precancerous polyps before they can become cancer.

Interviewer: So you have this long-term relationship with this family. What do you hope to do going forward?

Dr. Neklason: We would really like to try to piece together some of these other families that are across the country and figure out how they relate to each other, and a lot of that's just engagement of the existing research participants. Do you know your family history? Do you know the names of your great, great grandparents, and then all of a sudden you can start to piece together these families. And that's important because some of these other 15 families, odds are you can expand that family, just like we did the Utah family, to include hundreds of individuals who are at risk and don't know that they're at risk. It flies under the radar and sometimes it's very hard to pick out in the general population that colon cancer is not just bad luck in your family, you actually do have this genetic mutation that's leading to your risk.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.