A Promising Pancreatic Cancer Discovery

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Dan Simon, MD (Host): Hello, everyone. My name is Dr. Dan Simon. I'm your host of the Science@UH Podcast, sponsored by University Hospitals Research and Education Institute. This podcast series features University Hospital Health System's cutting edge research and innovations. Thank you for listening to another episode.

Today, I am happy to be joined by Dr. Jordan Winter, Director of Surgical Services at University Hospitals Seidman Cancer Center and Division Chief of Surgical Oncology, to talk about his latest research findings in the area of pancreatic cancer. Welcome, Jordan.

Jordan Winter, MD: Thanks, Dan. Great to be here.

Dan Simon, MD (Host): So Jordan, tell me a little bit about yourself. Where did you grow up? Where did you train? What inspired you to be a physician?

Jordan Winter, MD: I'm from northeast New Jersey…born and raised and went to college at Princeton and Medical School of Cornell, and then traveled around the east coast a little bit. I was at Johns Hopkins for general surgery, and it was there that I caught the research bug. I worked in the lab of Scott Kern, a pancreatic cancer geneticist for three years, and tried to understand the molecular underpinnings of pancreatic cancer. And it was that time in the lab, working with some brilliant colleagues and mentors trying to tackle together one of cancer's greatest problems, and that is how to treat the most aggressive cancer that we know better than our current treatment options. And I also had experiences around that time clinically with equally bright mentors who were tackling this problem from a clinical side. And being a surgeon-scientist allowed me to marriage those challenges in a single career and have them interplay with each other every day…was something that was really compelling, really exciting in the way I wanted to spend the next three decades of my career.

Dan Simon, MD (Host): You know, it's interesting, Jordan, some of us I guess you would say take the easier route to perhaps diseases that have more straightforward cures. I mean, I'm a cardiologist and it's basically plumbing. I'm an interventional cardiologist and we try to obviously prevent heart attacks, but we have good ways to treat them. Pancreatic cancer is often called the “silent killer.” It's the eighth most common cancer in women, the tenth most common cancer in men. Why is it so hard to treat? What are the challenges and the opportunities for patients, clinicians, and scientists, really to battle pancreatic cancer?

Jordan Winter, MD: Well, it's deep in the abdomen so there's no opportunity on the body surface to easily monitor or biopsy it. We have no screening tests. But, it's more than just late detection. There's something biologically about the cancer that we haven't figured out… where it's just more aggressive. And it's just more resistant to our conventional chemotherapeutics and are novel agents too - immunotherapy, mutation targeted therapy, where the cancer is just more refractory to these treatments and we don't know why.

But one of the most sort of core questions that we explore in our lab is trying to understand that exact question. And we think it's the fact that pancreatic cancer has a pretty unique microenvironment - where it's very hypoxic, it's more nutrient-deprived and as a result of living in those harsh conditions and evolving in those harsh conditions, the cancer cells acquire this extraordinary ability to adapt to stress…that I think it then leverages towards chemotherapy resistance and uses those same survival pathways against the tools that we use to treat cancer.

Dan Simon, MD (Host): Yeah. You know, it's interesting, although as the eighth and tenth most common cancers, it seems like it touches all of us in some way. So my uncle died of pancreatic cancer. And I had a good friend in college who happened to be an Olympic oarsman, he actually was the stroke of our national team boat, and he passed away from pancreatic cancer in his 40s. So I've seen sort of two extremes, pancreatic cancer in the young and pancreatic cancer more in the elderly and so I think all of us have these stories where we have friends or family members. And so obviously, we're really fortunate to be talking to you today, because hopefully we can make some progress.

So, congratulations on your recently published a paper in Nature Cancer. You and your team have identified a metabolic enzyme, IDH1, as a new target to treat pancreatic cancer. How did you discover this target and what strategies are used to block it?

Jordan Winter, MD: We discovered this target over an eight or ten-year process. It's amazing how the research cycle really takes shape and we all learned to follow the science. And that's what we did. We were studying a cancer cell pathway regulator called HuR. It's an RNA-binding protein. HuR binds to hundreds, if not thousands of different transcripts and it stabilizes them and can increase expression very quickly in a cancer cell across the transcriptome in the face of stress - and we started to use HuR as a lens or as a fishing line to catch important cancer genes, because we figured out that the transcripts HuR stabilizes tend to be more important in cancer cell survival. And I was interested in metabolism in the early 2000s when I was doing a post-doctoral fellowship…that was just when cancer cell metabolism began to really take hold as one of the prioritized fields in cancer research…and I became excited about it, and I wanted to understand whether or not HuR was regulating the metabolic program in pancreas cancer to allow them to survive.

So, we surveyed metabolic genes that HuR might be regulating, and we found that IDH1 was exquisitely regulated by this RNA-binding protein. We actually mapped the base pairs on the IDH1 transcripts where the HuR protein binds to and regulates it. And at that time, around 2011, there were two or three high impact papers in the journal Nature looking at IDH1, and they caught my interest…IDH1 is part of the central core carbon metabolism in cancer cells.

So…we started to pursue this as a possible and promising pancreatic cancer target. And when we knocked it out, the cancer cells didn't do well. But what was very interesting was under high-nutrient conditions, which are the standard cell culture conditions, the cancer cells did not care if you knocked out IDH1. So if you were just studying it on typical cell culture conditions you would never have found out that IDH1 was a target, but we realized that pancreas cancer doesn't live under those conditions. And when we tried to simulate the metabolic conditions of tumors, all of a sudden the cancer cells required IDH1 for survival and that led us on the path to ultimately looking for a drug that could target the enzyme.

Dan Simon, MD (Host): So your research findings have shown that ivosidenib, the FDA-approved inhibitor of mutant IDH1, is surprisingly potent against the wild-type form of IDH1 in a mouse model. Especially, as you mentioned when paired with the condition of a low magnesium level or stress. So what is your plan to translate this work into patient studies?

Jordan Winter, MD: Well, that finding was actually I think, the major innovation of our research to figure out that a drug… that was designed for a totally different cancer type, one with IDH1 mutations…unbeknownst to the drug manufacturer and the field at large also targets the wild-type enzyme. And again, this was kind of looking at cancer from a naive lens and we figured out that when we lowered the magnesium concentrations, all of a sudden the drug outcompeted that metal ion at a specific binding site and worked in the wild-type enzyme and then, we took the next step to figure out, at least in preclinical models, that magnesium levels are indeed much lower in tumors than in normal blood or in normal cell culture conditions. So all of a sudden we figured out that the drug really does work against pancreas cancer, which does not have the mutation.

So the next step is to take this drug, which is readily available…it's taken orally once a day, it's safe, it actually has no really well-described side effects in patients with solid tumors… and have patients with pancreatic cancer take the drug in combination with chemotherapy. And in fact, we're potentially consenting our first patient for the trial tomorrow… where we are going to enroll 16 patients over the next two years with resectable pancreatic cancer. And we're going to give them three months of this drug in conjunction with a month and a half of chemotherapy…and we have several different scientific correlative endpoints that we will then evaluate to try and confirm that the drug is actually working on the tumor.

Dan Simon, MD (Host): You know, it's incredibly exciting. As you know, I'm an inflammation researcher and I've cured lots of diseases in mice, but unfortunately had great difficulty in translating to the human. So I want to congratulate you and your team because the hurdles it takes to go from a mouse to man is greater than even the difference in size of a mouse and a man. It is just unbelievable to think of all of the regulatory hurdles that it takes and the funding that it takes to do that. So I'm so proud of you and your team that you were able to partner with Gateway… that you have other funders of the trial and that, you know… I don't want to jinx you because you're enrolling your first patient…but this is the kind of trial, this new therapeutics trial that Seidman Cancer Center specializes in and it's a game-changing technology potentially. So I got to say we definitely are going to have to have you back in 16 to 24 months. I hope you enroll early and that we start hearing about phase II clinical trials.

Have you tested ivosidenib in other cancer treatments besides pancreatic cancer? And what other indications do you think there could be for this IDH1 inhibitor?

Jordan Winter, MD: Well, the interesting thing is we chose pancreas cancer because it's what I study, but 99% of all cancers do not have the mutation in the protein. So theoretically, it's applicable or potentially applicable to all of those cancers. Every single cancer that we have tried so far, the drug has worked in mice and those include lung, ovarian, melanoma, cervical and colon cancer. In fact, we are resubmitting in the next day or two, our second wild-type IDH1 inhibition paper and that one focuses on melanoma. We actually have a patent pending for usage of the drug in wild-type IDH1 cancers, which would cover 99% of the spectrum…so, if we're lucky and the patent office sees merit to this, this would be another great advance for University Hospitals.

Dan Simon, MD (Host): Well, that's really great to hear. And I think obviously our efforts through the Harrington Discovery Institute, that non-profit-for-profit model to take these discoveries, and to get them into the clinic is something that we're doing across multiple disease areas. We have funded 135 investigators across the country, but it's really nice to know that right here in our own backyard, we have a phase I pancreatic cancer trial.

So, what are the next steps for you? You know, clearly, you need a lot of partners to move these studies along. You've got Gateway for your pancreatic trial. How do you think you're going to go about this? I understand that you're thinking about combining IDH1 inhibition with actually some other immunotherapy agents. Do you want to talk a little bit about that?

Jordan Winter, MD: Yeah. As you mentioned, it's hard to go from mouse to man, not just logistically and practically that requires extraordinary amounts of creativity and persistence and resilience, but scientifically. And with pancreas cancer, there have been close to 25 phase III trials looking at a novel drug with chemotherapy comparing to conventional chemotherapy. And of those 25, only four have had any benefit. And the benefit of the new drug has been minimal. So we're approaching this line of investigation thinking that statistically, our trial will be negative in terms of efficacy. And so we're trying to be proactive in figuring out how to optimize targeting this molecule by figuring out the best therapeutic partners. And we're trying to base that research plan on our biologic insights that we've gained over the last few years. So we think comparing it with DNA repair enzyme targets, like PARP or PARG, make a lot of sense for metabolic reasons. We think targeting IDH1 with a ketogenic diet, at least in the mice, seem to be an extremely effective therapeutic strategy. And that's something that you can imagine is easily translatable to patients. And there are some other collaborations that we're doing with scientific investigators in our program, like Ray Wong, who's a PhD that works in our department who studies targeting the EGFR3 receptor, and we think for metabolic reasons would be a great partner.

So, we're certainly working in preclinical context to try and figure out the best therapeutic strategies. And then, we're looking at other strategies as well, some practical, some scientific. We want to develop our own IDH1 inhibitor. And so we're working with our medicinal chemists to do that. We continue to work with pharma to try and get them engaged. So a little bit of a shotgun approach doing multiple parallel efforts to advance this and hopefully, get closer and closer to helping our patients.

Dan Simon, MD (Host): So Jordan, you mentioned that one of the challenges in pancreatic cancer is, you know… a deep internal organ, can't palpate it, can't see it, a little tougher to biopsy, but clearly, you know, we have great imaging tools now. I'm coming to you for a question. I have an uncle with pancreatic cancer who passed away from it. And so I guess the question would be what are the criteria, for instance, for me to have a screening MRI…let's say, to detect pancreatic cancer? Obviously, we know about mammography and screening for breast cancer that way. Are there programs for first degree relatives of pancreatic cancer and what are the present guidelines?

Jordan Winter, MD: Yeah, there is a program that University Hospitals is part of called the CAPS Program, started at Johns Hopkins where we do screen patients who are familial. So if you have a first-degree relative where you have one of the familial inherited syndromes associated with pancreatic cancer, those patients will be followed with yearly imaging, an endoscopic ultrasound and/or an MRI, or alternating those tests on a yearly basis. And Amitabh Chak, one of our gastroenterologists and scientists, is the leader here for that. So that's something that we actively participate in and we have patients that we've detected stage I pancreatic cancers through this program, resected and presumably have cured those patients.

There are patients that have a familial pattern to pancreas cancer that don't quite qualify for such a program…and even those patients…our radiology colleagues have designed a fast 10-minute MRI based on the most high-yield sequences of MRI imaging for those patients. It's not covered by insurance, but its $199 out of pocket, which is affordable to a lot of our patients. And we think that that is a smart strategy for patients who are concerned or have a family history that don't quite qualify for our CAPS Screening Program. And of course, investigationally, it is a huge area of emphasis in our research programs to develop new strategies to detect this cancer early…and that's done with both innovative imaging modalities…working very closely with our colleagues in bioengineering at the school of medicine and also blood tests, which we and others in our cancer center are working on as an early detection strategy.

Dan Simon, MD (Host): Well, that's really terrific. I think, you know, it obviously brings hope to families that have first degree relatives and I'd say, I guess, an uncle doesn't quite get me there, but the fast-scanning probably would, and I think makes a lot of sense because I think what we see is the advanced presentation of metastatic disease until now, before this Gateway trial, not a lot of hope.

Well, Dr. Winter, thank you so much for taking the time to speak with us today.

For our listeners, thank you for joining our second episode, and if you're interested in learning more about research at University Hospitals, please visit UHhospitals.org. Thank you.

Jordan Winter, MD: Thanks so much.

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