Chapter 12: Reflections on a Research Style; Collaborating with Clinical Trials

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Chapter 12: Reflections on a Research Style; Collaborating with Clinical Trials

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Dr. Arlinghaus first explains some of his research approach, noting that he uses intuition and logic to attack a problem as if he "peels back an onion."Next he talks about his contributions to clinical trials.He begins with trial to improve treatment of CML patients with Imatinib with period doses of a compound that would inhibit production of Janus kinase 2.He also talks about his work developing an assay to determine whether a patient is in remission or not based on the number of leukemia cells present.[The recorder is paused]Dr. Arlinghaus next sketches several other projects in progress: his collaboration with Dr. Xiaoyan Jian and her work on Janus kinase 2;his continued work on lipocalin 23p2 and host involvement in the spread of cancer;the role of BCR-ABL proteins in Janus Kinase 2 activation.He notes he is currently writing a proposal to extend current NCI grant funding after 2015 and explains that funding is much more competitive today.

Identifier

ArlinghausR_02_20140402_C12

Publication Date

4-2-2014

Publisher

The Making Cancer History® Voices Oral History Collection, The University of Texas MD Anderson Cancer Center

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; MD Anderson Impact; Overview; Definitions, Explanations, Translations; Understanding Cancer, the History of Science, Cancer Research; The Professional at Work; Character, Values, Beliefs, Talents; Discovery, Creativity and Innovation; Discovery and Success; Collaborations; Multi-disciplinary Approaches; On Research and Researchers; Understanding Cancer, the History of Science, Cancer Research; Business of Research

Disciplines

History of Science, Technology, and Medicine | Oncology | Oral History

Transcript

Tacey Ann Rosolowski, PhD:

So I’m starting to get a sense of how, once you get an image of the basic territory of these mechanisms, you unravel a little bit, and then you start to foresee, okay well, here’s where the next --- you know the next piece might form, if I can figure that out. Then the next piece, and the next piece. So I’m just trying to get a sense of it.

Ralph B. Arlinghaus, PhD:

No, that’s a good explanation. So I’m uncovering --- it’s like an onion. I’m peeling back an onion one layer at a time to make discoveries. What’s underneath that layer?

Tacey Ann Rosolowski, PhD:

What’s underneath or inside or in between?

Ralph B. Arlinghaus, PhD:

Yeah.

Tacey Ann Rosolowski, PhD:

Yeah. Yeah. Really, really fascinating.

Ralph B. Arlinghaus, PhD:

So I’m not --- you know, I’m not a genius. I’m just a very logical investigator who --- who follows intuition and guesses about what to do next, like in 1995. How does chronic myeloid leukemia take over blood cells? Well it must somehow control a ve --- a factor that’s involved in making more blood cells, a normal factor, and that’s janus kinase 2. That was 1995. I’m pa --- I published my first jak2 paper in 1996 --- no I’m sorry, 2006. Then 2011, 2013. So, I mean but the critical site was back in 1995. It was a guess. It could have been wrong, right?

Tacey Ann Rosolowski, PhD:

Sure.

Ralph B. Arlinghaus, PhD:

I could have been following a lost leader and wasting my time and postdocs’ time, but I wasn’t.

Tacey Ann Rosolowski, PhD:

Well I’m also seeing how in --- and this is kind of-- My interest in the way I put together, or when someone is telling me about what they do, how I put it together. You know, like how --- because the question I’m always asking myself when I sit down with an individual like you is, how do you do what you do? It’s quite simply how --- how do you make it work?

Ralph B. Arlinghaus, PhD:

First you have to have the drive to do it.

Tacey Ann Rosolowski, PhD:

Sure. Absolutely.

Ralph B. Arlinghaus, PhD:

Because there’s a lot of failure along the way. False leads, mistakes, people that don’t work well with you or for you. You know, whenever you work with people, you know, we’re imperfect, all of us. So sometimes things don’t work as smoothly as they should. So anyway --- so --- but I’m driven, right? When you have a wife and have three children and she dies you want to do something about it. This is serious and became very serious for me in 1967.

Tacey Ann Rosolowski, PhD:

And it seemed too that you, you know, harnessed your --- your abilities to take on the challenge of learning work in a new field or in a new area so that you would move in and use the tools that you could pick up from that to further your own goals.

Ralph B. Arlinghaus, PhD:

People used to ask me, “Arlinghaus, why did --- why did you work on ______ ) leukemia virus and now you don’t work on it anymore?” and “Why are you working on --- on CML now?” I just didn’t share with them what I’ve shared with you, that I’m on a mission. I just --- I just didn’t feel comfortable doing that. So I always had a --- I had a goal. I wasn’t sure I was going to get there but I always had in mind what I need to do so.

Tacey Ann Rosolowski, PhD:

And where do you feel you are with that mission now?

Ralph B. Arlinghaus, PhD:

Well, let me tell you. They’re running a human trial on CML. A guy named Jorge Cortez. He’s a leukemia physician. I had to interchange with him about some of my work and I had a suggestion with --- thanks to a colleague of mine in Vancouver ______ ). She helped me a lot. So I suggested to Jorge, how ---- you might have a better way to treat CML patients, and that was based on another collaborator _________ ), which we published together on jak2. I suggested to Dr. Cortez that there --- there’s a paper --- there’s a paper published not too long ago. I’m writing my grant, and I just had this reference out. Anyway, there’s a paper published by a guy named Mahon. Here it is. It’s in 2010 Lancet. Very high impact journal. “Discontinuation of Imatinib in Patients with Chronic Myeloid leukemia Who Have Maintained Complete Molecular Remission for at Least Two Years”. It’s a prospective [study] of a stopped treatment. So he’s doing it, and some of his patients stayed off of imatinib for some time. Some relapsed. So I suggested to Cortez and Dr. Kantarjian --- not Kantarjian, Dr. Champlain-- that instead of just treating them with imatinib, treat them with a combination of imatinib and periodically with an inhibitor of jak2. They’re going to do that trial on patients that have reached this point. But what you don’t know is, I’ve worked out a method. You know imatinib is so effective at removing disease. Let me explain it to you this way. A chronic myeloid leukemia patient, when he comes to the doctor, in their body they have 1012 leukemia cells. That’s an estimate. 1012. 103 is a thousand --- 6 is a million, 9 is a billion, 12th is a trillion. They have a trillion leukemia cells in their body. Now imatinib has done a great job in getting rid of most of them, but it doesn’t get rid of all of them. When --- Wh --- Perrotti published in another paper, the paper by Neviani in 2013, I’m co-author. There’s a reservoir in CML patients. A population of cells that are resistant to this imatinib drug. In other words they’re not killed like the normal CML cells. So this reservoir of resistant cells is always there. What Perrotti found with my help is that reservoir contains a high level of jak2 kinase and a very low level of BCR-ABL kinase. So the thing that’s driving that reservoir cell is jak2. So as I said to Dr. Cortez, let’s change this strategy and instead of just treating with imatinib, treat periodically with jak2 inhibitor because one of the problems with jak2 inhibitors at this state --- current date --- is because jak2 plays such a critical role in normal blood cell production that it can be toxic.

Tacey Ann Rosolowski, PhD:

I was going to ask you why periodically with jak2?

Ralph B. Arlinghaus, PhD:

Periodic to relieve the toxicity. So they’re doing that. Cortez is doing that on --- so I have to tell you now these patients that have complete remission I used --- I developed an assay to help a person like Cortez determine whether a patient is in complete remission. Because remember in the old days it used to be when you dropped a log of leukemia cells that was considered remission, but you had eleven logs of leukemia cells still there. Didn’t know it at the time.

Tacey Ann Rosolowski, PhD:

Now I don’t know what a log is.

Ralph B. Arlinghaus, PhD:

Well it’s a mathematical term.

Tacey Ann Rosolowski, PhD:

Okay.

Ralph B. Arlinghaus, PhD:

So --- So --- It’s a way to count cells. You could count them by one to a million or you could do one times 106. So you take ten --- ten multiply it times itself six times that --- that becomes a million. So it’s an abbreviate way. So that’s six logs. So in people that have 12 logs, they have 10 multiplied by itself 12 times. That’s the number of leukemia cells. That’s a tremendous number. So I developed this assay to monitor the number of leukemia cells and I could get down to a reduction of five logs and they use such a test to monitor CML patients that are being treated with imatinib. So many of the ones that Cortez --- many of the ones --- some of the ones that Cortez has that have reduced in leukemia cells, here’s numbers you can understand, a trillion-fold. So they have one trillionth the number of leukemia cells, but they still have a lot of leukemia cells. They still have 109.

Tacey Ann Rosolowski, PhD:

The numbers are staggering. I mean you really have to get your head around a different scale.

Ralph B. Arlinghaus, PhD:

When --- When I get cancer, I’m not going to have just a few cancer cells. I’m going to have millions and now I have to find a way to heal them and not our normal cells. Well imatinib is pretty good at that. It’s not chemotherapy. It’s targeted therapy. So now what I want to do is treat these people which have virtually undetectable by my assay …

Tacey Ann Rosolowski, PhD:

Shall I pause the recording while you answer your phone?

Ralph B. Arlinghaus, PhD:

Yeah go ahead. I don’t know who this would be.

Tacey Ann Rosolowski, PhD:

Okay, I’m pausing the recorder at 2:23. [The recorder is paused.] T. A. Rosolowski, PhD: We are back on record here, at 2:26, after just a quick break.

Ralph B. Arlinghaus, PhD:

So, where did I stop … T. A. Rosolowski, PhD: So, well, you were talking about doing the assessments or the creating the assay to determine the levels of this reservoir of ….

Ralph B. Arlinghaus, PhD:

Yes, …. T. A. Rosolowski, PhD: … of cells that …. Ralph B. Arlinghaus … so, I hope he’s going to start sending me patients’ cells … T. A. Rosolowski, PhD: … right.

Ralph B. Arlinghaus, PhD:

… so that I can measure that reservoir as it’s periodically treated. Now, whether they’ll do that or have someone else do it, it doesn’t matter to me. What matters if the patients can reach a point they don’t have to pay a hundred dollars a day for their medication. T. A. Rosolowski, PhD: Right.

Ralph B. Arlinghaus, PhD:

But, they’ve got a life ahead of them because of that hundred dollars a day. So… And, then, there’s a second lady that I work with. The first one was this guy, Neviani, in --- in Ohio, he’s now in ____ Sound 1:01. This lady helped me a lot. T. A. Rosolowski, PhD: This is Minh Chen?

Ralph B. Arlinghaus, PhD:

No, it’s the last author. T. A. Rosolowski, PhD: The last author…

Ralph B. Arlinghaus, PhD:

Xiaoyan Jian. T. A. Rosolowski, PhD: Xiaoyan Jian

Ralph B. Arlinghaus, PhD:

Pronounced “Jong.” T. A. Rosolowski, PhD: Yeah.

Ralph B. Arlinghaus, PhD:

Anyway, I’m a co-author on that paper. T. A. Rosolowski, PhD: “Targeting Primitive Chronic Myeloid Leukemia Cells by Effective Inhibition of the New AHI …. AHI-1-BCR-ABL-JAK2 Complex.”

Ralph B. Arlinghaus, PhD:

That’s right. T. A. Rosolowski, PhD: Yeah. And published in 2013.

Ralph B. Arlinghaus, PhD:

Right. T. A. Rosolowski, PhD: Yeah, okay. Just for the record, I mean for the record.

Ralph B. Arlinghaus, PhD:

So, anyway, what she’s discovered in here is that when you combine JAK-2 inhibitors with imatinib, it makes JAK-2 more effective. She doesn’t know why that is. I know why that is. I know why that is. I’m going to publish a paper on it. T. A. Rosolowski, PhD: How interesting. Okay.

Ralph B. Arlinghaus, PhD:

That’s because imatinib inhibits BCR-ABL which inhibits the production of activated JAK-2. And the JAK-2 inhibitor inhibits the activated JAK-2. So we have two --- two things operating on JAK-2. One preventing its imatinib, and the other inhibiting once --- once it gets formed. So, she doesn’t know why that allows one to use a lower dose of JAK-2 inhibitor, which is very important because JAK-2 inhibitor, will of --- inhibit normal blood cell formation, which would be toxic so you want to get the dose … T. A. Rosolowski, PhD: Exactly.

Ralph B. Arlinghaus, PhD:

… as low as you can. T. A. Rosolowski, PhD: Yep. Interesting.

Ralph B. Arlinghaus, PhD:

And I know why that is so I hope to publish a paper on that. But … T. A. Rosolowski, PhD: Any other research projects that you want to report on right now?

Ralph B. Arlinghaus, PhD:

I’m still working on lipocalin-2, as I mentioned, and the --- the host role in that --- working on JAK-2 and CML. Working on what ABL or BCR-ABL does to activate JAK-2 and why phosphorylation of that one site activates JAK-2. So, those are kind of some of the things I want to do. And I hope to be able to help these physicians who are doing trials. Now, there are two trials that will be affected by my work. The one based on this guy’s study, Mayhon [phonetic], where they’re going to combine JAK-2 inhibitor periodically … T. A. Rosolowski, PhD: Right.

Ralph B. Arlinghaus, PhD:

… with imatinib. And the other one I haven’t told you about is based on this lady’s work …. T. A. Rosolowski, PhD: Okay.

Ralph B. Arlinghaus, PhD:

… if you combine JAK-2 inhibitor with imatinib, you’re going to …. T. A. Rosolowski, PhD: Dr. Jian’s work.

Ralph B. Arlinghaus, PhD:

… make --- make JAK-2 more potent or more effective at lower dose and that will be very useful. T. A. Rosolowski, PhD: So, it’s taken a significant amount of time for your discoveries to kind of reach the clinical ….

Ralph B. Arlinghaus, PhD:

That’s right. T. A. Rosolowski, PhD: … clinical effectiveness.

Ralph B. Arlinghaus, PhD:

And when you think of 1967, nobody knew any of this. T. A. Rosolowski, PhD: That’s right. That’s right. It’s amazing.

Ralph B. Arlinghaus, PhD:

.:3 So I had --- with others, break ground and make discoveries. But there’s a whole group of people who’ve contributed. Like … all this information about JAK-2, I --- I had nothing to do within the normal situation, how it functions. T. A. Rosolowski, PhD: So, it’s just creating this foundation. Because you --- I mean, I’ve talked to a number of people and --- and it’s been a funny process for me, because I went to college in 1973 and, of course, I had all the info about DNA, and I had --- was dating a guy who was in biochem and, I had no idea this was all new. You know, that this was kind of groundbreaking research and this was formation of an entirely new field. I mean, you were there at the forefront of the --- the creation of an entirely new field of study.

Ralph B. Arlinghaus, PhD:

That’s right. T. A. Rosolowski, PhD: And now, we’re seeing --- now we’re seeing results. Now.

Ralph B. Arlinghaus, PhD:

So --- so, I’m still following the discoveries that I made and … T. A. Rosolowski, PhD: Yeah.

Ralph B. Arlinghaus, PhD:

… taking them to the next step. T. A. Rosolowski, PhD: Step by step.

Ralph B. Arlinghaus, PhD:

I don’t know how long I’ll be able to do that, because I’m writing this grant as ---- I’ve got all this paperwork, spread all over … I’m writing a grant trying to get funded when my grant in 2015 –July-- runs out. Am I going to be able to accomplish that? I have no idea. Getting funded by the National Cancer Institute or any agency is extremely difficult. T. A. Rosolowski, PhD: Yeah. I’ve --- a number of people have been talking about how the money situation is getting tighter and tighter.

Ralph B. Arlinghaus, PhD:

That’s right. Mainly because there are so many people trained. So now, the number of Ph.D.’s studying this area or any area has probably quadrupled. Because we are training more Ph.D.’s all the time and they’re going out and working, at least some of them. So, we’re training competitors. T. A. Rosolowski, PhD: Yeah. It’s a catch-22, isn’t it?

Ralph B. Arlinghaus, PhD:

That’s true. So…

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Chapter 12: Reflections on a Research Style; Collaborating with Clinical Trials

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