Chapter 01: Key Research on ABL Kinases

Title

Chapter 01: Key Research on ABL Kinases

Files

Loading...

Media is loading
 

Description

Dr. Arlinghaus first talks about a study he will soon initiate on the role of JANUS Kinase 2 on chronic lymphocytic leukemia. He next quickly defines the field of molecular pathology and techniques that molecular pathologists use to break open cells and analyze their functions. He gives the example of the drug, Gleevec, and his contributions to work that unraveled how Gleevec successfully deactivates a key cell function that maintains leukemia. Next he talks about his work on the ABL kinase protein and chronic myeloid leukemia). He explains how this protein is involved in cell abnormalities and signaling functions that support the production of leukemia cells. He then goes into detail about how the BCR-ABL onco-proteins lead to leukemia. He notes some of the early studies that advanced knowledge, but did not immediately lead to treatment because the drugs under study (a precursor of Gleevec) were too toxic.

Identifier

ArlinghausR_01_20140321_C01

Publication Date

3-21-2014

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; Overview; Definitions, Explanations, Translations; Devices, Drugs, Procedures; Professional Practice; Understanding Cancer, the History of Science, Cancer Research; On Pharmaceutical Companies and Industry; Discovery and Success

Disciplines

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

Transcript

Tacey Ann Rosolowski, PhD:

I am Tacey Ann Rosolowski. Today is the 21st of March, 2014, and today I’m in the Life Sciences Plaza, on the ninth floor, in the Department of Translational Molecular Pathology. Did I get that right?

Ralph B. Arlinghaus, PhD:

Yes.

Tacey Ann Rosolowski, PhD:

I did? Good. Interviewing Dr. Ralph Arlinghaus for the Making Cancer History® Voices Oral History project run by the Historical Resources Center at MD Anderson Cancer Center in Houston, Texas. Dr. Arlinghaus came to MD Anderson in 1969 – is that correct, 1969?

Ralph B. Arlinghaus, PhD:

Correct, yes.

Tacey Ann Rosolowski, PhD:

Okay, and you were a faculty member or a Chief of the Section of Environmental Biology?

Ralph B. Arlinghaus, PhD:

I was a faculty member in the Department of Biology …

Tacey Ann Rosolowski, PhD:

Department of Biology.

Ralph B. Arlinghaus, PhD:

… and a Chief of the Section of Environmental Biology.

Tacey Ann Rosolowski, PhD:

Okay, great. So, that’s how. Alright, that’s why I got those things together. And, today he’s Professor in the Department of Translational Molecular Pathology in the Division of Pathology and Laboratory Medicine.

Ralph B. Arlinghaus, PhD:

Correct.

Tacey Ann Rosolowski, PhD:

And Dr. Arlinghaus also holds the Hubert L. Stringer Chair in Cancer Research.

Ralph B. Arlinghaus, PhD:

Correct.

Tacey Ann Rosolowski, PhD:

Great. Today is the first interview session, we have two of them planned, and I want to thank you, Dr. Arlinghaus, for devoting the time …

Ralph B. Arlinghaus, PhD:

You’re welcome.

Tacey Ann Rosolowski, PhD:

… to this project.

Ralph B. Arlinghaus, PhD:

You’re welcome.  

Tacey Ann Rosolowski, PhD:

I know you ran down from the twelfth floor from your labs so I’m sure I’m interrupting you.

Ralph B. Arlinghaus, PhD:

No, I — I knew you were coming so I finished up. I was reading this. One of the things I do is try to catch up with experts in the field of areas that I work in. And, there was a mini review that I’m reading and I just made copies of this mini review and gave to my four people who work in my lab: trainees, PhDs.

Tacey Ann Rosolowski, PhD:

And what’s the review of?

Ralph B. Arlinghaus, PhD:

It's Structure and Dynamic Regulation of ABL Kinases.

Tacey Ann Rosolowski, PhD:

Wow. Okay. So, you kind of scour the literature and then pass the…

Ralph B. Arlinghaus, PhD:

Yes, I’m always interested

Tacey Ann Rosolowski, PhD:

… strategic things on.

Ralph B. Arlinghaus, PhD:

This is a mini review compendium put out every year by the Journal of Biological Chemistry. So, I often leaf through this thing, and the first article in here was something I’m going to end up studying.

Tacey Ann Rosolowski, PhD:

Wow. That’s very cool.

Ralph B. Arlinghaus, PhD:

Because it’s got lots of data that I’m familiar with but not some of the details and I’ve already learned some things.

Tacey Ann Rosolowski, PhD:

Wow. So this is like a brand new project that you’re planning on taking on.

Ralph B. Arlinghaus, PhD:

Well, let me tell you. Maybe I’m jumping the gun here but I’m studying the role of Janus kinase 2 in chronic myeloid leukemia and I’m kind of known in that small segment of science for that discovery. And, MD Anderson, by way of Jorge Cortez, a leukemia physician here, will be running a human — actually two human trials which is based on my discovery which began in 19 — I’ll have to go to my CV, but I think it’s 1995. So I started working on Janus kinase 2. The reason I bring that up is this protein called ABL kinase --we have a paper submitted for publication and it's in minor review. That ABL kinase that you and I have activates the Janus kinase 2 kinase. Activates it. That means that ABL does something to the Janus kinase to make it active. Many enzymes and kinases are dormant until acted upon to make the kinases functional for usually a short period of time.

Tacey Ann Rosolowski, PhD:

And the ABL kinase – I’m just checking back in my notes to make sure I have consistency here – so that’s ABL, all capitals?

Ralph B. Arlinghaus, PhD:

Yes.

Tacey Ann Rosolowski, PhD:

Okay. And the Janus kinase, I don’t think I’ve encountered that one before. How do you spell the Janus part of that?

Ralph B. Arlinghaus, PhD:

Janus is J-A-N-U-S, Janus kinase.

Tacey Ann Rosolowski, PhD:

Kinase.

Ralph B. Arlinghaus, PhD:

It's named after a Greek god that had two heads.

Tacey Ann Rosolowski, PhD:

The two faces. That’s right, I remember that.

Ralph B. Arlinghaus, PhD:

That’s right. Two faces, you’re right.

Tacey Ann Rosolowski, PhD:

Why is it called after that particular god?

Ralph B. Arlinghaus, PhD:

Well, because Janus kinase, when it was first discovered – I forget the name of the person who published first on Janus kinases – he noted that the structural entities of Janus kinase 2, argued that they had two catalytic domains like, the Janus, the two-head, two-face god.

Tacey Ann Rosolowski, PhD:

Right.

Ralph B. Arlinghaus, PhD:

So it had two — most kinases, protein kinases, have one catalytic domain. Janus kinase has two and …

Tacey Ann Rosolowski, PhD:

And do they function very differently or …

Ralph B. Arlinghaus, PhD:

They do.

Tacey Ann Rosolowski, PhD:

They do, very differently.

Ralph B. Arlinghaus, PhD:

059 They do.

Tacey Ann Rosolowski, PhD:

So …

Ralph B. Arlinghaus, PhD:

In fact, the one controls the other.

Tacey Ann Rosolowski, PhD:

Oh, wow.

Ralph B. Arlinghaus, PhD:

We now know.

Tacey Ann Rosolowski, PhD:

Interesting. Hmm.

Ralph B. Arlinghaus, PhD:

It’s not my work but others have shown that.

Tacey Ann Rosolowski, PhD:

Well, I’m glad you mentioned that and that we kind of dived in because one of the things that I wanted to ask you about - because as I mentioned to you before I turned on the recorder, I interviewed pathologists before, but I’ve never interviewed a molecular pathologist. And so, can you tell me what you do as a molecular pathologist that makes you unique?

Ralph B. Arlinghaus, PhD:

Well, pathologists – and I’m probably not going to do justice to this – they examine tissue and slides and they are looking at the tissue level with microscope, looking at the cells within the tissue. A molecular pathologist like me – I started this department in 1986, I guess, ’86. I heard people like myself who was interested in understanding the molecular details of what goes on inside the abnormal cell and how that differs from normal cells. So, you know, in pathology, they look at cells and they identify abnormal cells. We use special techniques to break open the cells to then analyze these various factors inside the cells, and how those factors interact with one another inside the cell, in normal cells and in cancer cells, or in my case, leukemia cells. So, that has led — I don’t want to overstate my role in Gleevec. Gleevec is a major targeted therapy for chronic myeloid leukemia discovered by Brian Druker in Oregon. And, that drug is not chemotherapy. It targets the ABL kinases which are actually fusion proteins, hybrid proteins, in chronic myeloid leukemia. So …

Tacey Ann Rosolowski, PhD:

So, you say it’s not chemotherapy because it actually ….

Ralph B. Arlinghaus, PhD:

It’s therapy, its targeted therapy.

Tacey Ann Rosolowski, PhD:

It’s targeted therapy.

Ralph B. Arlinghaus, PhD:

When I think of chemotherapy, and I’m not a physician, I think of things like 5-fluorouracil …

Tacey Ann Rosolowski, PhD:

Right

Ralph B. Arlinghaus, PhD:

… which is — targets a lot of nucleic acids …

Tacey Ann Rosolowski, PhD:

Right.

Ralph B. Arlinghaus, PhD:

… in normal cells.

Tacey Ann Rosolowski, PhD:

So, it infuses everything.

Ralph B. Arlinghaus, PhD:

It changes — changes lots of things in the cell.

Tacey Ann Rosolowski, PhD:

Right.

Ralph B. Arlinghaus, PhD:

And very toxic. So chemotherapy in general, you can take eight to 10 weeks if you’re a cancer patient. If you take it longer, it’s lethal.

Tacey Ann Rosolowski, PhD:

Mhmm.

Ralph B. Arlinghaus, PhD:

So Gleevec, being targeted therapy, affects one or two things inside the leukemia cell and it’s not toxic to any great extent so people can take Gleevec and have been taking Gleevec for five, six, seven, eight years.

Tacey Ann Rosolowski, PhD:

Wow.

Ralph B. Arlinghaus, PhD:

And there — and it maintains the leukemia in a dormant state, so to speak. It doesn’t cure the disease, but it maintains the disease in a quiescent state. So, that’s targeted therapy. You’re — you’re inactivating a key factor in the cancer.

Tacey Ann Rosolowski, PhD:

Now, am I assuming correctly that you had a contribution to discovering how Gleevec could be applied in the leukemia cell?

Ralph B. Arlinghaus, PhD:

I did.

Tacey Ann Rosolowski, PhD:

Can you tell me about that?

Ralph B. Arlinghaus, PhD:

Well, there were trials run on Gleevec in patients so I developed a method to measure quantitatively levels of the BCR-ABL protein – I’ll have to get to that for you but – in chronic myeloid leukemia, there’s an abnormal chromosome that develops, fuses parts of BCR to parts of ABL to give you a hybrid gene, BCR-ABL, that produces a hybrid protein that you and I and other healthy people do not have. So that BCR-ABL leukemia protein, when it forms in the right cell in leukemia patients, will cause chronic myeloid leukemia.

Tacey Ann Rosolowski, PhD:

So, the protein – what does the protein actually do? Is it does that lead to the --

Ralph B. Arlinghaus, PhD:

See, your cells are full of protein that are kind of doing all the heavy lifting inside the normal cell, carrying out things like -- this is not a good example now, but what comes to my mind is insulin. Insulin is a protein and what does insulin do to control blood sugar? It’s very complicated. It’s not my field, but we could talk about it a long time. But, the insulin gene doesn’t do much for you but the messenger RNA for insulin and then the protein that’s produced from the messenger RNA produces the insulin protein, which is doing all the work for us, to keep us with reasonable levels of in our blood, in our cells. So, proteins are the functional entities that carry out different things inside cells or between cells. Genes encode for those and that’s very important. But, the genes are not, in general, functional entities like proteins. Protein is actually and so, as a molecular pathologist, we want to understand what these various catalysts, these various proteins, these various enzymes, what they do normally in your blood cells and mine, and what they do in the leukemia cell, and how that differs. And then, we want to find out, 1), how to -- how to detect that abnormality – abnormal protein – and how to neutralize it or make in inactive. So, molecular pathology is looking at the functional parts of leukemia or cancer cells, the proteins to try to describe how they interact with the cellular machinery inside the cell, how they interact with other normal proteins, how they alter other normal proteins and that — all those process — processes contribute to how the BCR-ABL oncoprotein, leukemia protein, causes leukemia. What Brian Druker did many years ago now, working with Novartis, a pharmaceutical company. is ---

Tacey Ann Rosolowski, PhD:

Excuse me. Do you mind if I shut the door to make sure?

Ralph B. Arlinghaus, PhD:

You can go ahead and shut it. Sorry

Tacey Ann Rosolowski, PhD:

I got it. Little more noise control

Ralph B. Arlinghaus, PhD:

You can --- what Druker did — Brian Druker did was work with Novartis with their — they had a compound which was the forerunner of Gleevec, and he studied this compound in cells from patients that had leukemia, chronic myeloid leukemia, not just any leukemia, but chronic myeloid leukemia. And he studied that compound that they made and showed that it should be useful to kill chronic myeloid leukemia cells without having much effect on cells that have the forerunner of the BCR-ABL protein, called ABL, we talked about here. That ABL protein is in you and I and under certain conditions, Gleevec can inhibit ABL. So as I understand it, Novartis didn’t want to develop this drug compound that they developed because they were afraid it would be too toxic. Because not only would it inhibit or block the BCR-ABL enzyme, it would also block the normal ABL enzyme, creating lots of side effects. Well, it turns out that the level of their compound needed to block BCR-ABL was lower in concentration than what it took to inhibit ABL. So in other words, there was a low enough concentration of their drug, they could block BCR-ABL activity but not ABL activity. And that --- of course, Druker didn’t know that but he eventually found that out.

Tacey Ann Rosolowski, PhD:

But it opened the gateway to ---

Ralph B. Arlinghaus, PhD:

So it opened the gate ---

Tacey Ann Rosolowski, PhD:

Yeah.

Ralph B. Arlinghaus, PhD:

--- and plus they started treating patients in trials and some of those trials were done here at MD and I was asked – that’s how we got into this – I was asked because they paid me a little money from the trial – very little – to analyze blood fractions, some blood from chronic myeloid leukemia patients treated with Gleevec and what happens to the leukemia cells.

Tacey Ann Rosolowski, PhD:

How interesting.

Ralph B. Arlinghaus, PhD:

So I was kind of the — I had an advanced technique to analyze leukemia cells and determine whether they would be alive or dead.

Tacey Ann Rosolowski, PhD:

Interesting.

Ralph B. Arlinghaus, PhD:

And so, I — that was my mini role.

Tacey Ann Rosolowski, PhD:

Yeah, yeah. But a role.

Ralph B. Arlinghaus, PhD:

But, yeah, and this ---

Tacey Ann Rosolowski, PhD:

Yeah.

Ralph B. Arlinghaus, PhD:

So what I found out is when you use Gleevec, the BCR-ABL protein cell disappeared, and I found by my assay they died. They underwent cell death.

Tacey Ann Rosolowski, PhD:

That must have been an amazing moment to discover that.

Ralph B. Arlinghaus, PhD:

Well, Druker already knew that ---

Tacey Ann Rosolowski, PhD:

Yes.

Ralph B. Arlinghaus, PhD:

--- but I had a different assay that sort of confirmed that.

Tacey Ann Rosolowski, PhD:

Yeah.

Ralph B. Arlinghaus, PhD:

So again, a very small role.

Tacey Ann Rosolowski, PhD:

Yeah.

Ralph B. Arlinghaus, PhD:

I didn’t do the pioneering work that Brian Druker did. I am not going to detract from what he did. So I was one of the many players.

Tacey Ann Rosolowski, PhD:

Yeah. Over and over again, people have emphasized to me how many contributors there are to discover ---

Ralph B. Arlinghaus, PhD:

That’s right.

Tacey Ann Rosolowski, PhD:

--- discoveries of this kind

Ralph B. Arlinghaus, PhD:

I was one of the many contributors ---

Tacey Ann Rosolowski, PhD:

Yeah.

Ralph B. Arlinghaus, PhD:

--- played an interesting important problem.

Tacey Ann Rosolowski, PhD:

Yeah. Well, thank you for telling me that. And that does kind of orient me better as we go ahead kind of talking about how your career evolved.

Conditions Governing Access

Open

Chapter 01: Key Research on ABL Kinases

Share

COinS