Chapter 06: Looking at Chromosomal Patterns in Brain Tumors; Chromosomal Heterogeneity, Chemo-Sensitivity, and EGFR

Title

Chapter 06: Looking at Chromosomal Patterns in Brain Tumors; Chromosomal Heterogeneity, Chemo-Sensitivity, and EGFR

Files

Loading...

Media is loading
 

Description

Dr. Yung discusses the evolution of his research, beginning with work on chromosomal patterns at Memorial Sloan-Kettering in the late 70s. He sets this work in the context of the science at that time and its development into the entirely new field of genomic medicine. Next he explains the evolution of his work to include epidermal growth factor receptors (EPGR) and their importance in cells, discussing connections to work of other MD Anderson faculty. He describes the relationship of the gene to kinase and EGFR functions. He then talks about his shift into translational research since 1997. Dr. Yung then sketches the history of translational research at MD Anderson, noting that in the Eighties and Nineties, the institution became a forerunner in applying translational research to clinical questions.

Identifier

YungWKA_02_20140507_C06

Publication Date

5-7-2014

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; Understanding Cancer, the History of Science, Cancer Research; MD Anderson History; Multi-disciplinary Approaches; Discovery and Success; The Professional at Work; Understanding Cancer, the History of Science, Cancer Research; MD Anderson Impact; Institutional Mission and Values

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

Disciplines

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

Transcript

Tacey Ann Rosolowski, PhD:

Well why don’t we talk about your research then? Because we --- we had talked a little bit last time about you coming to MD Anderson. You talked about your dreams for making Neuro-Oncology really a clinical piece of what MD Anderson could offer. And but we didn’t talk about --- And you talked about how you set up your lab and then moved it to the main campus but we really didn’t talk about the projects you were working on and the evolution of your own research. So I’d really like to --- to get that story.

Wai-Kwan Alfred Yung, MD:

Well when --- When I was a fellow at --- at Memorial Sloan-Kettering I started on a project with --- with Dr. Joan Shapiro at that time at Memorial. We started a project looking at the question of heterogeneity.

Tacey Ann Rosolowski, PhD:

Okay.

Wai-Kwan Alfred Yung, MD:

Recognizing that, you know, brain tumor is not a, you know, homogeneous tumor

Tacey Ann Rosolowski, PhD:

Hmm

Wai-Kwan Alfred Yung, MD:

Like a liquid tumor like leukemia or lymphoma. You know, brain tumor is like other solid tumor, breast cancer, lung cancer, it is very heterogeneous.

Tacey Ann Rosolowski, PhD:

Hmm

Wai-Kwan Alfred Yung, MD:

with --- with multiple populations. So we started a project back then looking at chromosomal pattern back, but back then in 19 in the --- in the late 1970’s, you know, molecular genetic is coming online. And --- and, you know, genetics is starting with looking at karyotyping and looking at chromosome changes, chromosome gain, chromosome loss. And that is --- that was the time that, you know, in the brain tumor world we start --- with in terms of karyotyping begin --- began to identify some chromosomal change in brain tumor, including gaining chromosome 7 and loss of chromosome 10. These ---

Tacey Ann Rosolowski, PhD:

0/2 Wha --- What is the significance of those?

Wai-Kwan Alfred Yung, MD:

The --- These are the work done at Duke, you know, and also with Joan Shapiro. The --- The significance of chromosome changes is that you cannot --- you can use those changes as a marker

Tacey Ann Rosolowski, PhD:

Uhm.

Wai-Kwan Alfred Yung, MD:

for the tumor, you know, and also identify the m --- you know, clones of cells with a different chromosome pattern. So in fact, we di --- we did a project like th --- just like that in terms of looking at one patient’s tumor, how many different clones of cells are there are and what kind of chromosome, you know, pattern those clones of cells, you know, display.

Tacey Ann Rosolowski, PhD:

And what did you find?

Wai-Kwan Alfred Yung, MD:

And we find that, you know, from one tumor have many different clones and each clone has its own chromosome --- basic chromosome pattern. Changes in chromosome. And that’s --- I think that is --- is --- you know we ---- we start working on this question of how does the chromosome pattern influence the sensitivity of the cell to different drug? You know, using drug sensitivity again as a, you know, functional characteristic of the cell in relationship with --- with the chromosome pattern. Th --- Later on, now a day we don’t talk about chromosome pattern now. Now we talk about genes. What gene colony () with sensitivity, what drug?

Tacey Ann Rosolowski, PhD:

And what ca---

Wai-Kwan Alfred Yung, MD:

So that was the very beginning, so it is kind of, you know, early development on precision medicine _____ (). But the crude assay at that time is looking chromosome change.

Tacey Ann Rosolowski, PhD:

And what caused that wh --- you --- when you talked about used to talk about chromosome patterns and now you talk about genes, what caused that shift in vocabulary? It was a conceptional shift or ---

Wai-Kwan Alfred Yung, MD:

Well, because, you know, with the --- with the development of, you know, molecular genetics and molecular biology, you know, the technology advanced a lot. It was to look at, you know, the gene structure. We have the total number of genes in a human genome change in number, you know. Until the human genome project is completed, then there is a --- a better understanding of how many genes is in the human genome. And how many genes is in the enti --- the 22 chromosomes. So early days, you’re only looking at chromosome pattern and --- and --- and you can look at the character of the chromosome by different band, we call chromosome banding. And --- And we don’t have the knowledge of the gene yet at that point. But later on when the tech --- technology develops and now we start sequencing, you know, the chromosome or the DNA in the chromosome and now you are able to --- to really identify the gene and location of the gene and the structure Of the gene, whether it is normal or mutated or lost. So you evolve from a big picture of chromosome to the final picture of gene. And then also, you know, the structure of the gene that is involved. Exon, you know, non --- you know, the space between the exon --- intron and exon. And --- And all these just keep develop where we find with the technology coming up, you know.

Tacey Ann Rosolowski, PhD:

Uh-hmm. So this is really the development of an entirely new field.

Wai-Kwan Alfred Yung, MD:

There’s the development of an entirely new field in --- in, you know, genetics into molecular genetics and with molecular biology. And now, you know, we’re in the area of genomic medicine. You know, the application of the geno --- genomic knowledge into --- into the clinic and prescribing medicine according to the --- to the genetic makeup of the disease.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

So my first project in really looking at, you know, heterogeneity in terms of, you know, the technique that we will have at that time _____ () is --- is chromosome pattern. And --- And chemosensitivity. Then later on, you know, we --- when I moved to Anderson, we started looking at then --- then we beginning to --- again the --- the field developed that now we recognize there are some growth factors that you know, are important in the, you know, in the growth potential of these cells. And the first growth factor receptor that was identified is important to brain tumors is epidermal growth factor receptor. You know, so

Tacey Ann Rosolowski, PhD:

And that’s the EGFR.

Wai-Kwan Alfred Yung, MD:

EGFR

Tacey Ann Rosolowski, PhD:

Yeah. Okay.

Wai-Kwan Alfred Yung, MD:

Now EGFR is

Tacey Ann Rosolowski, PhD:

And you --- is --- your lab identified that, or

Wai-Kwan Alfred Yung, MD:

No. Our lab did not identify that. The EGF receptor is --- is identified by --- by, I don’t remember. Actually, Dr. Mendelson is --- is very essential in th --- in the work of EGF receptors functioning in cancer.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

But I don’t remember who discovered the EGF receptor.

Tacey Ann Rosolowski, PhD:

And I noticed as I was doing the background that EGFR comes up a lot in describing your focus. So you eventually began to work with that.

Wai-Kwan Alfred Yung, MD:

I wou --- We --- We --- We spent a lot of time working on EGF receptor and the --- the protein that stimulates EFG receptors. And --- And then in --- in the --- you know, when my lab first established and come over, you know, we moved the lab to Anderson in ’83 and then we --- we recruited a scientist, Peter Steck, to join us. Peter --- Peter joined --- was at Anderson already. He finished his post doctoral fellowship with Dr. Nicholson --- Nicholson and looking for a staff position and --- and I created a --- a scientist faculty position for him and he joined us. And --- And, so we work on EGF receptor together but he’s also a --- a protein chemist, you know, so

Tacey Ann Rosolowski, PhD:

So he’s a PhD.

Wai-Kwan Alfred Yung, MD:

He’s a PhD.

Tacey Ann Rosolowski, PhD:

PhD. Uh-hmm.

Wai-Kwan Alfred Yung, MD:

11: He’s a scien --- scientist to run EGF receptor together with --- and then at the same time he started a --- a --- a project of, you know, trying to --- to look at the observation of loss of chromosome 10 in these brain tumors. Glioblastoma cell. And --- And what’s behind this loss

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

of chromosome 10. Especially, there is a piece of chromosome 10 that is missing in many tumors and he wanted to identify what gene is located in that pie --- that piece of chromosome 10. And --- And, the thinking at that time is that, you know, when you have gene that is missing, that --- that is a tumor suppressive gene that --- that now plays a role in --- in preventing cancer development. But, then when you miss that tumor suppressive gene then

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

1.You know, the cell becomes malignant. So --- with a long story, it takes awhile for him to --- but he started with a technique of somato --- somato-cell fusion and --- and tried to reidentify this in bits --- bit by piece of the chromosome and --- and

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

Identify the gene ____ (1). But eventually in 1997, you know, we --- we sequenced and --- and --- and discovered the --- the PTNG ---- PTNG.

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

But there is a com ---, you know, --- competing lab in Columbia that is also working on the same --- same gene and that --- they’re proving in --- in Columbia by Ramon Parsons. And, we ended up actually announced the --- the --- the discovery together.

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

You know, the two labs announced the discovery together.

Tacey Ann Rosolowski, PhD:

Oh wow.

Wai-Kwan Alfred Yung, MD:

We --- At Anderson we id --- we call the gene as MMAC1. MMAC1, you know, stands for Mutated Multiple Advanced Cancer, because Peter was able to show that --- that missing gene the P10 ge --- the missing gene --- missing chromosome 10 is involved in not only glioblastoma but also involved in advanced breast cancer.

Tacey Ann Rosolowski, PhD:

Oh, wow.

Wai-Kwan Alfred Yung, MD:

and prostate cancer. That’s why --- he used the term --- he quickly named it as MMAC, but Dr. Parsons’ group named it PTEN --- PTEN because it’s on chromosome 10.

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

And --- And I think that --- that PTEN was adopted as the --- as the official name of that gene.

Tacey Ann Rosolowski, PhD:

Right.

Wai-Kwan Alfred Yung, MD:

But the --- the function of PTEN gene is intimately related to an enzyme called --- PI3 kinase --- PI3 kinase and it’s also --- and PI3 kinase is linked with EGF receptor function. So, that’s why we --- we --- we started with EGF receptor work and then Peter

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

branched off to look at, you know, tried to clone the gene of PTEN and then so from that point on with all that really worked on a goal, the function of the PTEN gene and how it’s length with growth factor receptor activity in --- in brain tumor. That has been the line of research that now we follow.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

) From 1997 onward. Unfortunately, Peter died in 1999 from a massive heart attack, you know.

Tacey Ann Rosolowski, PhD:

Hmm. That’s a loss.

Wai-Kwan Alfred Yung, MD:

So --- So it is a big loss.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

I took over some of his work, but, I mean I’m not since I --- I wear two hats at that time trying to be a physician scientist, run the lab as well as run the clinic. So, we --- we take a more translational direction trying to look at the function of the, you know, --- the PTEN regulated PI3 kinase pathway and how it influence cell growth and how we can --- how we can int --- you know, inhibit this function. And --- And you know, inhibit cell growth. So we took the e --- the --- the lab takes on a more translational direction instead of a basic science direction.

Tacey Ann Rosolowski, PhD:

Now I wanted to ask you about that, because, you know, we talked about how you --- your work and just you professional life has been evolved during the creation of entirely new fields and translational --- the translational approach has been part of that. And one of the things I’ve been interested in asking people about in these interviews is what is really the history of translational research? You know, what did translational research, how are pe --- how were people thinking about it i --- in the early days and how has it developed? How has it changed or become more complex. So that --- I --- you know, you’ll have to tell me what the evolution has been.

Wai-Kwan Alfred Yung, MD:

It’s --- That’s a interesting question. Because, I think you could get different answers from different people.

Tacey Ann Rosolowski, PhD:

Yeah.

Wai-Kwan Alfred Yung, MD:

I --- I mean is --- if I look back as, you know, in --- in --- in cancer research as well as you know, --- you know, medical research, you know, even when I was, you know, very active in terms of st --- study section review of giving out grants, you --- in --- in th --- back then in the ‘70s and ‘80s very strong emphasis on basic science. So, that’s the time that we’re developing fundamental knowledge of disease and the biology of the disease and --- and there’s a lot of emphasis on understanding the biology in the very fund --- basic levels. Cellular level, organ --- organ level. And so, you know, basic science is --- is the foundation of the knowledge.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

And the clinical --- clinical research come along in a --- you know, you’re looking at clinical research. Besides understanding the anatomy and the cause of the disease is, you know, the treatment of the disease. And, the treatment of the disease, especially in the cancer world, is really, you know, besides radiation therapy and surgery, chemotherapy the use of drug came pretty much after the second World War.

Tacey Ann Rosolowski, PhD:

Uh-hmm. Yeah.

Wai-Kwan Alfred Yung, MD:

) I mean I think when you look at the history of development and even at Anderson using, you know, --- Dr. Freireich (1) and Emil Frei, these are people who are really champions and the forefathers of developing chemotherapy

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

Using a drug for cancer treatment.

Tacey Ann Rosolowski, PhD:

Uh-hmm

Wai-Kwan Alfred Yung, MD:

Before that is surgery, radiation. And --- and so clinical research really is --- is totally separate from the fundamental basic research. The laboratory knowledge accumulate in the laboratory --- in the structural level and, you know, cellular level under --- understanding protein and understanding DNA and those are all fundamental development. And there’s no improvements into the clinic because the clinic research is interaction back in behind. In --- and so the --- the two directions really dev --- develop independently of each of other

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

for a long time until --- until, you know, probably I would say late ‘80, early ‘90 when --- when --- when --- when the two sides start talking. The clinical people and the basic science people talking. There are more physician scientists. You know, people like, you know MD, PhDs --- that or MD with P --- MD PhD to s --- to start with thinking about we need to bring the clinical question into the lab.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

And take the lab observation back into the clinic. And --- And that’s where, you know, the way translation research come up is we need to bring some more of the clinical observation into the lab, you know, as our scientists, you know, how --- what do you think about this ob --- clinical observation and how do we, you know, sort of like, you know, we see when we --- when we take the cell and we treat it with this drug and it is not working. Well, why is it not working? Or we use this drug for this group of patient and it’s not working, well why is not working? And we take that question to the lab and say can you help us answer why I treat this tumor with this drug and it not working. And then the people in the lab start saying well let’s create some --- some model system.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

Can we --- Can we isolate the cell from this tumor or the cell (2). Can we, you know, make --- make a tumor --- similar tumor in the animal, in the mouse, in the dog so that we can study the tumor in mouse and dog.

Tacey Ann Rosolowski, PhD:

Now what ---

Wai-Kwan Alfred Yung, MD:

That’s where they’re at beginning of translational

Tacey Ann Rosolowski, PhD:

Uh-hmm. research.

Tacey Ann Rosolowski, PhD:

Now what was happening at MD Anderson in the ‘90s --- in the late ‘90s that made it more attractive, necessary, to have those conversations?

Wai-Kwan Alfred Yung, MD:

I --- I think we in the --- well when I came to Anderson in ’81 --- between ’81 and ’85, you know, that’s when, you know, Nic --- [Garth] Nicholson, Fidler --- Dr. [Isaiah Joshua] Fidler, Dr. [Margaret] Kripke, joined MD Anderson. And I --- I would say, you know, they bring in the --- the more translational branch --- more translational research.

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

into it --- into MD Anderson. And --- And this --- at the --- at the time that we are also --- Anderson is really developing clinical research.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

And with under --- under the group with --- with at that time we called Developmental Therapeutics. You know, with Dr. Freireich and his group.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

And then later on Dr. Krakoff came in to con --- to continue with --- with that development of emph --- elevating the sophistication and the level of clinical research. And then in the laboratory, Dr. Becker would bring in people like Nicholson, Fidler, Kripke and other people. I think from the beginning --- in the beginning of the ‘80s maybe even the ‘90s, Anderson is --- become the fore --- forerunner in more applied, more transitional laboratory usage. And I think we remain the leader in that transition as opposed to, you know, institutions like Rockefellers and Memorial Sloan-Kettering and they have, you know, they started with a strong focus on the basic issues. They have a separation from clinic to basic ______ (2), but at Anderson even I came in and joined in the ‘80s --- early ‘80s and mid ‘80s we start with focus on the translational issues and clinical research.

Tacey Ann Rosolowski, PhD:

Hmm. Hmm. Now wh --- in the ‘80s when you were beginning this project looking at heterogeneity and, you know, unraveling this whole

Wai-Kwan Alfred Yung, MD:

Uh-hmm.

Tacey Ann Rosolowski, PhD:

--- all these mechanisms involved with PTEN, how were --- I mean it seemed from the very beginning that just thinking about that research --- you were posing research questions that had clinical implications from the very beginning.

Wai-Kwan Alfred Yung, MD:

Uh-hmm.

Conditions Governing Access

Open

Chapter 06: Looking at Chromosomal Patterns in Brain Tumors; Chromosomal Heterogeneity, Chemo-Sensitivity, and EGFR

Share

COinS