Chapter 07: Research Pathways and Research Issues that Emerge from EGFR Work

Title

Chapter 07: Research Pathways and Research Issues that Emerge from EGFR Work

Files

Loading...

Media is loading
 

Description

In this chapter, Dr. Yung talks about the research paths that evolved from his work on EGFR, though he has been unsuccessful so far in discovering how to render glioblastoma sensitive to the receptor. He goes on to describe the lines of research that have opened up and also discusses controversies that have arisen around the issue of sequencing the cancer genome. He notes that MD Anderson is one of the suppliers of tissue to The Cancer Genome Atlas project -and he is involved in this. Dr. Yung also explains how the body of knowledge growing from this project and the International Cancer Genome Continuum has influenced how researchers look at tumors. Dr. Yung explains that the fundamental question is Can we understand the evolution of a tumor? He notes the special technical and ethical difficulties that arise with examining brain tumors.

Identifier

Chapter 07: Research Pathways and Research Issues that Emerge from EGFR Work

Publication Date

5-7-2014

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; Definitions, Explanations, Translations; The Professional at Work; Understanding Cancer, the History of Science, Cancer Research; Controversies; Ethics; Activities Outside Institution; Beyond the Institution; Healing, Hope, and the Promise of Research

Transcript

Tacey Ann Rosolowski, PhD:

Now how did that research lead to other projects --- well maybe I should ask you first, what were some of the key findings that you’ve made with that research about the epider --- epidermal growth factor receptor and with PTEN that have taken a turn into affecting patient care with therapies?

Wai-Kwan Alfred Yung, MD:

Well I --- I think the research in epidermal growth factor functions in brain tumor and --- led to, you know, many clinical trials.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

You know, foll --- actually following the --- the --- the timeline of dev --- the development of epiderm --- EGF receptor inhibitor and EGF receptor antibody.

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

in --- in --- in cancer research. And so the --- the laboratory study that we do in our laboratory and other labs in the brain tumor world actually convinced, you know, several drug companies to give us EGF receptor inhibitor.

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

to --- to --- to treat brain tumor in the glioblastoma patient. We did not see a who --- un --- un --- unfortunately it is not highly active, you know, in --- in --- in glioblastoma, you know. But it was also not very active in other cancer until the --- the --- the, you know, development of molecular biology and --- and molecular genetic, you know, when we start matching the genetic changes

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

To the reason of responding or not responding and --- and the lung cancer people is able to identify the mutation --- specific mutation in the EGF receptor gene. Spec --- that match with sensitivity to the EGF receptor inhibitor. I mean that’s the time --- when --- when we start identify as this specific mutation in the --- in the kinase domain of the --- of the EGF receptor gene that is present in the higher frequency in Asia --- you know, Asia population in Asian man and woman than Caucasian. And there is a discrepancy of that gene mutation

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

20% --- 20% in --- in --- in Asian population and only 5% in --- in Caucasian and --- and those who carry this mutation is highly sens --- highly responsive or sensitive to the EGF receptor inhibitor. They --- th ---- so that again takes a long time when we go to that stage of now we’re able to match the gene mutation with sensitivity drug.

Tacey Ann Rosolowski, PhD:

Can I just ask you bec ---

Wai-Kwan Alfred Yung, MD:

And brain tumor does not have that mutation

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

Unfortunately.

Tacey Ann Rosolowski, PhD:

Right.

Wai-Kwan Alfred Yung, MD:

There is very low frequency with --- with in --- that’s why right now up to this time, almost 20 years now, we still have not really increased the responsiveness of brain tumor patients to EGF receptor inhibitor.

Tacey Ann Rosolowski, PhD:

Uh-Hmm.

Wai-Kwan Alfred Yung, MD:

We have some clue but we ha --- we are not there yet.

Tacey Ann Rosolowski, PhD:

____, I was just going to ask you that question about the time. You know, 20 years, looking at this one problem. I mean this may be a naïve question, but are you --- if you --- the persistence question. You know, why --- what is that you are unraveling that gives you the sense that

Wai-Kwan Alfred Yung, MD:

Well --- I --- I think that

Tacey Ann Rosolowski, PhD:

Eventually there will be

Wai-Kwan Alfred Yung, MD:

What the --- the --- the so --- I mean --- if I look at, you know, the question of, you know, are you disappointed that after that many years of focusing on EGF receptor for brain tumor we still have not find a --- a

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

--- a --- a, you know, solution or we have not find a hit to really in --- increase the responsiveness of the tumor to EGF receptor. I am --- I am disappointed for that end, but I am not disappointed because of focusing on EGF receptor also unraveled all the parallel relationship discovering other pathways.

Tacey Ann Rosolowski, PhD:

Right

Wai-Kwan Alfred Yung, MD:

other linkage to Uh-hmm.

Wai-Kwan Alfred Yung, MD:

to the PI3 kinase pathway to other growth factor. I mean, it open up an --- a --- a whole, you know, line of research to look at, you know, what propelled glioblastoma cell growth. What propelled glioma cell growth. Because the same --- the same question is being asked in different tumor types of glioblastoma, even in the brain tumor world, glioblastoma, astrocytoma, oligodendroglioma, and we got different laboratory stuff, building models to look at this question.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

What is the role of growth factor in these ___ ____ (3)? What is the role of signal pathway? And --- And that really generated a whole new line of research

Tacey Ann Rosolowski, PhD:

) 32.Uh-hmm.

Wai-Kwan Alfred Yung, MD:

Of --- and we bring in all this complicated pathway and --- of course --- I can --- we also benefit greatly, you know, when NCI and NIH, you know, decided to develop, you know, the genome Atlas for cancer

Tacey Ann Rosolowski, PhD:

The gene ---

Wai-Kwan Alfred Yung, MD:

After they --- after --- after --- you know, in the mid ‘90s, the NIH --- was it --- was it the mid ‘90s or late --- yeah late ‘90s I think. I don’t remember when the project began. NIH and NCI decided to, you know, follow the success of sequencing the entire human genome, the entire mouse genome, and --- and start asking the question well can --- can we sequence cancer genomes. And --- and there was --- actually there was big debate whether NIH will spend time and effort to try to sequence

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

the cancer genome because cancer is such a complicated disease and such a dynamic disease and it keeps changing. Cancer is not a static process. You know, --- we --- but we --- but we all known that when --- when cancer --- cancer can present in a early stage, late stage, you know, early malignancy, late malignancy and so there is a dynamic change of cancer. Can you really sequence the genome in a dynamic disease as opposed to the human normal gene that is static.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

The normal. It doesn’t ch --- when it changes it changes in a small way _____ (3) and --- and they identify disease in that small way.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

But cancer keeps changing. So there was a big debate. The --- The cancer people win and say we will learn something

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

3:But let’s sequence gene and NIH invest --- invest, you know a big chunk of money into sequencing it and it caused the --- the cancer genome Atlas project. And they select three cancers as a pilot and glioblastoma was selected as one of the three cancers besides squamous cell carcinoma of the lung and --- glioblastoma, squamous cell carcinoma of the lung, and what is the third one? Is it ovarian cancer? I think it is ovarian cancer.

Tacey Ann Rosolowski, PhD:

Ovarian?

Wai-Kwan Alfred Yung, MD:

Yeah.

Tacey Ann Rosolowski, PhD:

UIh-hmm.

Wai-Kwan Alfred Yung, MD:

And that’s the pilot. And --- And so

Tacey Ann Rosolowski, PhD:

What’s your view of the value?

Wai-Kwan Alfred Yung, MD:

We --- actually at MD Anderson is one of the tissue supplier --- the tissue supply --- brain tumor tissue as well as all the other lung cancer tissues and ovarian cancer tissue to --- to --- to the project of the TCGA. But we have high quality tissue, you know, for them to do the sequencing. So we are the tissue supplier and then we also participate with ____ (3

Tacey Ann Rosolowski, PhD:

And TGCA that stands for

Wai-Kwan Alfred Yung, MD:

T is The, C Cancer, G --- G is Genome

Tacey Ann Rosolowski, PhD:

Oh.

Wai-Kwan Alfred Yung, MD:

A Atlas. So, its --- so TCGA

Tacey Ann Rosolowski, PhD:

There we go.

Wai-Kwan Alfred Yung, MD:

The Cancer Genome Atlas. And that actually evolved into an --- into the TCGA, the ____ is a US effort (3).

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

And that evolved into an international effort called ICGC. International Cancer Genome Consortium.

Tacey Ann Rosolowski, PhD:

How have --- have you benefited? Has your work benefitted in any way from this project?

Wai-Kwan Alfred Yung, MD:

I think so. Yeah. We --- We --- We benefit I think not only our work at Anderson or my work and I’m intimately involved with the TCGA effort for brain tumor.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

I’m involved in --- in --- because we --- we then from sequencing glioblastoma then we convince you know TCGA to also improve lower grade brain tumor. So, we have basically two projects. One with the high grade glioblastoma and then the lower grade tumor and I was involved in both projects.

Tacey Ann Rosolowski, PhD:

So if you’re

Wai-Kwan Alfred Yung, MD:

So we benefited greatly because the knowledge --- really we define how we look at the --- the tumor.

Tacey Ann Rosolowski, PhD:

How so?

Wai-Kwan Alfred Yung, MD:

): Not on --- Not only from the morphology side. I mean in the past we defined a tumor by, you know, this is --- this tumor comes from astrocyt --- astrocytoma. This tumor comes from oligodendroglioma --- is oligodendroglioma from oligodendrocyte. And this tumor comes from astrocyte and is a lower degree of malignancies because not that many cells are dividing and not that many blood vessels, so it’s astrocytoma grade 2.

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

Lots of cells dividing a lot of blood vessels as --- in astrocytoma grade 3. There is a lot of dead tissue necrosis, so it is glioblastoma. It’s all based morphology. Now that we go into the molecular area we start looking at well this group of tumor had EGF receptor mutation. This group of tumor has NF1 mutation and this group of tumor has different mutation and --- and the meaning of this mutation and how do we --- and so we’re now actually building a so-called molecular classification besides, you know, being parallel to the histologic classification. And in the future de --- we believe that the molecular classification will tell us a lot more how to treat these tumors. Then purely histologic classification because each histologic classification had multiple molecular subgroup.

Tacey Ann Rosolowski, PhD:

Now how have you finessed the problem of can --- of these cancers being so dynamic? You know, are you taking samples longitudinally? So h ---

Wai-Kwan Alfred Yung, MD:

And so now, is --- that’s a very good question too. You know, it’s --- that is --- that is a fundamental question. Can we understand the evolution of a tumor as it develops, as it’s being treated, and in the different stages of treatment how does the cancer change? It is a much difficult question to answer for solid tumor than in liquid tumor.

Tacey Ann Rosolowski, PhD:

Hmmm.

Wai-Kwan Alfred Yung, MD:

) The liqui --- you know, leukemia you can actually --- is not --- it is much less invasive to the patient to draw blood in different stages of the tumor. But being a solid tumor depending on the location of the tumor is much more difficult to get tissue in different stages. For example in brain tumor where is the most --- being the most difficult location. Trying to --- to get a piece of the tumor is n --- is pretty invasive. You have to open the brain to get a piece of tissue. Even if --- if you can do a needle biopsy you still need to drill a hole and stick a needle into the brain passing through normal brain to get to the tumor to get a piece, so its not a --- not a simple innocuous procedure. You cannot do it --- you certainly cannot do it many times

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

as opposed to draw blood many times. So we are pretty limited in how many times we can sample the tumor. In the beginning of treatment, during treatment, or after treatment. It’s not like leukemia when you get the blood easy or even malignant melanoma like in the surface of the --- the skin you can ta --- take a nip without that much damage or that much trauma to the patient. You know, you can take a snip of the --- of the tumor in the beginning, you know, one week after treatment and one month after treatment is still kind of on the surface you can, you know --- and the brain I cannot tap the brain weekly or monthly.

Tacey Ann Rosolowski, PhD:

Yeah.

Wai-Kwan Alfred Yung, MD:

Without a lot of damage. So it’s a lot more

Tacey Ann Rosolowski, PhD:

So

Wai-Kwan Alfred Yung, MD:

It’s a lot more difficult to answer that question but that’s what we want to a --- wh --- that’s what we are doing.

Tacey Ann Rosolowski, PhD:

Um-hmm. So

Wai-Kwan Alfred Yung, MD:

Want to do, yeah.

Tacey Ann Rosolowski, PhD:

How are you deciding the timing of the samples since you have these limitations?

Wai-Kwan Alfred Yung, MD:

It’s again --- it is --- it is difficult. I mean I think wha --- what we can do --- right now we’re actually only limited to the first piece

Tacey Ann Rosolowski, PhD:

Uh-hmm

Wai-Kwan Alfred Yung, MD:

To make the diagnosis that you have the tumor or the second piece when the tumor comes back and we need to remove the tumor, you know, to --- you know, either for needle diagnosis or we need to remove it to decompress the brain so to --- you know, to relieive symptoms.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

You know so a second surgery is to --- to --- and that --- and we’re --- you know, I --- I don’t think, you know, we can really take biopsy when the patient is doing well from treatment and stable and you say I’m going to stick a needle into your brain now and get a biopsy even though we, you know, it’s --- it’s two months after the treatment or three months after the treatment and you’re doing well, the tumor is stable and you don’t need it, you know, we just want to have a piece of the tumor to study it.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

Not only insurance will not pay for it.

Tacey Ann Rosolowski, PhD:

Right.

Wai-Kwan Alfred Yung, MD:

The patient probably don’t want to subject that risk, right? Because it’s high risk.

Tacey Ann Rosolowski, PhD:

Right.

Wai-Kwan Alfred Yung, MD:

So that’s a --- right now it’s a big limitation for us to answer the question of how brain tumor evolves and respond to treatment.

Tacey Ann Rosolowski, PhD:

Uh-hmm. Sounds like a classic ethical issue too.

Wai-Kwan Alfred Yung, MD:

Yeah.

Tacey Ann Rosolowski, PhD:

Yeah. I mean there are a lot of controversy around the whole thing.

Wai-Kwan Alfred Yung, MD:

--- controversy. Yeah.

Tacey Ann Rosolowski, PhD:

Yep. Yep.

Wai-Kwan Alfred Yung, MD:

But we need to be able to do that in order

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

You know --- you know then --- because we do --- we do know that even though we have a good understanding of the --- of the molecular profile or the genetic profile of the tumor in the beginning. Once we treat with radiation or with drug, that structure, that profile, changes. Because we are disturbing with the --- with the --- with the treatment modality with radiation or the drug we are disturbing that.

Tacey Ann Rosolowski, PhD:

Wow.

Wai-Kwan Alfred Yung, MD:

The genetic pattern.

Tacey Ann Rosolowski, PhD:

That is a real gap in knowledge

Wai-Kwan Alfred Yung, MD:

Yeah. And then when we --- when we try to propose a --- a new treatment when the tumor grows after the first set of treatment

Tacey Ann Rosolowski, PhD:

Uh-hmm

Wai-Kwan Alfred Yung, MD:

If we base on the profile here, we’re proba --- is wrong is because that profile is changed by the treatment.

Tacey Ann Rosolowski, PhD:

Right. Interesting.

Wai-Kwan Alfred Yung, MD:

And --- And we need to have a new profile.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

Wh ---, you know, in that new tumor.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

And --- And treatment needs to be based on that new profile. Leukemia can do that. Malignant melanomas do it easier and even breast cancer can do it easier at least, but brain is very difficult.

Tacey Ann Rosolowski, PhD:

Hmm. Hmm.

Wai-Kwan Alfred Yung, MD:

Yeah.

Chapter 07: Research Pathways and Research Issues that Emerge from EGFR Work

Share

COinS