Chapter 09: The Challenges of Glioblastoma; MD Anderson's Moon Shot Program; No Low-Hanging Fruit for Neuro-Oncology Research

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Chapter 09: The Challenges of Glioblastoma; MD Anderson's Moon Shot Program; No Low-Hanging Fruit for Neuro-Oncology Research

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Dr. Yung explains the challenges that glioblastoma presents to the researcher then sketches the work he is doing to build collaboration among the brain tumor community. He notes that Dr. Charles A. LeMaistre [Oral History Interview] started the Brain Tumor Group, now the largest in the country and the world. Dr. Yung next talks about MD Anderson's Moon Shots Program, now expanding to include more than the six cancers. He talks about the structure of the Moon Shots program and evaluates the lessons learned from its early years. He notes the aim of the Program to focus on "low hanging fruit" that can lead quickly to treatment advances, and explains that there are no such quick remedies on the horizon for treating glioblastoma.

Identifier

YungWKA_02_20140507_C09

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; Professional Practice; The Professional at Work; On Research and Researchers; Critical Perspectives on MD Anderson; Definitions, Explanations, Translations; Understanding Cancer, the History of Science, Cancer Research; The History of Health Care, Patient Care; Building/Transforming the Institution; Multi-disciplinary Approaches; Growth and/or Change

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:

Uh-hmm. Well, thinking too of what you said earlier about PTEN that --- and --- and that the --- the work that you were doing on those related pathways that it hasn’t had the dramatic effect on glioblastoma, but it had some for lung cancer.

Wai-Kwan Alfred Yung, MD:

Uh-hmm.

Tacey Ann Rosolowski, PhD:

So there are --- you know, there can be collateral

Wai-Kwan Alfred Yung, MD:

____ (5) collateral

Tacey Ann Rosolowski, PhD:

Right. Very interesting. I had wanted to ask you what makes glioblastoma and glioblastoma multiform such challenging cancers? Because I read that --- somewhere that you had said how difficult they are to treat.

Wai-Kwan Alfred Yung, MD:

Well, I think it’s a challenge in many ways. One --- One is the --- the --- the degree of heterogeneity is very high.

Tacey Ann Rosolowski, PhD:

Okay.

Wai-Kwan Alfred Yung, MD:

You know. And two is we still, you know --- and --- and --- and we do not have enough understanding of the --- the intricate interaction among different signals. Signals of growth. Signals of migration. Because brain tumor is a very mobile tumor. It moves around the brain. Bu --- And we also do not understand enough why glioblastoma do not metastasize to the lung and to bone but

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

--- only move around in the brain. The other challenge we have about difficulty is because the brain --- the tumor in the brain is --- is --- is a, you know, occupies different location in the brain but the surrounding brain is a very sensitive organ and it’s not very forgiving when we start treating the tumor at the same time effecting the brain. So the --- the --- the therapeutic index or the tolerance of the brain to the --- to the treatment is not very high. So we damage the brain very frequently when we try to treat the tumor. So that’s a limitation as opposed to free standing tumor that --- that surrounding tissue is more tolerant to the tumor and we have that problem.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

The other problem we have is delivering of the drug to brain is limited by the protecting --- protective mechanism of the blood/brain barrier. Many drugs that’s --- that is effectively treating cancer in the lung, in the liver, or in the breast do not the cross blood/brain barrier and cannot

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

get to the brain. And so we --- we cannot treat, you know, a tumor in the brain like glioblastoma or even metastasis in the brain in the same level of effectiveness with the same drug that --- that is active for lung cancer or breast cancer because it just doesn’t go to the brain. So delivery of --- of the --- of the treatment is a hurdle for --- for brain tumor also.

Tacey Ann Rosolowski, PhD:

So I am dying to ask. How do you deliver the drugs in that situation?

Wai-Kwan Alfred Yung, MD:

Well, you know, --- I mean --- so you have to really work on --- number one there is a way to make the drug cross blood/brain barrier.

Tacey Ann Rosolowski, PhD:

Hmm. Uh-hmm.

Wai-Kwan Alfred Yung, MD:

Smaller molecule or molecule that is more lipid soluble. You know, react with the --- with the cell membrane and can jump past the blood/brain barrier. They are people who try open the blood/brain barrier by heat, by wave and follow by infusion. There are different ways of doing that. E --- you know, --- mechanical way op --- open the blood/brain barrier has --- has a limitation of also exposing normal brain to the toxic drug ___ ____ ()

Tacey Ann Rosolowski, PhD:

Right.

Wai-Kwan Alfred Yung, MD:

So --- And the --- the --- the other --- the other challenge we face in --- yeah --- we know there’s ways to make the drug cross the blood/brain barrier, but in some situations you do want --- you do not want the brain --- you do not want the drug to cross the blood/brain barrier. For, you know because, --- you know, for a long time the pharmaceutical companies think we really don’t want the drug to cross the blood/brain barrier because we’re treating lung cancer and we’re treating breast cancer. We don’t want the drug to cross

Tacey Ann Rosolowski, PhD:

Right.

Wai-Kwan Alfred Yung, MD:

the blood/brain barrier to cause toxicity in the brain.

Tacey Ann Rosolowski, PhD:

Right. Right.

Wai-Kwan Alfred Yung, MD:

) So they deli --- they --- they would rather see the drug do not cross the blood/brain barrier so that they can treat the system --- systemic organ effectively without hurting the brain. But the other side of the coin is those drugs, even those highly effective in breast cancer and lung cancer, is no good for us --- for to treat brain cancer so --- so we --- even though you may share the same mechanism of kill betw --- you know, between the cancer in the breast or the cancer in the brain I cannot us --- you cannot use that drug. It doesn’t _____ () --- so we have to redefine a way to modify that drug

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

To make it cross the blood/brain barrier. Alright.

Tacey Ann Rosolowski, PhD:

Are there any other research related projects that you’d like to talk about?

Wai-Kwan Alfred Yung, MD:

Well I mean, I think, at this stage I --- I, you know --- I am working with, you know, several brain tumor foundations to re --- to --- to foster, you know collaboration within, you know, the brain tumor community.

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

So that we have a, you know, unifying, you know, effort of identifying, you know, a way that we really can advance the treatment for brain tumor. T--- So I’m working with brain tumor founda --- with the Bra --- The Brain Tumor Society. And we want to establish a --- a national network as well as, you know, working with several groups to develop an international network so that we can do, you know, collaborative research to move things faster by --- by involving, you know, more groups working together. Which is not --- I mean, I think, you know, the same kind of thinking, you know, stand up to cancer is the same thing as getting people hi --- a --- a group of experts and people working --- can work together to really focus on

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

one direction. And I think that in the ____ () working with the --- The Brain Tumor Society to really foster that kind of national initiative. And we --- we want to have, of course, locally at Anderson, the Brain Tumor Center, the Brain Tumor Group, Neurosurgery, Neuro-Oncology, Neuropathology, Radiation and really --- really working together to really --- to again put our --- put our experts together, you know, to form --- the --- the Moon Shot Team to --- to really make a strong and concerted effort to --- to --- to change the --- the --- the --- the landscape --and upwardly some strong impact. We are --- We are really in need of some new drug. But right now in t --- in the brain tumor world in glioblastoma we only have two drugs that is specifically approved.

Tacey Ann Rosolowski, PhD:

What are those?

Wai-Kwan Alfred Yung, MD:

for this disease besides radiation. BCNU and temozolomide.

Tacey Ann Rosolowski, PhD:

B-C-N-U?

Wai-Kwan Alfred Yung, MD:

U and temozolomide.

Tacey Ann Rosolowski, PhD:

Yeah.

Wai-Kwan Alfred Yung, MD:

And the third one approved for recurring disease is bevacizumab or Avastin. So in total we have three drugs --- drugs that’s approved for --- for glioblastoma. Two for newly diagnosed disease and one for recurrent disease.

Tacey Ann Rosolowski, PhD:

Are there specific drugs on the horizon that

Wai-Kwan Alfred Yung, MD:

Close to being, no.

Tacey Ann Rosolowski, PhD:

Really? What’s the impediment? The blood/brain barrier is one.

Wai-Kwan Alfred Yung, MD:

Blood brain/barrier, the really strong resistant ____ ()

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

Of the --- of the tumor.

Tacey Ann Rosolowski, PhD:

Wow.

Wai-Kwan Alfred Yung, MD:

I don’t think that there is one drug close to approval right now.

Tacey Ann Rosolowski, PhD:

Wow. Why is the glioblastoma so resistant?

Wai-Kwan Alfred Yung, MD:

I don’t know.

Tacey Ann Rosolowski, PhD:

That’s part of what you’re figuring out.

Wai-Kwan Alfred Yung, MD:

That’s what we’re trying to figure out. Trying to figure out. But I sa --- I must say though I think, you know --- you know, I’m certainly very --- I mean over the years at Anderson, you know, I’m very appreciative in terms of the kind of investment the institution is --- has placed in o --- in brain tumor --- in the brain tumor group. And we have the largest brain tumor group in the country and probably the world because --- and --- and --- and this is the investment that started with Dr. [Charles] LeMaistre [Oral History Interview] and continued with Dr.[John] Mendelson [Oral History Interview] and now continuing with Dr. [Ronald] DePinho [Oral History Interview].

Tacey Ann Rosolowski, PhD:

Tell me about the Moon Shots platform for glioblastoma.

Wai-Kwan Alfred Yung, MD:

Well we don’t have it yet.

Tacey Ann Rosolowski, PhD:

Oh, really.

Wai-Kwan Alfred Yung, MD:

We’re not --- We are not, I mean --- as you know, the --- the six cancers that we’ve included in the Moon Shot, you know, initiative is melanoma, prostate, CML, AML, ovarian and woman cancer. The six cancers.

Tacey Ann Rosolowski, PhD:

I had forgotten that glioblastoma was not part of it.

Wai-Kwan Alfred Yung, MD:

Glioblastoma is not part of it.

Tacey Ann Rosolowski, PhD:

Right.

Wai-Kwan Alfred Yung, MD:

We --- The institution is, you know --- is going to extend, you know, ne --- this year --- is going to extend to include more cancer. So the Brain Tumor Group is, you know, working to put together a proposal.

Tacey Ann Rosolowski, PhD:

Hmm. And what are your strategies for putting that together?

Wai-Kwan Alfred Yung, MD:

I --- It, you know --- I think we --- we certainly want --- is looking at, you know, the --- the expertise that we have in terms of drug development and also, you know, immunotherapy. Brain tumor is --- especially glioblastoma, you know, has some prior success in ap --- in applying immunotherapy to this disease and there has --- and also with the institutional immunotherapy platform that really opened up many --- many opportunities

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

to utilize that to attack brain tumors so we --- we are looking at how to really look both at new drug, signal transduction drug, cytotoxic drug, and immunotherapy how it amplifies each other.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

You know, that’s going to be, you know the --- the --- the strategy. We also have developed a --- I think I forgot to mention actually one of the other projects that we developed internally is a oncolytic virus

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

Project, that I also have a part of it. It’s --- Dr. Juan Fueyo is --- is one of the researchers in ou --- in our department that --- that he took the --- the --- the --- the --- the --- the flu --- the influenza virus --- the adenovirus. They did a piece of the genome. They did 24 base pair from the genome. And, you know, according to --- to the discovery of Dr. Frank McCormick we deleted the 24 --- he deleted the 24 base pair and created a virus called Delta 24. With the deletion of that 24 base pair the virus only replicates in dividing cells but would not --- would not divide until --- until resting cell like normal neuron and normal astrocyte. So we make the virus only kill tumor and not affecting the brain. And we --- we, you know, developed --- that --- that virus in the laboratory. We showed that the working animal model and we also had a grant from the --- from the NIH, from NCI to do all the preclinical studies that required by the FDA. And we get a grant from the Marcus Foundation, you know, with Dr. Bass’ help to ----. And we finish the Phase 1 clinical trial to show very interested in activity in this virus. And --- And --- And so this is homegrown viral therapy direction. We call viral or viral therapy

Tacey Ann Rosolowski, PhD:

Yeah. Interesting.

Wai-Kwan Alfred Yung, MD:

That will be integrated into the Moon Shot.

Tacey Ann Rosolowski, PhD:

Hmm. What’s you impression of the way the Moon Shots Program has been structured with it --- with it --- it’s very different as I understand.

Wai-Kwan Alfred Yung, MD:

It’s very different. I --- I think, you know, the idea --- the idea that we should look at a disease in a very focused fashion and we also invest, you know --- you know, in a very high level and sort of like, you know, we must land on the moon. So we must make something happen. We’ve done put a lot of resources, put a lot of talent, and put a lot of research to make something happen. I think that’s the right concept --- great concept. I don’t think, you know --- without --- without that kind of, you know, investment you will make things happen slowly. With that kind of --- say I’m going to make a concentrated effort and I’m going to make big effort, big investment and put a lot of talents in it and w --- we’ll make things happen fast. The question really is how selective we want --- can we really use the same strategy to many, many different cancers.

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

Or we have to select --- be selective --- and if we have to be selective, how do we select?

Tacey Ann Rosolowski, PhD:

I’m wondering too at a practical level since this is such a different way of putting together research. I can imagine there are some people who are glad in a certain way not to be part of the first Moon Shots and maybe to be applying in the second wave because they can kind of look at well that didn’t work so well maybe thi --- I mean, were there lessons learned? Are there lessons that you learned by observing that first couple of years of Moon Shot so that you can tweak what you’re imaging is going to happen with glioblastoma?

Wai-Kwan Alfred Yung, MD:

Well I --- I think there is a lot of lessons learned.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

And I observe it is, you know, whether you --- you know, whether we have over promise the community and the speed of things. And --- And --- And where the lesson learned in terms of how fast that we --- we can develop the infrastructure to support it. You know, how easy and how difficult to put the team together to make the team work together. You know, I think there’s a lot of lessons learned in that.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

You know, and of course I think, you know we can --- ____ ___ (), you know, just like you said, that people may feel that it’s better not to be in the first wave because, you know, more is given and more is demanded. You know.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

If you’re in the first wave you need to deliver quickly.

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

You know, you may not be --- I mean that’s also what Dr. DePinho’s emphasis is to say, you know, let’s focus on something that has low-hanging fruit.

Tacey Ann Rosolowski, PhD:

Right.

Wai-Kwan Alfred Yung, MD:

When you do not have the low-hanging fruit

Tacey Ann Rosolowski, PhD:

Uh-hmm.

Wai-Kwan Alfred Yung, MD:

You know, you’re not going to be able to deliver, you know, in the first few --- first three years.

Tacey Ann Rosolowski, PhD:

Right.

Wai-Kwan Alfred Yung, MD:

But the lesson also can be learned in what is low-hanging fruit.

Tacey Ann Rosolowski, PhD:

I hadn’t actually thought of that question. Yeah. Interesting. Is there is any low-hanging fruit or what is the low-hanging fruit in the arena of glioblastoma?

Wai-Kwan Alfred Yung, MD:

We don’t have low-hanging fruit.

Tacey Ann Rosolowski, PhD:

Yeah. I kind of thought that might be your answer.

Wai-Kwan Alfred Yung, MD:

Because if I --- if I define low-hanging fruit by something that I can change the survival of the brain tumor patient, you know, in a big way in the --- in the three year span, we don’t have anything. If we define it just such a rigid way. If I --- If I’m defining it the --- if there --- is there a drug, is there a treatment, or is there an understanding of the biology that will allow me to save twice as many people in the next three years, I don’t.

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

To be honest, I don’t.

Tacey Ann Rosolowski, PhD:

Uh-hmm. So what is the fruit that y ---

Wai-Kwan Alfred Yung, MD:

Do I have anything --- Do I have anything that I can move --- that’ll move the response rate, you know, 10%, 15%. Yes, we have leads to work on. And then some of the immunotherapy, you know, antibody that we can get a hold on and we can --- we have opportunity there. Virus, opportunity there. Combination of several drugs will get --- you know, it’s possible we learn more about those drugs. So, in --- in a way if we m --- if we’re looking at, you know, --- it --- in the baseball analogy we’re looking for a second base hit.

Tacey Ann Rosolowski, PhD:

Hmm.

Wai-Kwan Alfred Yung, MD:

We may --- We have. If we’re looking for home run, we don’t.

Tacey Ann Rosolowski, PhD:

Well we’re at two o’clock now and I --- I know you’re a very busy person right now. So, is there is anything else you’d like to add for our session today?

Wai-Kwan Alfred Yung, MD:

It’s --- It’s --- So no, I don’t have anything that I am --- I --- I am. --- Now let me ask you, _____ () If you look back in the last session, I don’t know whether you have really, you know, looked at the transcripts or any

Tacey Ann Rosolowski, PhD:

That hasn’t been transcribed yet.

Wai-Kwan Alfred Yung, MD:

or --- or just ____ ____ (

Tacey Ann Rosolowski, PhD:

I --- I’m --- going by my notes.

Wai-Kwan Alfred Yung, MD:

___ _____ ___ (: 19) the mental, go back mentally to what we talk about from the last time, but I was --- I mean I was even less --- I mean I --- I actually have much better idea around this session.

Tacey Ann Rosolowski, PhD:

Oh, okay.

Wai-Kwan Alfred Yung, MD:

Then the last session.

Tacey Ann Rosolowski, PhD:

Yeah.

Wai-Kwan Alfred Yung, MD:

which, you know --- so I don’t know what --- if you think back if there’s anything that you want to go back. Any --- Any questions or anything that you want to go back

Tacey Ann Rosolowski, PhD:

Nothing.

Wai-Kwan Alfred Yung, MD:

that --- that we talked about last --- in our last session.

Tacey Ann Rosolowski, PhD:

Nothing emerged. I mean --- I --- I, you know, as you notice I take a lot of notes and so I --- I typed all those up and I reviewed them. And if --- if things spring to mind that looked like they were kind of holes, I didn’t come across any. I mean, I’ll do the same with this session and we can follow --- we can fill in. We do have another session.

Wai-Kwan Alfred Yung, MD:

Okay. scheduled. And I did want to say that after I looked at my notes from last time, you gave a beautiful, beautiful explanation of the impact of the move from departments to divisions in the institution. It was just really great. It was a great explanation of that piece of MD Anderson history. So I wanted to thank you for that. It was really terrific. Well I look forward to talking to you again next time.

Wai-Kwan Alfred Yung, MD:

Okay. Good. Good. Good.

Tacey Ann Rosolowski, PhD:

Alright. And I am turning off the recorder at about three minutes after two.

Wai-Kwan Alfred Yung, MD:

Great.

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Chapter 09: The Challenges of Glioblastoma; MD Anderson's Moon Shot Program; No Low-Hanging Fruit for Neuro-Oncology Research

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