Chapter 07: Early Work on Oncogenes and Adenoviruses: The First Gene Therapy

Chapter 07: Early Work on Oncogenes and Adenoviruses: The First Gene Therapy

Files

Loading...

Media is loading
 

Description

Dr. Hung first describes how he set up his lab to have an impact on research into human oncogenes. His goal was to identify a transcription suppressor and his work on clarified that the EIB gene has oncogene activity, whereas EIA does not. Dr. Hung explains how “over-interpretation of data” can result in these types of assumptions about molecular and genetic function. His next move was to take this knowledge to breast cancer.

Next Dr. Hung explains that he and others formed an MD Anderson-based biotech company in the 90s to take therapy using EIA to (successful) clinical trials. He then explains how he began to think in new ways about the HER2/neu gene, looking for transcription factors.

Dr. Hung describes a clinical trial: the first trial of gene therapy for breast cancer and ovarian cancer. He explains the implications of this study.

He talks about controversies over gene therapy, then explains practical challenges of gene therapy research, many relating to the vector used to transport the gene-related agents to cancer cells.

Identifier

HumgMC_02_20140307_C07

Publication Date

3-7-2014

City

Houston, Texas

Topics Covered

The Interview Subject's Story - The Researcher; The Researcher; Overview; Definitions, Explanations, Translations; Discovery and Success; Professional Path; On Research and Researchers; Understanding Cancer, the History of Science, Cancer Research; Formative Experiences; Discovery, Creativity and Innovation; Finance, Entrepreneur, Biotechnology

Transcript

T.A. Rosolowski, PhD:

Now, I don’t know very much about the history of translational research. Was that even a phrase that was used ….

Mien-Chie Hung, PhD:

Not yet, at that time.

T.A. Rosolowski, PhD:

Yeah, because you were already thinking in those terms.

Mien-Chie Hung, PhD:

Yeah. I think for translation, to me, to affect me is later on.

T.A. Rosolowski, PhD:

Okay.

Mien-Chie Hung, PhD:

At the very beginning when I came here as an Assistant Professor, what I’m trying to do is set up my laboratory and get my own grant, right. And then, soon as set up laboratory, you had to recruit a student, recruit post-doc fellows, recruit research assistant so you have group, that we can work together … Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:10:27.0] … and go the direction you want to go. And I certainly would like to, at that time, I didn’t say to myself, what I should do. I said to myself, I want to have some impact on the human oncogene area. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:10:39.4] And then, since I was involved in tu --- onco --- the --- the HER2/neu oncogene in cloning, and as I mentioned earlier, that --- this gene at that time, in the mid 1980s, it happen just been known to be overexpressed in breast cancer and ovarian cancer. Therefore, I was kind of interested in that. In addition to that, at the time when I cloned this gene, this come from an a --- animal model which pertained to rat to, you know, carcinogen, and then offspring frequently develop neuroblastomas. So --- so I actually ended up one project and collaborated on neuroblastoma with Dr. Alfred Yung [oral history interview] here …. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:11:15.9]. And he’s ___ --- he’s still here.

T.A. Rosolowski, PhD:

Yeah, I’m going to be interviewing him soon.

Mien-Chie Hung, PhD:

And --- and then --- but, you know, it turned out to be this particular gene is not really involved in that human neuroblastoma … Tacey Ann Rosolowski, PhD: Ahmm.

Mien-Chie Hung, PhD:

: [0:11:27.7] … bbecause that --- in the animal case, you only need one single permutation to get that, you know, oone nucleotide change to get this in the same aminal chain. But in human, it requires two.

T.A. Rosolowski, PhD:

Interesting.

Mien-Chie Hung, PhD:

Now when you need --- you cut to the chase, it’s very, very long. However, having said that, this gene is important for causing cancer. It’s still valid. Although it --- in --- in the animal model, it cause a neuroblastoma, glioblastoma. In human, that isn’t really the case but enough. It was found to be overexpressed in breast cancer and ovarian cancer. So at that time, I thought --- I was a molecular biologist. , sSo I thought, I iff we can identify something through regulated transcription – you know what transcription, right? Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:12:10.6] Okay, so the gene had to be transcribed. S athen Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:12:14.0] So overexpression causes human cancer, breast cancer, ovarian cancer. A And so, molecular biology, I was thinking cannot identify something to shock overexpression …. Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:12:23.6] iIf --- if this --- this gene overexpress --cause cancer--, then if I can control its expression, cannot control being an anticancer agent. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:12:31.3] With that very naïve thoughtout very ____, give thought, then we are looking for a tran --- tran --- transcription factor to suppress gene expression. And for peri --- short period of time, that worked. Quite a few year, I --- you know, I don’t long ____ 0:12:50.2 if you fi --- if you identify. Another gene from virus is called E1A, capital E-1-A. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:12:57.1] It’s probably not in there, yet. E1A. ____ which was original --- it come from adenovirus.

T.A. Rosolowski, PhD:

Mhmm. Okay, yeah, there we go. Yeah, actually I do have that.

Mien-Chie Hung, PhD:

Yeah.

T.A. Rosolowski, PhD:

Type 5 E1A.

Mien-Chie Hung, PhD:

Yeah, type 5 E1A.

T.A. Rosolowski, PhD:

Right, right.

Mien-Chie Hung, PhD:

Which was originally from adenovirus. A and traditionally in the literature, the E1A gene is considered as oncogene. But we found this gene from type 5 adenovirus. Transcriptional depress HER2/neu. So then we argue, if that’s the case, if E1A can suppress HER2/neu, then E1A is a gene can suppress tumor. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:13:46.0] But in the literature, this is an oncogene. So went through literature carefully to looking for, then we realize that E1 eas ----- E1 is represent early region 1. When a virus vector --- when a virus infects a human being, there is a region where transcription starts first. T then after that, they have a late gene so they become virus. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:14:09.0] . So the E1 region is considered as oncogene but the --- the gene which really have it transforming – transforming meaning oncogenic activity, is E1B, it is not with E1A.

T.A. Rosolowski, PhD:

Interesting.

Mien-Chie Hung, PhD:

Especially for this type of 5. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:14:22.0] There are many, many serotypes. Adenovirus type 5 E1A actually does not really have oncogenic activity. However, E1B does. And also other serum type. This --- the --- you know, this virus has a different kind of serum --- that’s the E. T1 --- the serum type adenovirus was --- the other serum type, I don’t remember specific number. That E1A --- some of E1A maybe be associated with some transforming activity. When I say transforming, it’s in the lab say related to cancer, okay? Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:14:54.7] But the adeno type 5 E1A, it --- they don’t understand this. There is no oncogene. There is no oncogenic activity. It was just historically, E1, historically --- E1 it’s --- and this happened many, many times in the literature. People, based on some published data --, and then the ____ 0:15:12published data is correct, but people sometime over-interpret it. Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:15:16.2] And so, E1 is oncogene. So E1A is oncogene, E1B is oncogene --- oncogene. So when we start to say E1 can suppress HER2/neu, then would that be a tumor suppressant gene, then that become an issue.

T.A. Rosolowski, PhD:

And a lot of questions is are coming up for me. Now, basically, what you were discovering was a new level of scrutiny that you had to apply to this data in order to understand the mechanisms.

Mien-Chie Hung, PhD:

Yeah.

T.A. Rosolowski, PhD:

Okay.

Mien-Chie Hung, PhD:

And also, while we understand mechanism, identify a particular transcriptional factor, a particularly protein called E1A, that comes from a virus, t … Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:15:49.7] … which come from virus. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [15:52.0] That can suppress HER2 overexpression. And HER2 overexpression causes breast cancer and ovarian cancer, … Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:15:58.4] … so we thought, well, if we can put this gene into the cancer cell, can this cancer cell because of the suppression? And then, that was a very naïve … Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:16:09.4] … concept. Then we did it. And it took a --- a lot of effort. And here, I should mention, this --- it’s involved in many --- many people’s cooperation --- was initially discovered from one of my students and that’s her PhD thesis …

T.A. Rosolowski, PhD:

Oh, wow.

Mien-Chie Hung, PhD:

… and she’s --- she’s a faculty here.

T.A. Rosolowski, PhD:

Oh, is she?

Mien-Chie Hung, PhD:

… Dr. D. YuDihua Yu.

T.A. Rosolowski, PhD:

Oh, okay, yes.

Mien-Chie Hung, PhD:

So she --- she’s still here ___, okay. ___

T.A. Rosolowski, PhD:

Yes, I know her name.

Mien-Chie Hung, PhD:

Okay.

T.A. Rosolowski, PhD:

Yes. Great. Thank you.

Mien-Chie Hung, PhD:

And then I’m going --- those people and Alfred Yung, you know it, too.

T.A. Rosolowski, PhD:

Yes.

Mien-Chie Hung, PhD:

And so that actually her PhD thesis.

T.A. Rosolowski, PhD:

Wow.

Mien-Chie Hung, PhD:

And then --- but then, after that, this is a concept that we need to work with the company and to really --- because now this is a gene. E1A is a gene. So for me to put a gene into a cancer cell, this become gene therapy, right?. This become gene therapy. And this gene therapy, and then we start to --- I file patent, then our technology officer writes me. So remember in early 1990, gene therapy is very hot. … Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:17:14.9] So I was through our --- our technology officer, Bill Doughty , who retired already and with another guy, Gabriel Lopez.

T.A. Rosolowski, PhD:

Yeah, don’t know that name.

Mien-Chie Hung, PhD:

He’s in Experimental [Therapeutics]. He’s still here. Lopez --- Gabriel Lopez.

T.A. Rosolowski, PhD:

Lopez, okay.

Mien-Chie Hung, PhD:

So then we actually, through their link, we form a small biotech company …

T.A. Rosolowski, PhD:

Oh, wow.

Mien-Chie Hung, PhD:

… and to move this into the clinical trial. Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:17:40.7] And that --- and when we moved this over from the company, and the company actually originally called R-Gen. “R” represent --- and then it was located in The Woodlands. And then --- and then this R-Gen was in two years, pretty successful. So we --- we been approved by FDA to do the clinical trial--- clinical trial at that time. Time is different now. That kind of situation nowadays may not be that hot but at that time, another company want to buy it.

T.A. Rosolowski, PhD:

Ah, okay.

Mien-Chie Hung, PhD:

Two years. That’s okay. And investor probably and we all get --- everybody get their own fair share.

T.A. Rosolowski, PhD:

Yeah.

Mien-Chie Hung, PhD:

And then when we --- at that time, we want to move to clinical trial, then I started work with Gabriel Lopez. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:18:24.5] And I develop --- you know how to spell it, right?

T.A. Rosolowski, PhD:

Spell it for me, please.

Mien-Chie Hung, PhD:

Gabriel Lopez

T.A. Rosolowski, PhD:

L-O-P…

Mien-Chie Hung, PhD:

Gabriel Lopez-Bernstien. He’s a MD Anderson faculty.

T.A. Rosolowski, PhD:

Okay, great. Thank you.

Mien-Chie Hung, PhD:

And then, when we move to clin --- clinical trial --- Gabriel has a lot of experience to --- to, you know, communicate with FDA and those --- those kind of stuff. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:18:47.3] But because we try to deal with the breast cancer, so now my close friend, Gabriel Hortobagyi [oral history interview]. Y … Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:18:53.2] … you know Hortobagyii ___??

T.A. Rosolowski, PhD:

I do, yes. I’ve interviewed him.

Mien-Chie Hung, PhD:

Okay. He’s the first Breast Mmedical ___ [Oncology] Chair. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:18:57.8] So three of us, you know, worked together very closely and then Dr. Hortobagyi, who at that time was a breast cancer surgeon, too, you know. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:19:07.9] So, he took the lead to -- for the clinical trial. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:19:11.2] Then FDA approved it and then we started.

T.A. Rosolowski, PhD:

Let me ask you, what was the thought process that led you to examine the E1A in this way? You know, what --- what were your thinking, to turn it around and look at it from a different perspective?

Mien-Chie Hung, PhD:

Let me think about it, how we discover that. There’s a long story about how we ________.

T.A. Rosolowski, PhD:

Actually, just for a second, do you mind, Dr. Hung,

Mien-Chie Hung, PhD:

:, if I move this back a little? Because I’m a little worried. S, Sometimes, when your voice drops, I’m worried that the sound will ____

Mien-Chie Hung, PhD:

No, we don’t ….

T.A. Rosolowski, PhD:

We can move it back here, and I think just moving it away from the microphone helps. Perfect. Yes, that’s already better. Alright. Okay.

Mien-Chie Hung, PhD:

Remember I told you that when we --- I realized HER2/neu was overexpressing cancer, … Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:20:11.4] … anand I was molecular biologist. So, I was thinking, looking for the known transcriptional factor …

T.A. Rosolowski, PhD:

Okay.

Mien-Chie Hung, PhD:

… that may be down regulated HER2/neu. Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:20:22.4] So we looking for quite a few, and this is the one that jumped out. So, it’s not like we just pick up this one. It worked.

T.A. Rosolowski, PhD:

Right. Okay.

Mien-Chie Hung, PhD:

We were just looking for --- looking for transcriptional factor. And remember that was back to the early days. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:20:39.2] Nott many, many transcriptional factors available. So it --- and it’s --- it was manageable. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:20:44.7] So we can actually test it --- then when we tested it we find this one.

T.A. Rosolowski, PhD:

Okay.

Mien-Chie Hung, PhD:

And then --- then when we moved into clinical trial to initiate, and then ____ and that --- this is a early stage of gene therapy. So, as a matter of fact, this trial which was led by Hortobagyi and Gabriel Lopez and myself was involved with --- both of us co-PI and Hortobagyi PI. So this actually is the first human breast cancer, ovarian cancer gene therapy. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:21:18.6] I.e, the first time people put a gene into breast cancer and ovarian cancer patient. And I think it was started in 1994 or ‘95, around that time.

T.A. Rosolowski, PhD:

Now, what were the implications of that? You know, I mean, the success of that. What did you see? What did you perceive?

Mien-Chie Hung, PhD:

I was very excited …

T.A. Rosolowski, PhD:

Yeah.

Mien-Chie Hung, PhD:

… because we did animal experiment … Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:21:42.4] …and we did some animal experiments. and I still remember some of my --- one of my --- some students who did experiments and originally were not quite sure, it’s real real. Bbut when you do it, say, Hhey, that one is real. Tumor shrinks.

T.A. Rosolowski, PhD:

Laughs.

Mien-Chie Hung, PhD:

Tumor shrinks.

T.A. Rosolowski, PhD:

Yeah.

Mien-Chie Hung, PhD:

And so we see it, but if it cures the animal, it doesn’t mean it can cure humans. T, that’s a different ball game.

T.A. Rosolowski, PhD:

Right.

Mien-Chie Hung, PhD:

But you --- you see that it’s very impressive, very impressive. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:22:10.2] As I mentioned, this started with ____ Dr. Dihua Yu’s PhD thesis. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:22:13.0] And then now, she’s very --- very successful. She’s a faculty member here. And then --- yeah, so --- so when R-gen Gen was moving in clinical trial and at the time when we moved to clinical trial, it was supported by R-genGen. But when Phase 1 started, it was then another company bought it, you know … Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:22:32.8] … and after that, they passed to. And then, the other company was a ___ Seattle company called Targeted Genetics. A and later on they --- they ran out of funding and so this project was not ______. pursued. They returned the patent to MD Anderson, that’s where it is.

T.A. Rosolowski, PhD:

Hmm. So when you say this other company bought it, what does that mean?

Mien-Chie Hung, PhD:

Okay, when MD Anderson, the company was MD Anderson-based, right? Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:22:56.0] MD Anderson is like, it’s a major shareholder and then --- then the --- another company licensed genetic technology, so kind of --- this company then disappear and merged with them. And some of the ---

T.A. Rosolowski, PhD:

Okay.

Mien-Chie Hung, PhD:

… this company. The officer CEO or whatever become the consultant so they can develop project together. But MD Anderson still owned the patent rights. Right? Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:23:18.4] But then MD Anderson ___ always says because we’re licensed, because our purpose is not making money. Our purpose make --- to benefit the patient. So they can help us to develop the drug, then the patient would be happy to see that. But in the future they don’t do it, if they don’t have activity they have to return to us. Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:23:34.7] Okay. So then that was diverted. And then, let me share with you --- then, you may know 1998, there’s a big event in gene therapy.

T.A. Rosolowski, PhD:

I didn’t know.

Mien-Chie Hung, PhD:

There’s one 18-years-old kid in University of Pennsylvania, of Pennsylvania … Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:23:51.4] … under a clinical trial. I forgot the name of the disease, but it’s --- it’s not a major disease, it’s a genetic disease. But he just kind of volunteered to be in the clinical trial. In that clinical trial, somehow was not done well --- controlled well-- … Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:24:05.3] … the patient died. But keep in mind that’s another deadly disease. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:24:10.7] So that patient, he ___ but he died, right, so --- so suddenly that gene therapy field was being (ripping sound).

T.A. Rosolowski, PhD:

Yeah.

Mien-Chie Hung, PhD:

Because the purpose to develop new therapy to --- to cure patient. But before that, we kill patient. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: 24:25.7] So anyway. And also, gene therapy, we faced some technical problems. No, problem, yeah, issue. That is, when you develop gene, it’s different from chemo. Chemo, when you treat a human being, every cell is exposed. So cancer cells are exposed. E except that chemo is a problem, has side effects because normal cell can be killed. And then when we do gene therapy, the same, too --but gene therapy is even worse. When you do gene therapy, the gene may not go in to the cancer cell only; they’ll go to normal cells, right? Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:24:49.1] And also, the gene that --you want gene --- that you want to put into --- we have to make sure it’s going to every cancer cell. B … Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:25:06.6] … but technically, it’s difficult. And even right now, it’s still difficult. And so it’s different from chemo. Chemo is --- when exposed to the drug, every tumor cell is exposed to the drug. But when we do a trans_____ cription 0:25:16.7 to allow a gene to go in to cancer cell, not every cancer cell--- let’s say this tumor has one million cell there, it may be only 20% have this gene go in…

T.A. Rosolowski, PhD:

Wow.

Mien-Chie Hung, PhD:

… 80%. Then, you might not be able to totally kill them.

T.A. Rosolowski, PhD:

Right.

Mien-Chie Hung, PhD:

And --- and also, we don’t have selectivity to go to the cancer; it may also go to normal. Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:25:38.1] Right? And so…

T.A. Rosolowski, PhD:

Now, just educate me here. What is the impediment to getting the genes --- the gene therapy into every cell?

Mien-Chie Hung, PhD:

Okay, so technically --, right now people using either virus vector – it’s called vector or liposome vector or non-virus vector – we have to still use that. And technically, it’s still in the development. It’s still not 100% yet. But now, it’s much improved. In addition to that, now gene therapy has been silent for more than one decade now. It’s coming up now. Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:26:11.5] Remember gene therapy have some advantage that --human genome ____ 0:26:13sequenced now, right? So who has what mutation in the future, so it’s not difficult. So if you know what gene is mutated, what gene is the problem, you can always use gene therapy. But technically, it impor --- as you pointed out, how to develop gene into right place, …. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:26:29.8] … and how to make sure that gene gets in all the cells, if it for cancer for cell --- all the cells have those genes. And they are several different ways one can handle that. And now in the last decade, there are a lot of improvements. Many, many people have made contributions. We have contributed a little bit. We tried to design a gene expressed only, or primarily, in cancer cells, but not in normal cells. Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:26:52.8] So in that way, when you do therapy, you prevent side effects. So that --you want gene therapy, the company has other interest in the company. A, and also up to 2,000 --- before 2,000 there’s a biotech company going up. But stock market up to 2,000 is going up. You probably begin withremember that.

T.A. Rosolowski, PhD:

Yeah.

Mien-Chie Hung, PhD:

So --- so there are many biotech company didn’t really survive well. So the company will survive well. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:27:17.3] And --- but then up to that scientifically, we still continue to develop. So now they told us just more recently we have developed expression vector, which allows the gene to express only in cancer cell. So we’ve now successful enough to develop that into pancreatic cancer, breast cancer, lung cancer, and ___ liver cancer (0::27:38.0). And that one, some of the stuff is being licensed just more recently. So if we talk about chronologically, then that’s not chronological. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:27:48.1] That’s developed later on.

T.A. Rosolowski, PhD:

Right. Let’s talk about that there then.

Mien-Chie Hung, PhD:

: Then we can talk about biological.

T.A. Rosolowski, PhD:

Right.

Mien-Chie Hung, PhD:

So, the E1A gene therapy was kind of --- after it’s sold to Targeted Genetics and then the clinical trial, then they are running the show. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:27:59.8] But that was the first trial. First, the human breast cancer, ovarian cancer trial. But unfortunately at that time, the vector is not efficient … Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:28:13.9] … and then also, the gene expression system is not highly selective for cancer. And actually, we can talk about this one. I can finish gene therapy_____ ___. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:28:22.4] And therefore, we continue to develop and later on, we develop an expression factor which we now call VISA ____ 0:28:30.

T.A. Rosolowski, PhD:

Uhuh. V-I-S-A? Okay.

Mien-Chie Hung, PhD:

It’s an abbreviation. Tacey Ann Rosolowski, PhD: [0:28:35.3] Uhuh.

Mien-Chie Hung, PhD:

: [0:28:35.8] The VISA vector is a special design. That special design was modified from an earlier vector developed by UCLA. They called it TSTA, but we modified it and it become a VISA. And the --the purpose is to allow a gene to selectively express in cancer cell, not in normal cell. Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:29:01.3] So now, if we can put this --- if this gene is a killer gene …

T.A. Rosolowski, PhD:

Right. You can just put it right …

Mien-Chie Hung, PhD:

… and then we --- we also identify killer gene from … Tacey Ann Rosolowski, PhD: Hmm.

Mien-Chie Hung, PhD:

: [0:29:11.4] … it’s called BIK.

T.A. Rosolowski, PhD:

Right. Oh, okay.

Mien-Chie Hung, PhD:

BIK. But, part of the reason, we chose the BIK. BIK is one of the genes which can cause cancer cell --- which cau --- can cause cell damage. It’s very broad. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:29:24.9] And this kind of gene, they are --- they are family. Many of them. Part of the reason we particularly chose this one, it’s because we noticed there’s some amino acid in this gene where we can mutate it and make this gene much more portent than the ___ 0:29:41. So that’s what we called DT. You probably see that BIKTT. T Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:29:26.6] These stand for aspartic acid. It’s one of the amino acids. Because there are two mutations, mutate into aspartic acid. We find out this mutant. It’s a highly potent inducer of cell death, with regard to normal cell, cancer cell. It’s very, very potent. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:30:07.3] In that situation now, it’s – this gene, it’s very potent for killing cells. It can kill normal cell, it can kill cancer cell, but we have a VISA vector which carries this gene to cancer cell only. It’s just like a --- a --- astronaut, take space shuttle. Tacey Ann Rosolowski, PhD: Mhmm.

Mien-Chie Hung, PhD:

: [0:03:29.0] This shu --- this space shuttle ….

T.A. Rosolowski, PhD:

Right.

Mien-Chie Hung, PhD:

…send it to the moon. We go to the moon, we don’t go to Mars.

T.A. Rosolowski, PhD:

We don’t go to Saturn. (Laughter)

Mien-Chie Hung, PhD:

So this vector allows it. So this vector allows this gene selectively express in the cancer cell by normal cell. So now this one has been licensed by a ___ company called TTY. Just recently. This is a couple years ago. And they are working this one very heavily, try to move things forward. And this one … … we work with MD Anderson clinician, Jim ___. Abbruzzese. He just left and the other one who’s still here, that is Milind JavieWaun Ki Hong. --I may have to spell it for you.

T.A. Rosolowski, PhD:

Thank you.

Mien-Chie Hung, PhD:

Milind Javie.Wuan Ki Hong. He’s still here. He was a junior faculty at that time and Jim ___ Abbruzzese was the chair.

T.A. Rosolowski, PhD:

Okay, I haven’t heard of him.

Conditions Governing Access

Open

Chapter 07: Early Work on Oncogenes and Adenoviruses: The First Gene Therapy

Share

COinS