Chapter 15: The Next Phase of Gene Therapy Research and Funding from the Breast Cancer Research Foundation

Chapter 15: The Next Phase of Gene Therapy Research and Funding from the Breast Cancer Research Foundation

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In this chapter, Dr. Hortobagyi describes the next phase of his gene therapy research. He begins by explaining that the funding organization, the Breast Cancer Research Foundation, was started by Evelyn Lauder when she was diagnosed with breast cancer. Dr. Hortobagyi and others were asked to be scientific advisors. The Foundation brought together powerful women who raised a great deal of money, a lot of which came to MD Anderson. The gene therapy project was also funded by a SPORE grant. Dr. Hortobagyi sketches the state of the gene therapy projects. He explains why it was difficult to secure NCI funding for the E1-A project then discusses why it is so difficult to deliver a gene product. He tells the story of a University of Pennsylvania project in which some children died from gene therapy; an event that helped turn the NCI away from funding this kind of research. He then describes how the Breast Cancer Research Foundation uses different criteria than the NCI to award money to high-risk projects. The BCRF is now funding such areas of research as cancer vaccines, early genetic screening, the development of targeted agents, and diagnostic tests.

Identifier

HortobagyiGN_02_20130107_C15

Publication Date

1-7-2013

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 ResearcherThe Researcher Professional Practice The Professional at Work Collaborations On Research and Researchers Devices, Drugs, Procedures Business of Research Philanthropy, Fundraising, Donations, Volunteers Understanding Cancer, the History of Science, Cancer Research

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

Gabriel Hortobagyi, MD:

In the meantime, while we were involved in that first and second gene therapy project, Evelyn Lauder, the daughter-in-law of Estee Lauder, developed breast cancer. And being a wealthy woman, she said, “How come you cannot guarantee me that I get cured of breast cancer? I need to do something about this.” So, she started the Breast Cancer Research Foundation, and she recruited Larry Norton, who was my counterpart at Memorial, to be the chair of the Scientific Advisory Board, and Larry’s first act was to call me saying, “Could you help me with this?” Larry and Nancy Davidson and a fellow from the NIH called Peter Greenwald and I became the Scientific Advisory Board for the Breast Cancer Research Foundation, and these incredibly powerful women started to raise a heap of money, and we were charged with distributing that. Part of distributing that ended up being a lot of money coming to MD Anderson, and part of that supported the research of several of my colleagues, including Mien-Chie Hung and our gene therapy project.

We developed the next couple of gene therapy concepts entirely on the basis of BCRF funding, and while Mien-Chie got some NIH funds for that, it was very hard because, again, it was thinking outside the box. But it was also with the first gene therapy project that we got our first SPORE—breast cancer SPORE—and one of the projects was our first gene therapy—actually our second gene therapy project. That was very gratifying because despite gene therapy not being terribly popular in the NIH circle, we got funds for that. Between the NIH and BCRF, we were able to take several of these things to the clinic. We are about to get our fourth gene therapy proposal into phase I trial. And in fact, sometime within this month we are going to submit to the FDA.

Tacey Ann Rosolowski, PhD:

What were the projects that were initially funded, and why were they innovative in a way that would not have made them appealing to the NCI?

Gabriel Hortobagyi, MD:

Well, the second one, which was the E1-A project—by the time we got to the stage of requiring extra funding from the NCI, there were some events nationwide in which there were some—you could call them accidents with gene therapy where people got hurt because people were sloppy. Investigators were sloppy and mostly because by then the field had become aware of how difficult it was to deliver the gene therapy product to the right target.

Tacey Ann Rosolowski, PhD:

What happened to these individuals? I have no idea what the effects might be of a mistake in that way.

Gabriel Hortobagyi, MD:

One of the approaches to delivering a gene product to your cell is to load a virus with the DNA sequence that you want to deliver and then inject the virus into people. Well, it is somewhat unpredictable where that ends up. For instance, you can use a retrovirus—for instance, the HIV virus. We don’t use that, but that’s a retrovirus, and it has certain properties that are favorable. There are other retroviruses that have been used, and there was a project in Philadelphia for a genetic deficiency disease. The scientist developed a protocol and started to administer this virally delivered DNA sequence to children and young people, and he killed a couple of them. Of course, that is a huge problem in and of itself, but then it also became apparent that both him and members of his lab and the IRB from UPenn were negligent and had done a lot of inappropriate things without following procedure. That gave a pretty bad name to UPenn and this investigator but also in general terms to the field.

Also, by the mid-1990s, late 1990s, there were a number of publications from other investigators working on gene therapy that suggested that in their hands and with what they were doing it wasn’t working very well, and the problem is largely the delivery system. For instance, with our E1-A project, we were able to infect about one or two percent of the target cells with what we were doing. Out of let’s say your ideal target of 100 cells, we were able to transfer the gene in question to one or two cells. Even with that, we had a biological effect, but it was very hard to improve on that. We went away from viruses, and we started to use other vehicles which improved a little bit the efficiency of the project, but it was still in the single digits. NCI reviewers considered that there were more exciting projects to look at, and when a review committee decides that an area is exciting, then a lot of investigators looking for funds go in the same direction. That was a problem. To a large extent, we are not doing viral delivery of gene sequences, but we use other methods. But it still continues to be a problem, and until we figure out a truly revolutionary way to increase the efficiency of the delivery aspect, gene therapy is going to be restricted to institutions like this because it’s complicated. It’s very labor intensive, very effort and resource intensive.

Tacey Ann Rosolowski, PhD:



What did the Breast Cancer Research Foundation see in the proposals that you put to them?

Gabriel Hortobagyi, MD:

The Breast Cancer Research Foundation is structured differently from the NCI, the DoD, Komen, Avon, et cetera. These other agencies have a pot of money. They identify a number of prominent scientists, which turn out to be in many cases not to be very prominent because the most prominent ones always write back saying, “I'm sorry, but I'm too busy. I cannot review for you.” And then they review a series of projects. They score them according to the ideas of each of the reviewers, and then they distribute the money. In the BCRF what we decided to do was to say, “We are not interested in reinventing the wheel. That funding system is out there. If anyone wants to follow that, that’s fine. We don’t think that’s the best way to enhance the quality of research.” What we decided to do was the reverse. We said, “Let’s build on accomplishment. Let’s identify—depending on how much money we have—five or ten or twenty or thirty or forty of the most accomplished cancer researchers in the country, and let’s solicit from them proposals, and let’s fund them, and let’s emphasize that we want proposals that are high risk.” And we got some of the most outstanding investigators in the country, and we continue to fund a number of them, and the response has been incredible. The utilization of funds has been incredible, and the accomplishments of these people have been wonderful.

Tacey Ann Rosolowski, PhD:

What are some of the areas that these researchers have been working in? Just a sampling.

Gabriel Hortobagyi, MD:

Cancer vaccines, some of the early genetic screening methods, development of specific targeted agents for very specific types of genetic abnormalities. For instance, one of our grantees—who was one of the three original describers of the HER2 gene, which was done in 1983—just a couple of months ago came up with a new chemical compound which is going to be based on his preclinical data—a better anti-HER2 drug than anything else we have out in the market or in development—and it is based on painstaking work over a number of years based on a different concept from developing an antibody or a tyrosine kinase inhibitor. There are individuals working on biomarkers. One of the problems of targeted therapy, for instance, is that most of what we consider targeted therapy is not targeted because we don’t have biomarkers to identify the target population. Biomarkers are not big business, because while you can charge $10,000 a shot for a drug, you cannot charge more than a couple hundred dollars for a test. So, drug companies don’t get involved in developing tests, and because of that, that has held the field back by decades. These folks are developing biomarkers. They have developed new diagnostic methods that are much more precise than immunohistochemistry or FISH or a number of other things. We try to get not only different disciplines and different orientations so as not to get ten people doing the same thing but try to identify people where the need is or the needs are. We have grantees in France, in the UK, in Israel, in Singapore, but they’re handpicked and selected based on their area of expertise and their track record.

Tacey Ann Rosolowski, PhD:

We’re at about ten minutes after 3:00, and we were scheduled to stop at 3:00. I just don’t want to abuse your time. Would you like to stop for today and make another appointment?

Gabriel Hortobagyi, MD:

How are we doing in terms of your overall plan?

Tacey Ann Rosolowski, PhD:

Well, we’re doing great. This kind of material is exactly what I'm delighted to have recorded. I would suspect that we would need probably another two sessions.

Gabriel Hortobagyi, MD:

Okay.

Tacey Ann Rosolowski, PhD:

Is that okay?

Gabriel Hortobagyi, MD:

Yeah. Then let’s reschedule, because I do need to do some other things this afternoon.

Tacey Ann Rosolowski, PhD:

I'm turning off the recorder at ten minutes after 3:00.

(end of audio)

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Chapter 15: The Next Phase of Gene Therapy Research and Funding from the Breast Cancer Research Foundation

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