Chapter 08: Research to Develop a Big Picture of Ovarian Cancer; Creating a Collaborative Laboratory Environment

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Chapter 08: Research to Develop a Big Picture of Ovarian Cancer; Creating a Collaborative Laboratory Environment

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Dr. Bast describes the final area of research underway in his laboratory: collating studies of ovarian cancer to develop a big picture of the disease to identify the molecular/genetic studies required to further develop the fine details. He sketches the themes emerging from this study and their implications for targeted therapy. Dr. Bast talks about the strategies he has used to develop his laboratory. He also notes that it has been very collaborative, participating in many multi-author and multi-laboratory studies. He lists key people in the laboratory and notes the "stellar" students who have embarked on strong careers. Dr. Bast also describes how he tries to identify students who have a future in research and who will take the knowledge acquired by working in a translational setting to other institutions or back to their countries of origin. Dr. Bast then talks about different activities held in the lab to build collaboration and sharing of ideas.

Identifier

BastRC_01_20140707_C08

Publication Date

7-7-2014

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; Discovery and Success; Professional Practice; The Professional at Work; Leadership; Mentoring; MD Anderson Culture; Multi-disciplinary Approaches; Understanding the Institution

Transcript

Tacey A. Rosolowski, PhD:

Interesting. Well, my question kind of derailed you from your story about the research. I’m just wondering if there are other areas that—we haven’t really talked about the epithelial ovarian cancer.

Robert Bast, MD:

Well, there’s—most of the ovarian cancers are epithelial ovarian cancers.

Tacey A. Rosolowski, PhD:

Okay. So, this was the immune stimulants. Have we fully covered that? You mentioned some of them.

Robert Bast, MD:

Yes, immunostimulants were important in the early days of my own work . Over the years, our group has really gotten much more into cell biology—

Tacey A. Rosolowski, PhD:

Cell biology.

Robert Bast, MD:

—of ovarian cancer, and modulating drug sensitivity.

Tacey A. Rosolowski, PhD:

Okay. Let’s see, now, with the—I’m just going to run through, I may have used slightly different language to describe the various areas of your research, and so I need to kind of connect the dots. We certainly—just to make sure we’ve covered all the areas. So, we’ve talked about the detection and the screening and the biomarkers. We talked about the autophagy, and ARHI. I’m wondering, because I have down here, too, it’s marked as 2011, the models of personalized care for patients with ovarian cancer? Have we—I don’t know if that’s, like, a code that you’re not recognizing. (laughter)

Robert Bast, MD:

No, clearly that’s an interesting—one of the things that our group has done over the years has been, tried to pull together an overview of all of the ovarian cancer research—

Tacey A. Rosolowski, PhD:

Oh, okay.

Robert Bast, MD:

—that is being done both in the laboratory and the clinic, and written the ovarian cancer chapter for the last editions of John Mendelsohn [MD]’s book, Molecular Biology of Cancer. To get the bigger picture, with both the forest and the trees has been one of our goals over the years. To some extent, that gives you leads about what other targets might be exploited.

Tacey A. Rosolowski, PhD:

Mm-hmm. And so, I mean, tell me about that. Are there themes that are emerging from that, big picture?

Robert Bast, MD:

For ovarian cancer, for sure. About eighty or ninety percent of epithelial ovarian cancers are so-called high grade, the cells look more abnormal under the microscope; about ten percent are low-grade cancers. With high grade cancers, there are a couple of major changes. Almost all of them have mutations of p53. Currently, we don’t have many strategies for targeting mutant p53, new work suggests that small molecule drugs can normalize the conformation of mutant p53. Abnormalities of the PI3 kinase pathway occur in forty percent to fifty percent of ovarian cancers. Only about fifteen percent of ovarian cancers have mutations of BRCA that are inherited, but forty percent of ovarian cancers have abnormalities of DNA repair mimicking BRCA mutation. Gordon Mills [MD, PhD], and others are trying to target PI3 kinase or BRCA-ness, with different drugs or combinations of drugs. Combinations of drugs against these targets maybe more effective than individual agents.

Tacey A. Rosolowski, PhD:

Mm-hmm.

Robert Bast, MD:

I have headed the NCI sponsored Ovarian Specialized Program of Research Excellence (SPORE) at MD Anderson for the last fifteen years and we’re in the process of renewing that grant again this year. Most of the high grade ovarian cancers are driven by the amplification of genes, where you’ve got too many copies of the normal DNA. Low grade ovarian cancers are driven by mutations, most frequently of Ras, but also of PI3 kinase and PTEN. Many of the targeted therapies are most successful where there are mutations, or where there’s a translocation involved. Targeting amplified genes has been more difficult. So, ovarian cancer, in that regard, is probably the next frontier.

Tacey A. Rosolowski, PhD:

Hmm. I’m curious, when you came to the institution in, let me think, ’94, I think it was—

Robert Bast, MD:

Mm-hmm.

Tacey A. Rosolowski, PhD:

—yes, remembering, and set up your laboratory, did you bring part of your laboratory with you?

Robert Bast, MD:

I did.

Tacey A. Rosolowski, PhD:

Your personnel? And so, I mean, it’s obvious that you’re, you know, you have a very strategically established laboratory army, if you will.

Robert Bast, MD:

It’s a pretty small army, but...

Tacey A. Rosolowski, PhD:

Well, but, you know, obviously, you’re talking about, you know, you’ve got this dimension that’s kind of looking at the big picture, then you’ve got these people who are really looking at very detailed dimensions of pathways and mutations. So, I’m curious, you know, how did your own strategies for setting up a lab evolve over time? Or, is that not the best way to ask the question?

Robert Bast, MD:

No, it’s a very good question. I’m just trying to think of the right answer. .

Tacey A. Rosolowski, PhD:

Mm-hmm.

Robert Bast, MD:

But I guess one thing is that our laboratory has done has been to jump on new technologies over the years.

Tacey A. Rosolowski, PhD:

Mm-hmm?

Robert Bast, MD:

Discovering CA125 depended on developing the OC-125 antibody which, in turn, depended upon Kohler and Milstein’s earlier studies that developed the monoclonal technology. Our discovery of ARHI, again, depended upon the precursor of gene expression array analysis. When compared to normal ovarian epithelium, ARHI is the most down-regulated gene on gene expression array analysis. SIK2 was discovered by using high throughput SIRNA screens, which, again, is a relatively new technology. So, that’s been a big component.

Tacey A. Rosolowski, PhD:

Mm-hmm.

Robert Bast, MD:

Also, our laboratory has been very collaborative. A lot of the work that we’ve published is multi-authored and multi-laboratory, realizing that if we’re going to get those done most effectively, then doing that with other people who have different expertise, has been helpful.

Tacey A. Rosolowski, PhD:

Mm-hmm. Mm-hmm.

Robert Bast, MD:

Within our lab, we have depended upon faculty members and post-doctoral fellows. Over the last several years I have just gotten seriously involved in the Graduate School of Biological Sciences, creating a curriculum and program in Clinical and Translational Research with Khandan Keyomarsi and colleagues at UT Health. Over the last three years, Margie Sutton has been our first graduate student. Research assistants have also been very important and included as authors on our papers.

Tacey A. Rosolowski, PhD:

Mm-hmm.

Robert Bast, MD:

Over the years, we’ve had several real superstars pass through our laboaratory. Ian Jacobs was a little farther along in his career, when he came to visit our laboratory at Duke [University]. In 2000 Ian had started the 200,000 women UKCTOCS trial in the UK, and then served as Dean at the University College London Medical School, and then had been provost at the University of Manchester. Now, he’s going to be president at the University of New South Wales, in Sydney, Australia. He really has had a very effective administrative, as well as scientific career. He’s also highly respected in GYN Oncology in the UK and in Europe as past president of the British Society of Gynecologic Oncology. Andy Berchuck [MD], who is now head of GYN Oncology at Duke, joined forces with our lab while he was on the junior faculty at Duke. Andy’s insights and drive were a tremendous help to our lab. Ahmed Ahmed is another extremely talented person who was a postdoctoral fellow. Ahmed had started the SIK2 studies, which ended up in Cancer Cell. He is now full professor of Gynecologic Oncology at Oxford. So, we’ve had some really incredible people come through.

Tacey A. Rosolowski, PhD:

Mm-hmm.

Robert Bast, MD:

Over the years, however, I’ve realized that’s only a fraction of the people whom we’ve trained have remained in full time research. One of the things that I’ve tried to do more is to identify people for our laboratory who really have a future. So often, if in training people from other countries who go home to their hospital, they’re never really given the opportunity to do enough research to really have an impact. Coming to the US for a year or a year and a half doesn’t really prepare them adequately for what they’re going to do, and then they’re not given the opportunity to really do laboratory-based or translational research when they get home. So, I’ve been trying harder to find people with a different trajectory.

Tacey A. Rosolowski, PhD:

Mm-hmm. Right.

Robert Bast, MD:

Tacey A. Rosolowski, PhD:

Mm-hmm. Mm-hmm.

Robert Bast, MD:

The success of our laboratory depends upon having really great junior faculty members like Zhen Lu. Finding technicians who are really professional and competent provides some continuity. Post-doctorate fellows come and go over a two or three year period.

Tacey A. Rosolowski, PhD:

Right. Right.

Robert Bast, MD:

As an aside, what sort of answers have you gotten to that question from other people?

Tacey A. Rosolowski, PhD:

I think it’s the first time I’ve asked it directly, frankly. Some people have kind of spontaneously talked about it, you know? But I was just curious, because you had added—the reason I asked the question is that you had, you know, talked about wanting to bring in this, you know, 20,000 foot view, or I can’t remember how you phrased it, exactly, and it just seemed like a very, you know, precise moment. Like, okay, now we’re going to add this dimension to the laboratory, because it’s needed. So, I was wondering, you know, if you had kind of a philosophy of setting up a lab, or a strat—or a larger path?

Robert Bast, MD:

That is really two different, but related questions.

Tacey A. Rosolowski, PhD:

Mm-hmm?

Robert Bast, MD:

One is what you do with your laboratory, once it’s set up. The other is, what kind of people do you select for your laboratory?

Tacey A. Rosolowski, PhD:

Exactly.

Robert Bast, MD:

And what are the criteria for them?

Tacey A. Rosolowski, PhD:

Right. Right. And I think it’s also an evolving question of—because, you know, people in any position change over time. And Mien Chie Hung [Oral History Interview] was telling me about the importance of the journal club, and the way he has set up what the journal club looks like, because it’s sort of a practice pad for looking at the state of the field, you know? And so, that’s a very intentional decision about what he wants his laboratory to provide, training-wise. So, I just—and that was a new idea for him, basically.

Robert Bast, MD:

Yes.

Tacey A. Rosolowski, PhD:

You know, now I’m going to do this as an educator, as a leader, or as an administrator, you know, as a leader of a lab. So, I was just kind of curious about your decisions in these areas.

Robert Bast, MD:

Each Monday, we have had a lab lunch where people present their developing papers. We also have had guest speakers in the same forum. Most recently, our guest speakers have been interested in autophagy and/or ovarian cancer. We have also started an autophagy journal club for the Houston community.

Tacey A. Rosolowski, PhD:

Oh, really?

Robert Bast, MD:

Yes, Margie Sutton, a graduate student in my laboratory is taking the lead in doing that. There are a number of people here at MD Anderson who are interested in autophagy. So, I think we’ll see how the experiment works, but my guess is, we’ll probably find an opportunity to share our work in progress.

Tacey A. Rosolowski, PhD:

Right.

Robert Bast, MD:

We also have another data session each Friday for our lab and then spend at least a half an hour, if not more, with each one of our trainees during the week, to make plans for their next experiments and papers.

Tacey A. Rosolowski, PhD:

Hmm, which is kind of incredible, because, you know, your busy-ness level has increased, and people’s workloads in general has increased, and often those training moments, or mentoring moments, are cut back.

Robert Bast, MD:

Sure.

Tacey A. Rosolowski, PhD:

You know, out of necessity. But you’ve gone against the grain, and now—(laughing)

Robert Bast, MD:

It’s the one thing that we can’t [inaudible], at least not often.

Tacey A. Rosolowski, PhD:

Oh, that’s funny! Do you need to stop a little bit early today?

Robert Bast, MD:

No, 11:30 will be fine.

Tacey A. Rosolowski, PhD:

It’ll be fine? Okay, just wanted to check with you about that.

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Chapter 08: Research to Develop a Big Picture of Ovarian Cancer; Creating a Collaborative Laboratory Environment

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