Chapter 13: The Moon Shots Program; Genomic Medicine

Title

Chapter 13: The Moon Shots Program; Genomic Medicine

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Description

Dr. Bast first responds to some of the criticisms leveled at the Moon Shots Program. He explains that some individuals were skeptical that additional investment in research could bring big rewards. He then sketches advances that have been made since the National Cancer Act was passed in the seventies. He then lists some key administrators who have been working to build greater support for the Moon Shots. Next, Dr. Bast defines genomic medicine, summarizes the perspective of the Genomic Institute, and notes that this field is addressing the challenge of how much gene sequencing to conduct at MD Anderson. He concludes that the most important genes to sequence are those for which we have drugs.

Identifier

BastRC_02_20140724_C13

Publication Date

7-24-2014

Publisher

The Making Cancer History® Voices Oral History Collection, The University of Texas MD Anderson Cancer Center

City

Houston, Texas

Topics Covered

The University of Texas MD Anderson Cancer Center - Overview; Critical Perspectives on MD Anderson; Overview; Definitions, Explanations, Translations; Healing, Hope, and the Promise of Research; Discovery and Success

Transcript

Tacey A. Rosolowski, PhD:

What’s been controversial about the Moon Shots? What’s been really successful and what have been the lessons learned in these past years? Or things that maybe were perfectly designed immediately but now you learned something, you can go forward.

Robert Bast, MD:

I think there’s huge skepticism on the land that you can intentionally do much to accelerate progress. The National Cancer Act of 1979, declared war on cancer, which it wasn’t. Over the last four decades it is a half full or half empty track record depending on your outlook. Clearly things are much, much better for many cancer patients now than they were in 1979 [1971]. Adding adjuvant chemotherapy to surgery and radiation therapy has now cured seventy percent of all breast care patients. I wish it were 100 percent. Particularly for patients with node-positive disease, the statistics are dramatically better now. In testicular cancer ten or twenty percent of people used to survive. Now it’s greater than ninety percent. And similarly things like chronic myelogenous leukemia, which was chronic but was lethal. Now people are living up to a decade and longer by taking a pill a day and most are probably cured. So there’s been huge progress. The trouble is it’s never enough and it’s never fast enough from a patient’s perspective. So there are relatively few people who believe that additional investment will bring more rapid progress. So you’ve got to overcome that skepticism. As the Moon Shots mature, positive outcomes will help to change that attitude. I think one of the concerns, which was not a fair criticism, was that Moon Shots were being built on the backs of the clinicians who had to work harder. As I understand it, almost all the moon shot money has come from philanthropy. So that really was a misperception. Preventing misperceptions like that is always difficult. The Moon Shots have not been as controversial as some of the other initiatives in asking clinicians to work harder to make up for perceived financial downturns that were not as severe as predicted. Any miscalculations were not so much from Ron, but ultimately he’s the president. You have to take responsibility for all of the institution. From the business side there also seemed to be the belief that we could increase the targets for clinicians and that they would gladly contribute to that year in, year out, without changing the infrastructure, without motivating people, and without explaining why all this is really important and having them really buy into greater sustained effort. This may be one of the causes for some of the concerns that have been raised. I guess my own view on this is that things are dramatically better over the last six months. I’m a medical oncologist and a perpetual optimist, but I think there’s evidence for that. Ron has really chosen wisely in people like Ethan Dmitrovsky, who is caring, transparent, fair, honest, and I think is being increasingly perceived that way as Provost, which is a huge help. Certainly Helen Piwnica-Worms is marvelous. She’s just another great recruit as is George Wilding. Getting Tom Buchholz to head the clinics was another wise choice. He is a person who’s hugely respected, and also really understands and appreciates and values the academic side of MD Anderson. We are not just a clinical operation. The clinical enterprise is hugely important, but it’s not the only reason we’re here. Choosing Tom to lead that has been another great move. So I think we’re headed toward smoother waters with any amount of luck. It is important though to really empower our people in the trenches and also to have them believe that they’re being heard. We now have people in place who are doing that. I think that’s going to be very helpful.

Tacey A. Rosolowski, PhD:

Yeah. And the institution has certainly gone through some rough waters. Thinking too with the moon shots, I mean I pick up statements here, statements there. But it sounded as though this concentrated organization focused on specific cancers purified or intensified what people were already doing. And then putting a very short time limit on it added additional pressure. And I’m wondering how has implementing that gone. And what are some lessons learned? What are some things that have worked really well? Where are some things that have emerged that needed a slightly different organization to go forward and create this pattern again?

Robert Bast, MD:

Well, again I’m most familiar with the breast and ovarian work, which I think has gone very extremely well. I think it’s gone well because people like Anil Sood have really taken the time. Karen Lu, much to her credit, as the new head for GYN oncology has been very supportive of this through retreats to get consensus. People raise their concerns, to talk that through, to try to figure out, develop even better protocols in the process, and really to get buy-in from everybody, so they’re just not being told to do something but they really want to do it because they’ve bought into it and it’s their project. I think that’s good practice in general. But I think it’s been particularly effective there.

Tacey A. Rosolowski, PhD:

What were some concerns that people were raising?

Robert Bast, MD:

I wasn’t part of those retreats, so I can’t tell you directly. My guess is that we had a lot of particularly more established faculty members who want to do their own thing for patient care. Often that has been really good patient care, but if you want to do research I think you can have both. You can have really good patient care and also be consistent practices, provided that you attain consensus, and also be willing to make exceptions for individual patients to best meet their needs. There needs to be a mechanism for making those exceptions, if there’s a really good reason. And so I think those things worked out well. As I have a particular interest in diagnostics, one there are projects in some of the other Moon Shots, where people haven’t really thought through the steps that you need to validate some of the diagnostic predictive biomarkers. For some of the other disease sites there are a number of biomarker projects that were simply up there on the board that were suggested and are good ideas but really thinking through all the steps that you’d need to do to get there hasn’t been accomplished yet. In part we’ve talked about the possibility of getting a coach or resident expert in diagnostics for the moon shots and for the institution. That’s still a work in progress.

Tacey A. Rosolowski, PhD:

It sounds as though the Moon Shots have created an opportunity to really look at a number of different patient care practices as well as research practices and see well, how do they mesh, where are we missing certain steps. Is that correct?

Robert Bast, MD:

It is, although I think that each one of the different disease sites has approached that in a little different way and I don’t think there’s been a consistent approach either suggested or taken. The plans and progress for each Moon Shot have been presented repeatedly to inside and outside groups for input to be sure that what was being done made sense. The Moon Shots have and should be driven in large part by the research opportunities that were out there on the therapeutic side. For example in the Breast and Ovarian Moon Shot, PARP inhibitors have been effective not only for women who have germline mutations of BRCA1 and BRCA2, but for a much larger group of people whose cancers for other reasons have problems repairing DNA. And so there’s been a large emphasis on identifying the drugs that you need to mix with PARP inhibitors to be even more effective. So that part of the agenda has been driven by the opportunities that are out there. Same thing for ibrutinib, an inhibitor of Bruton’s tyrosine kinase, for the Chronic Lymphocytic Leukemia Moon Shot. That is the drug of the year, if not of the decade, for CLL. A lot of the work is being driven by that opportunity.

Tacey A. Rosolowski, PhD:

One thing that—a word that has come up over and over is genomic. And I’m curious. How do you define genomic medicine and then place it within the context of translational research and then personalized care?

Robert Bast, MD:

I guess in its narrowest sense genomics has often meant deep sequencing of DNA. Increasingly most investigators also worry about expression of coding and non-coding RNA and the epigenetic regulation of DNA and histones, as well as proteomics - both defined signaling proteomics that Gordon Mills does and mass spec proteomics. So it’s really putting together what’s known at multiple levels of regulation within the cell what’s different about a cancer cell from a particular patient from normal cells. For personalized therapy, investigators are using these omic technologies to identify drugs that would target either those abnormal molecules or something downstream of those molecules and/or the other pathways that are causing resistance to inhibiting that particular molecule. The challenge, in my view, is to get the clinical side of this together. Certainly you can do a pretty good job of identifying targets with cell lines and xenografts, but again to make sure that that actually works in patients the way you hope it will, and also to get the biopsies from patients before, during and after treatment so you can actually sort out why they’re becoming resistant to a drug is extremely important. Again we’re working on methods to do that and ways to pay for it. But that’s I think been a lot of the challenge. If we’re going to make decisions that affect patient care based on molecular changes in their cancers, laboratory testing must be done under CLIA-approved conditions. Again this is very expensive and a lot of work to develop these assays under CLIA-approved conditions, even when you can cover the expense.

Tacey A. Rosolowski, PhD:

What is it that makes them so challenging and expensive?

Robert Bast, MD:

The CLIA law requires that you do the tests at a dedicated facility, that you measure standards before, during, and after the assays, and that you show the rigor of the tests in terms of day-to-day variation and within-assay variations. For some of these new tests, that’s a lot of work, and that costs time, effort and large sums of money. This means very high charges for new tests. Whether a new predictive test will be reimbursed is always a question. MD Anderson has set up committees to look at what’s ready for prime time and what’s not, as well as ways to fund some of these tests that are needed. But it’s a work in progress. It’s a huge work in progress. This really falls very heavily on our Pathology Division and which is very busy in the first place. So it’s been an extra stress I think for them. Stan Hamilton has done an extraordinary job as leader of this division.

Tacey A. Rosolowski, PhD:

So it sounds to me—what’s the relationship between—because there’s an Institute of Genomic Medicine now. And what’s the relationship between that institute and your office? And do you oversee those grants?

Robert Bast, MD:

The Genomic Institute, as I understand it, is one of the Centers that sets its own agenda for sequencing. Sequencing across MD Anderson involves many different groups. Helen Piwnica-Worms has brought together faculty from North and South Campus to see how much gene sequencing we needed institutionally, how much we should have here and how much we should outsource, determining how many more sequencers we really need. It’s obviously an important question. Through the core grant we have gene sequencing for the individual investigators who might not fit into the Genome Institute or the IPCT or routine patient care in the CLIA facility.

Tacey A. Rosolowski, PhD:

When I was speaking with John Mendelsohn he was talking about the challenge of collaborating with people across the institution to enroll their patients in protocols that take periodic sequences to profile a tumor over the course of an individual disease. Would the ideal be for information acquisition to do as much gene sequencing as possible? I mean is that the ideal? Or is there some other model that’s in mind that would really work to create a bank of information for the institution?

Robert Bast, MD:

Well, as I’m sure John mentioned, until gene sequencing gets even less expensive, there’s a balancing act between how deeply you sequence and what you can afford. Like computers, with every passing year, sequencing the whole genome has become less and less expensive, but this is still in the thousands of dollars, I believe. It will necessary to find ways to pay for gene sequencing, perhaps from philanthropy in the short run, but certainly from third parties in the long run. The most important genes to sequence are those for which we have drugs. And that’s been the strategy so far, to try to develop a panel of genes that would match up with the kinds of drugs that we’re testing in the clinic to find which patients would be candidates for treatment. There are other groups like Foundation Medicine, a private sector group in the Boston area, who will perform whole genome sequencing or will sequence ten times as many genes as most of these panels involve. Clearly it will be crucial to be able to save and to share the data that’s obtained not only within the institution but to develop ways to do that that protect patient confidentiality across institutions, because particularly for these rarer abnormalities you’ve simply got to. Even here where we see 30,000 new patients a year we’re not going to see enough of every subset to be able to make conclusions about how reliable these correlations really are. So one of the things Steve Friend was talking about at AACR this year was the importance of figuring out ways to share data. And it is a very important need for the scientific community at the moment. And perhaps even ways to share data before it’s published. That’s even more of a challenge.

Tacey A. Rosolowski, PhD:

Interesting.

Robert Bast, MD:

This is driven by the fact that if you look in different databases for what’s abnormal in adenocarcinoma of the lung you won’t always get consensus and particularly won’t get consensus if you look for prognostic subgroups within ovarian cancer or breast cancer or whatever. And in part this is related to the fact that you’ve got 26,000 genes on a gene expression array and you’ve got 50 patients or 100 patients. And just by chance alone you can find something that will fit your data. Different groups doing the same experiment will find different genes that fit their data. So the way to get around that is to have much larger databases and analyze those using similar techniques.

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Chapter 13: The Moon Shots Program; Genomic Medicine

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