Chapter 24: The Institute for Personalized Care
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Description
Here Dr. Mendelsohn discusses the mission and activities of the new Institute for Personalized Care, which he directs. Through the Institute faculty are studying the molecular, chemical, and genetic profiles of tumors in order to tailor care. He explains that the procedures under study are not reimbursed by insurance so Institute activities currently require philanthropic support so the mechanisms can be scientifically proven and admitted to the roster of “standard of care” procedures. He goes on to explain that this kind of personalized care requires a sophisticated infrastructure of support fields such as pathology and radiology. He also notes that it is a challenge to shift the thinking of clinicians and researchers so they understand that profiling tumors along the course of treatment can influence the treatment prescribed. Dr. Mendelsohn describes two protocols currently underway. The Clearing House Study of individuals with advanced cancer profiles tumors to insure these individuals are receiving the correct therapy. The Unusual Responders protocol focuses on patients who receive an experimental drug and seem to respond, but then no longer react positively to the drug. These tumors are sequenced a second time to investigate why responsiveness ceased. Dr. Mendelsohn notes that Institute protocols are currently examining forty-six genes, but will expand to two hundred. He notes that he will soon be meeting with the group that handles lung cancer to integrate tumor sequencing into their course of treatment so the results can tailor therapy.
He explains that this pioneering work will insure that MD Anderson continues to be the number one cancer center. The Institute is developing instructional tools so that physicians can quickly take advantage of discoveries. He stresses how important it is to build a medical informatics system to process the complex data from these studies. The Institute is currently talking to IBM about means of tracking and packaging data.
Next, Dr. Mendelsohn outlines future plans for the Institute for Personalized Care. The Institute will continue to build up training, particularly in data-interpretation. (One challenge is creating programs to account for the genetic degradation of samples, for example.) He notes that a project on the genomes of survivors will be linked to Dr. Ronald DePinho’s “moonshots.” There are also many areas for further research. The tools are all available, he explains, to discover how the genes of a tumors influence RNA and protein expression. It will also be important to examine the role of patients’ immune systems and eventually the immune profile will form part of what the Institute for Personalize Care provides. Dr. Mendelsohn explains that it is important to investigate less invasive ways of getting to a patient’s tumor and explains a blood test that will eventually yield information about the tumor profile. He then explains tumor heterogeneity –tumors change genetically at a very rapid pace.
Identifier
MendelsohnJ_03_20121017_C24
Publication Date
10-17-2012
City
Houston, Texas
Interview Session
John Mendelsohn, MD, Oral History Interview, October 17, 2012
Topics Covered
The University of Texas MD Anderson Cancer Center - An Institutional UnitThe AdministratorThe LeaderThe ResearcherOverviewDefinitions, Explanations, TranslationsDiscovery and SuccessBuilding/Transforming the InstitutionInstitutional Mission and ValuesUnderstanding the InstitutionOn Research and ResearchersUnderstanding Cancer, the History of Science, Cancer Research The History of Health Care, Patient CareEducationMD Anderson in the FutureBusiness of Research
Creative Commons 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:
How does the mission of the Institute for Personalized Cancer Therapy go about putting that into operation and what is your role as director of that institution?
John Mendelsohn, MD:
Right now there are maybe a dozen genetic aberrations where testing is paid for because they determine therapy. Other than that, the approach that I just outlined is research that requires funds. It’s not reimbursed, so one of the goals here is to raise the philanthropy and the grants and the commitment of some of our hospital margins to set up research protocols that prove this works for the benefit of the patient’s care. Now maybe we’ll prove it doesn’t work; then we’ll quit. We think it’s very likely it will work based on research we’ve done and other people have done. It’s not standard of practice yet in most situations. The 2nd thing is, in order to do this you need a more sophisticated infrastructure. Pathologists become even more important because you can’t treat a patient on the basis of a lab test unless that lab test has been done in a laboratory that has been certified. They have very high standards. It’s not a government certification. It’s the pathologists. It’s called CLIA. We have a CLIA lab. When the pathology department does a blood count, sodium and potassium, they have to have CLIA certification. Well, now we had to build in CLIA certification to do gene work. One of the challenges is that nobody knew what CMS would demand. Nobody knew what the FDA would demand. There were a lot of people that suddenly feel they should have some say in how all these tests are done. They’re hard tests. They’re hard to interpret.
Tacey Ann Rosolowski, PhD:
Can you give me an example?
John Mendelsohn, MD:
If you’re sequencing a genome, you’re getting 3 billion pieces of information. The error rate in the machine is 1 in 1 to 10 million. Then you’re identifying genetic aberrations, putting the information together and discarding errors. It took 10 years to sequence the first genome. Now we’re trying to do it in 11 days, or faster. We cut up the DNA into little pieces and sequence them all simultaneously, and then we use statistical algorithms to fit them all together. The process needs a sophisticated approach to look at the data that comes out and say these are the genomic aberrations. Then in many cancers we’re finding 100 genes are abnormal. They aren’t all causing the cancer. Cancer is a disease where your genes get beat up. There’s a lot of thinking and planning and information that we are mostly carrying in our heads that will someday be validated and fed in by a computer to say, well, these are the 3 or 4 abnormal genes that matter. Right now, many of the genes that matter are ones for which we happen to have targeted drugs, and the drugs have been produced because somebody found that those genes seem to be important and the experiments in animals showed that if you attack that gene and the product of that gene with a drug, the animal’s cancer gets better. So it’s a complicated learning process.
We’re setting up the tools in pathology and also in diagnostic imaging, because if a person has cancer and they’re doing well on standard care, and 5 years later a recurrence occurs, you don’t want to look at genetic aberrations in that original cancer. You want to look at the new evolving cancer. We have to biopsy the the tumor in order to do the gene tests on it, so we have to expand interventional radiology while we expand pathology. Finally, we have to show the faculty that this part of the workup is very likely to be useful, and encourage the faculty to design the trials which will test our hypothesis. It’s still a hypothesis, doing this on a routine basis for all patients that are not being cured or well-controlled in their cancer care. This is the next step. So we’re meeting with the faculty, and they’re very excited about doing this kind of research. It’s a 5-year plan. We will reach the point where this year we’ll probably sequence 1,000 patients, the next year probably 4,000. At the end of 5 years we hope that we will have shown that this is important and useful for every patient that has advanced cancer that is not cured by standard care, and that might be 30,000 a year.
This is very different from other institutes. This is an institute that’s trying to set up a process and a way of thinking. The only full-time member of that institute on the faculty is me. I also have an appointment in experimental therapeutics. Most of the people that are doing this work are members of the Pathology Department or the Systems Biology Department or the Medical Breast Cancer Department, or many other departments like Investigational Cancer Therapeutics. We are pulling together a matrix. This is going to become important for caring for any kind of cancer. It’s a project that maybe I’m suited for because I used to run the institution, so I know most of the players, although there’s a lot of new ones coming in every year. I think people know that I’m not in here trying to build my own research career on what’s coming out of this. The people that are doing these studies are going to be the authors of the publications.
Tacey Ann Rosolowski, PhD:
Can you tell me about some of the specific studies that are being done?
John Mendelsohn, MD:
There are 2 main protocols that have been set up. One is called Clearinghouse, and that’s a protocol that was piloted in breast and colon cancer and now is opening up gradually to all types of cancer. When people with advanced cancer are considering an experimental therapy, we do the genomic testing, and we help their physicians to select an experimental therapy that is most likely to be effective. There are a few dozen protocols now where the patients with different types of cancer get their tumors sequenced and then we give the information to the treating physician who is a physician scientist - but the science is on their patient. That’s just starting. If you ask me how many times a patient has gotten a drug as a result of this test, I can’t give you the data right now. I think probably Dr. Funda Meric-Bernstam could, if you wanted to ask her. We’re just setting up the process. It didn’t start until March. It was only a pilot project for 6 months, so we’re just opening it up.
The other protocol is called Unusual Responders. These all have consent forms and IRB approval. Let’s say the patient receives an experimental drug and it works. Unfortunately, most experimental drugs only work for a while. The tumor starts growing again. We’d like to biopsy that tumor again, and we’d like to see what’s changed, what new gene abnormalities have occurred. We’d also like to study patients who sometimes have an incredibly effective response to a drug, and go back to the original tumor to do more complete genetic sequencing which may explain the success. The first part of this year, we were testing only about 12 different genes. Now we’re testing 46 genes, and we’re testing certain hot spots on those genes where common mutations are seen. We’re going to be expanding them to probably 80 genes and then 200 genes. We will be expanding and looking at not just the known important mutations but looking for all mutations, because the technology is allowing us to do that.
Suppose somebody has a wonderful, complete response and another patient didn’t respond. We’d like to go back to their original tumor. Both tumors had that target genetic aberration. They were assigned the drug. Well, we’d like to now look at all the genes in those 2 tumors, pair them up, and see are there other genes that are abnormal in the one that responded or abnormal in the one that didn’t respond. We can begin to understand the mechanism. Maybe we can add a 2nd drug for that person that didn’t respond. Maybe we should say to a patient, “We’re not going to give you a particular targeted drug even though you have the genetic target for that drug, because you’ve got other genetic problems, so it won’t work.” This is part of the research in the Unusual Responder program.
Those 2 protocols are set up, and we’re going to meet with the lung group and other groups soon. They’re beginning to look at genetic aberrations in lung cancer patients. I think eventually this is going to become a standard way to look at any patient, but we’re pioneering, showing the way how to do it.
We think about cancer in a Darwinian sense. There is natural selection going on in our bodies due to mutations in the cancer that accumulate. It happens with tuberculosis, too. You need 3 drugs to treat tuberculosis, because you give the one drug and the bug develops a resistance to it. It’s a very challenging battle you’re doing with that cancer.
Tacey Ann Rosolowski, PhD:
How quickly do these mutations take place?
John Mendelsohn, MD:
They can take place within weeks.
Tacey Ann Rosolowski, PhD:
Then you have to revise your protocol.
John Mendelsohn, MD:
Typically, they probably take place in weeks and months, but not decades.
Tacey Ann Rosolowski, PhD:
Do you find that with this vision this could become the standard way that all patients are handled? Obviously you’re going to set up work with a lung cancer group.
John Mendelsohn, MD:
Well, we’re working with all of them. It will be the standard way. I think it is likely enough it will be the standard way so that if we want to be the number 1 cancer center, we’d better be prepared to offer it. And if we’re pioneering how to offer it, we’re doing the right thing. Enough people agree with this so that the institution and philanthropy are willing to put resources into it.
Tacey Ann Rosolowski, PhD:
The question I was trying to formulate had to do with the vision issue. You said that one of the interesting things about this institute is it’s really about changing the way people are thinking.
John Mendelsohn, MD:
And putting in the infrastructure.
Tacey Ann Rosolowski, PhD:
With the cognitive piece, we are focusing on this moving target idea, the Darwinian battle that’s happening over weeks and months. That’s what you’re trying to really focus on?
John Mendelsohn, MD:
Yes, but it’s a huge challenge. There’s all kinds of information coming out now, the literature about different genes in different types of cancer. You’re one of our crackerjack colon cancer docs. You can’t keep up with all that literature. One of the things we’re developing is a decision support tool. We want to be able to take the literature as it comes out and funnel it so that the physician who gets the report, X gene is abnormal in your patient, can have a little background. Here’s the literature on that gene that’s relevant to you, and here’s the literature where somebody has shown that if you treat that gene aberration with a particular targeted therapy, it will help your patient. We’re not going to say to a physician who is treating a colon cancer patient, “Here’s the result of the test. You treat X way.” They decide the treatment, and we want to give them the tools so that they can decide what is the right thing to do. And we also have to give these tools to the patient. There’s a huge structure, medical informatics, that’s needed here that we’re just beginning to adequately staff. Many medical schools have departments of medical informatics and we have one.
Tacey Ann Rosolowski, PhD:
Why was MD Anderson slow to develop that?
John Mendelsohn, MD:
At first we didn’t need it as a formal department.
Tacey Ann Rosolowski, PhD:
What’s the plan that you’re putting into place to address that now?
John Mendelsohn, MD:
The Institute is scaling up its informatics capacity. Dr. Mills and Dr. Meric-Bernstam are working with many biostatisticians and bioinformaticians in the institution and Dr. DePinho has taken on this need in a big way. The institution is working with Oracle and talking with IBM, and we want to get the information systems in place here partly to just keep track of all our data and mine the data and learn from it but partly to package the data in a way that is useful for the clinician and the patient who has cancer. This is going on everywhere in American medicine, and it will be worked out in the next few years. We’ll be part of the solution, and you’ll be able to buy something off the shelf 5 years from now. We may be contributing to it. It’s a huge project, and there’s very little funding for it in the standard research grants that pay for cloning genes and doing biology and things like that. That’s another reason we need all these people, I told you, trained in computer science and bioinformatics and systems biology.
Tacey Ann Rosolowski, PhD:
I remember hearing that it used to be that the phrase was knowledge is power, and I was hearing somebody say more recently that that’s not true anymore. Now power is what you know how to do with that knowledge, and it isn’t just that you can push a button on the internet and get a list of a million and five hits where you might go to sites. It is how do you do exactly what you’ve described? How can I get that information in small bundles that have meaning to what I need to do in accomplishing my work and my mission? That’s really amazing, and it sounds like the funding organizations need to catch up with that idea.
John Mendelsohn, MD:
This country isn’t in a strong funding position right now. The NIH budget is going down rather than up. Hospital margins in general are going down. Ours, fortunately, is not. Informatics, information management is very expensive. MD Anderson spends a fortune on computers and many millions of dollars on recording and managing information.
Tacey Ann Rosolowski, PhD:
What are some other projects that the institute is taking on to move ahead this vision?
John Mendelsohn, MD:
We’re starting an education program. We’re going to be taking people that have been trained in medical oncology or surgical oncology and giving them training in some of these areas I was talking about. They get a stipend, and they have time off, and they do research. The research is oriented not only on learning how to clone a gene or how to do molecular biology. It’s also about learning how to interpret data. Dr. Robert Wolff is in charge of the program. For example, some trainees may work with Dr. Andy Futreal on a survivorship project that he’s developing, and I think he’s probably going to work with 2 or 3 of the Moon Shots doing that kind of thing.
Tacey Ann Rosolowski, PhD:
If a patient has been treated from diagnosis forward at MD Anderson, do you keep tissue samples of all of those?
John Mendelsohn, MD:
Oh, Yes. In fact, we have lots of tissue samples and tumors saved up in many different banks, and one of the things that was a challenge is identifying them and getting access to them. Under Dr. Kripke we worked together to set up a location with special freezers and an emergency power system. All these precious samples are now annotated stored off campus, I hope away from floods, in a building that has an extra power source if the power goes down. That situation occurred in the TMC about 8 years ago during one of the floods; Baylor lost a huge repository of frozen breast cancer tissue. So yes, we have a very precious bank of tumors.
Tacey Ann Rosolowski, PhD:
If there have been multiple cancers with the survivors, of course, it would be so important to go back and look at the tumor profiles of all of those.
John Mendelsohn, MD:
We definitely can do that.
Tacey Ann Rosolowski, PhD:
That’s where the bioinformatics comes in to help with the algorithms.
John Mendelsohn, MD:
We have internal experts and many algorithms are available on the internet. We can get help from the Broad Institute, Baylor, and Wash U which have major genomic sequencing centers. There are probably a couple of dozen different sources of computer packages, and you can’t do them all, so part of it is picking out which ones are the right ones. Well, fortunately there are a dozen people here, like Dr. Weinstein, Dr. Chen, Dr. Futreal, and Gordon Mills and people in the Bioinformatics Department that know these tools and can help us decide which ones are the right ones. The pathology department has some people with these skills, too in the CLIA lab. We’ve got to work together. That’s one of the missions of the institute, the IPCT. We’d like to make it happen as smoothly and as seamlessly as possible. Linda Chin’s department, Medical Genomics, and Gordon Mills’ department have faculty with computational skills, and then you always have to have internal people that are writing code too to make it all happen.
Tacey Ann Rosolowski, PhD:
Any other areas that you’d like to talk about with the institute’s activities?
John Mendelsohn, MD:
In the future? We’re just looking into genes now. We need to look in the future at whether the gene is expressed or not at the RNA level. We need to look at the proteins that are produced by the genes, see if they’re functioning differently or not at all. For example, are they phosphorylated, or are they not phosphorylated? The tools to do that are all available. It adds cost. This isn’t paid for by insurance, so it’s all research. You can’t just go and take 30,000 patients and do all that. You’d break the bank. We have to selectively begin to look at the RNA expression, and we have to selectively look at the proteins. We have to look at the immune environment in the patient. It turns out that the immune system can promote cancer, and it can also fight cancer, and Dr. Allison, who is moving here this month from Sloan-Kettering is an expert in that, and Dr. Grimm, already here, is an expert in that. I think 5 years from now, part of the IPCT will be an immunology profile. Is the patient fighting their tumor, or is the immune system actually promoting the tumor, and what can we do to promote the former and inhibit the latter?
The other thing we want to develop in the IPCT is a better way than sticking biopsy needles in people and getting pieces of their tumor or cutting with a knife into people and getting pieces of their tumor out and looking at the genes.
There are 2 approaches. One is imaging, nuclear medicine, and PET imaging and approaches like that. Right now it’s much more developed in mice than it is in people. We started building a program but the person that was running it is leaving, and we’re going to be recruiting a new major investigator for imaging research. Another way to go is blood tests, because blood is easy to draw. When cells die, they typically release DNA into the blood, and there are ways we can determine if a segment of DNA came from the tumor or not. If a treatment is working, the tumor DNA might go up, because the tumor cells are dying, and then it might go down after that because they are gone. If your disease is under control and then all of a sudden the tumor starts growing again, some cells are dying again and the DNA may tick up. There are ways to monitor DNA in the blood, or circulating tumor cells in the blood, and this is an area of testing that’s being studied here and in a variety of different labs around the country. If it becomes useful we want to be there with it for our patients. There are a number of people here that are interested in looking at the proteins in the blood. Dr. Hanash has just been recruited here by Dr. DePinho, and he’s a world expert on measuring proteins. Any blood test that we can use instead of biopsying a tumor is better. The other reason blood tests are better is that tumors are heterogeneous. Suppose you’ve got a metastasis growing in your lung and another one growing in your liver. There could be new mutations in the lung and not in the liver or new mutations in the liver and not in the lung. All of a sudden, the genetics of the tumor is is more complicated. You might have to use different chemo to treat the lung than you do in the liver, even though the cancer originally came from the breast. If those tumor cells are all leaking DNA out in the blood, we can detect this and say, “Okay, there are 2 populations here. One we better treat with this drug, and one we better treat with that drug, without having to stick needles in the liver and the lung.”
Tacey Ann Rosolowski, PhD:
Do you have a sense of when the institute might be prepared to start really investigating this aggressively?
John Mendelsohn, MD:
I think it will happen through the Moon Shots, because there’s going to be a lot of money invested. Studying these kinds of diagnostic and therapeutic approaches are good ways to change death rates, so I think it’s going to happen. It’s also going to happen because people are being urged to collaborate, taking advantage of the sequencing equipment and the technology and the informatics we have, and the huge number of patients we treat.
Recommended Citation
Mendelsohn, John MD and Rosolowski, Tacey A. PhD, "Chapter 24: The Institute for Personalized Care" (2012). Interview Chapters. 1440.
https://openworks.mdanderson.org/mchv_interviewchapters/1440
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