Transcription:
Multidisciplinary Cancer Care and Translational Research

Dr. Leonard:  Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care and research. I'm your host, Dr. John Leonard.

And today, we will be talking about multidisciplinary cancer care and translational research. I'm very happy to have as today's guest, Dr. Manuel Hidalgo. Dr. Hidalgo is Chief of the Division of Hematology and Medical Oncology at Weill Cornell Medicine and New York Presbyterian hospital, where he leads a team of world-renowned hematologist and medical oncologist who offer state-of-the-art patient-centered care for people with solid tumors, blood cancers, and nonmalignant blood disorders.

Dr. Hidalgo's main research focus is on strategies for personalized medicine and immunotherapy for pancreatic cancer. And it's especially fitting as we record today as it is World Pancreatic Cancer Day. And so it's great to have and we'll come back to pancreatic cancer and what's new there in a few minutes. It's great to have Dr. Hidalgo here. So thank you for joining us.

Dr. Hidalgo: Thank you very much for inviting me.

Dr. Leonard: So Manuel, I like to start with our guests to get a sense of how people end up working in the field of cancer care and research. So how did you get your start? What drew you to taking care of patients with cancer and doing research in this field?

Dr. Hidalgo: John, I became interested in oncology probably in the last year and a half of medical school. I went to medical school in Spain and in my last year, I took a semester at Harvard and I did urology, infectious diseases and oncology at the Dana-Farber. And it was that experience in Boston in which I had the opportunity to, in a very dedicated manner, see the care of cancer patients and we're talking, you know, many years ago, and that was attractive to me how we were in the infancy of the first few years of offered chemotherapy. There were not that many things that work as we have today, but these were complicated patients, very complex cases. And I was attracted by their medical issues and their medical care. How compassionate and dedicated these doctors were was also a model that I wanted to do follow in my career. But importantly, I learned also, started to understand or began interested in cancer biology, and how a cell becomes transformed, becomes malignant, spread to other organs. And I thought that the biological basis of cancer were just very interesting. And for that reason, I went back to Spain, decided to do internal medicine and then oncology.

Dr. Leonard: I think one of the great areas as you alluded to is the connection in cancer care with research, probably I would say more than really any other field in medicine in reality. And you came to Weill Cornell and New York Presbyterian Hospital recently, and your role is really to serve as a leader in the development and the advancement of the care and the research relating to cancer treatment here at our center.

And it really highlights the importance of the role and the connection of research to clinical care at academic medical centers like ours. Can you maybe explain a bit to our audience how you think about that and how they should think about that from the standpoint of where to get their care and why it's so important to be at a center where all of this is connected?

Dr. Hidalgo: That's a very important point. In an academic center such as ours, the first thing that we have is a very integrated multidisciplinary cancer care. Pancreatic cancer, like many other tumors are, as everyone knows, very complex, complicated diseases that required a multidisciplinary approach. Classically, radiation therapy, surgical oncology, medical oncology, but we know that is way beyond that, with nutrition. Now with immunotherapy, we need the help of many other experts to manage toxicities. So the first important thing to highlight is that there is a very integrated, comprehensive clinical team addressing the problems of these patients.

But as you said, in oncology and in pancreatic cancer in particular, the boundary or the connection between a clinical care and research and clinical research is basically none because the best treatment that we can offer for our patients often is a clinical trial, a protocol with some experimental treatment. So we are very active in that field and have a very strong portfolio of innovative clinical trials addressing most, if not all, of the clinical scenarios that our patients present with.

Now, these trials are based on fundamental discoveries done in the laboratory. In a center like ours and in other university and industry centers and the pharmaceutical centers in the country, we're constantly looking for new targets for new strategies to develop new treatments, early diagnosis, strategies and really areas that can be applied to clinical medicine. So working in an environment such as this where we can really cross between the lab and the clinic and the lab is how we identified targets, new mechanisms, new abnormalities, and then go on develop drugs sometimes on our own, sometimes in partnership and in collaboration with industry and with other centers and base our clinical research trials on those discoveries. So it's very well-integrated. It has to be that way. If you look at the progress that have been made over the last few years, it has been really integrating a new biology and converting those findings into therapeutic interventions.

Dr. Leonard: Yes. I think one of the great things at a center like ours is being able to meet directly with colleagues. I mean, obviously we're all on Zoom now, but still even with Zoom, we're regularly talking about cases and presenting research and going back and forth. Is there an example in your career or in your field or the work you've done where that interaction with the laboratory and the clinic has made an impact for patients or at least in the future, you expect to make an impact for patients, a scenario that the audience would bring this home for people as they understand it?

Dr. Hidalgo: It does and it does almost every week when we discuss new cases. And there’s one field that I think is particularly interesting and innovative in that area, which is the integration of precision medicine. So we have an entire institute called the Institute of Precision Medicine in which we're able to analyze and sequence in great detail patient tumors. And the information that is obtained by doing those techniques is huge. And that learning a significant number of mutations, genetic alterations in those tumors, that really requires a very sophisticated bioinformatics, artificial intelligence and an expert to understand what is relevant, what is less relevant.

So often when we discuss new patients and we discuss cases, we look at those genetic alterations. And by talking to these experts, we're able to identify genes that are altered, that are unique in that particular tumor and then start pairing those abnormalities with therapeutic interventions.

So often we end up recommending a treatment, which sometimes is not what is written in the textbook. Things that are really very new, medicines that maybe approved in other indications are applied to patients with pancreas cancer and to other tumors because we're able to identify these abnormalities. And of course, we do this by Zoom these days. It was better when we were able to get in a room and have a face-to-face discussion.

But another thing that we're doing in the Zoom even now is many patients consult with us and sometimes the first visit is a televisit. We do this by an integrated Zoom system in our medical record system. And now that is an impediment for the face-to-face discussion, but it does facilitate that we can sort of have all the experts Zoom with the same patient almost simultaneously. So a patient has a visit and we can basically go from medical oncology, radiation oncology, surgical oncology in that same Zoom meeting. And at the end of the day, when that visit is concluded, we're able to provide a very comprehensive plan for that patient. So Zoom is a limitation, but I think if you use it properly, that there are some advantages and we're using it in that way.

Dr. Leonard: One other area that I wanted to ask you about relates to some of novel technologies and tools that you've been studying. I know, I like the term avatar. I've heard you use several times, but there are these organoids and patient-derived xenografts. These are things that I think patients hear about, the idea that you can represent the tumor in the laboratory and study it in one way or another and use that ultimately hopefully for therapy. Can you tell us a little bit about your experience and why you think that's so promising?

Dr. Hidalgo: Yeah. We started that number of years ago initially using PDX models, the avatars, and growing patients tumor in mice in the laboratory, more recently using three-dimensional sculptures called organoids. And here at Weill Cornell, we have the capability of doing in both.

Those models have been very useful to understand the biology of the disease, to understand genes are important, processes like metastasis. But, more recently, we are really able to do this almost in real time and can use the models once developed to screen drugs that can be effective against a particular individual tumor. So I've said before that we sequence the tumor, we learn genes are altered. Sometimes we identify targets that are very important for that particular patient, but sometimes we don't identify anything that we know related to susceptibility to a drug.

In those cases, we can agnostically test the patient model, the organoid, against 100 drugs, 200 drugs, and you identify those are more likely to be effective and then provide those for clinical care on one end. But at the same time, as we said before, connecting that to the research labs to try to identify why that particular drug worked in that individual tumor. It's a very nice technology. I think we still have a way to go to make it more standardized and user-friendly. Now, it's a very intense process and that's an advantage of a center like ours, we can take those big projects, but it's very interesting. And I think eventually it's going to provide important information to manage individual patients.

Dr. Leonard: On occasion, I've had patients, I'm sure you have as well where the patient says, "Why can't you just pour the chemotherapy some of the tumor cells in the lab and see if it's sensitive like an antibiotic sensitivity." In fact, going back years, I think there were some companies that would even do that and probably charge people an amount to come up with the obvious drugs in some cases. But this is really many steps beyond that. I mean, as you say, not perfect, but many steps beyond. Why is this? What's better about this? The ability to try to recapitulate the tumor in the patient, what's special about this that makes it better?

Dr. Hidalgo: I think there are three components. On one end, the modeling of the cancer is better because we're able to use a three-dimensional sculpture, scaffolds and growth factors that are more physiological. So the similarity between the model and tumor in the patient is closer. And for that reason, we think that predictability is going to be higher.

Second, many of these systems have been adapted for med or high throughput screening. So we can test not only the obvious drugs, but many more drugs along and in combination. We are able to model the cancer with tumor microenvironment with the fibroblasts and the stroma, and more recently also with the immune system. So it becomes a little bioreactor where you can test not only classic chemotherapy, but also immunotherapies.

And, finally, what is very critical as well is just not finding-- "Okay. Drug A works. We're going to use it in the clinic." Of course. But then why drug A works? Is there a biomarker? Is there a potential new mutation or alteration that explains why a particular drug is effective? Because by doing that, we're able to identify biomarkers that then can be measured in tumors without having to go through the entire process of growing the tumor and testing it again in many drugs. So the biomarker discovery component is very important and unique. And I think these three areas together is what is making those models more effective and attractive these days.

Dr. Leonard: I want to ask you about the field of immuno-oncology and that in part relates to what we've talked about, but and part in is a little bit different. I mean, this clearly revolutionized the treatment of many types of cancer, where options were quite limited and, in some cases, have been quite traumatic with this type of therapy. Can you kind of briefly orient people as to how this has worked and where that field is going?

Dr. Hidalgo: It's a fascinating field. And in the last few years, the discovery of the checkpoint inhibitors as the more relevant set of agents, which now there are more others in development has changed the way almost any disease is treated.

Pancreatic cancer, however, is one of the tumors that is still considered to be immune resistant. So the classic drugs nivolumab, ipilimumab, pembrolizumab that are now approved to treat so many other cancers, they just don't work in pancreatic cancer. And the reasons why that happened, the reason why they don't work is not totally clear.

Here at Weill Cornell and NYP, we have a very strong immunotherapy program working in many areas, but pancreas cancer being one of the key emphasis of some laboratories, including my own, where we're trying to identify what are the mechanisms by which of these tumors are resistant to immunotherapy. And there are a few very interesting targets and very interesting hypothesis out there that we're just testing in some of the models, the organoids and the PDXs as we mentioned before. But also in very targeted and hypothesis-driven clinical trials to understand if the combining checkpoint inhibitors with other inhibitors will render those tumor sensitive to immunotherapy. There's some interesting early data, it's still not approved by the FDA or anything like that, but certainly very interesting early clinical data that I hope soon will provide good news for patients.

Dr. Leonard: That's really a great segue into the field of pancreatic cancer. And again, since we're recording on World Pancreatic Cancer Day, it's only fitting to ask you, given your expertise in this area, and I'm sure some of our audience recognizes this either from their own experience or just, you know, reading and seeing people, I mean, pancreatic cancer has been such a difficult disease to make progress in beyond surgery for a limited size of disease. Why has it been such a difficult tumor and what is the sort of strategies that you see beyond what we've talked about that lead you to think we're going to make some big progress in that area soon?

Dr. Hidalgo: It's a very hard to treat tumor. And the reason why the progress has been so far limited is probably multifactorial. On one end, many patients are diagnosed with the disease in late stages. There are no biomarkers or there are no early diagnostic strategies that are universally applied or are clinically applied to detect the tumors on an earlier stage when surgery surgical resection and chemotherapy can be curative.

An area of high interest is to identify markers that can indicate the risk of pancreatic cancer. And there are few studies going on at the moment, we participate in some of them, looking at exosomes, for example, the substances secreted by the cancer that can be identified by just sampling blood. There's also very interesting group of patients that develop late onset diabetes. And apparently, it's becoming clear that the risk of pancreas cancer in these patients that develop late onset diabetes is higher.

And so early diagnosis is an important field, but the second area that is quite problematic is that the cancer, once it develops, is very resistant to current treatments. And we have mentioned, immunotherapy and how it's one of the very few tumors that does not respond to immunotherapy and we are doing some work to try to identify why is that.

But also in the field of precision medicine that we also discussed before, when do you analyze the genomics of those tumors of pancreas cancers, it's very dry. It doesn't contain mutations for which we have good inhibitors, good drugs to attack them. So it's the combination of a very aggressive genotype, very aggressive landscape of mutations without drugs so far. And that's a very important area of research to develop new agents that will inhibit some of those mutations. I think it's the core reason why we have not made enough progress.

Now, having said that, there are multiple studies going on at the moment. The laboratory research that we alluded to before is really identifying many potential vulnerabilities. We understand much better how these tumors develop. There are very good animal models in which can basically recapitulate the entire genomic alterations that occur in patients and these laboratory animals develop cancer, which is very similar to the human disease. I hope and I think that by drilling into those models and discoveries, soon we will have treatments that are more effective. But at the moment, it is still a very hard to treat disease.

Dr. Leonard: One area that on earlier, and I want to move to the clinical side of things, briefly is the idea and the importance of multidisciplinary cancer care. And certainly pancreatic cancer is one example of that, where you have surgeons, medical oncologists, radiation oncologists, I'm sure nutrition and other areas are also very important, why is that so critical for patients and these patients who are looking for a treatment center, having it expertise in all those areas, why does that make such a difference in patient's outcome from your perspective?

Dr. Hidalgo: It's key. The key aspect of managing pancreas cancer is to have a strong multidisciplinary team for multiple reasons, but I will highlight two that I think are critical. The first one is that, as we said before, the best or actually the only option for cure is to have an operation, to have the tumor resected. And it's not a trivial operation. It's a very complicated operation. And often patients present with tumors that are too large or invading blood vessels and cannot be resected.

If we are able to administer preoperative chemotherapy, preoperative radiation therapy, sometimes we can decrease the size of this tumor, free out the margins and then the surgeon can go in and do a resection. So the planning of this integrated treatment, and when you do the operation, when you do chemotherapy, when you do radiation, it requires a lot of expertise requires very sophisticated radiology, an expert imaging of the pancreas and the surrounding structures to really identify tumors, where it sits, which vessels are involved. Doing that process is complicated. And if you don't have a team that is well-trained and has a lot of expertise doing it, you can miss surgical opportunities. And that of course is not good because if you miss that, you're essentially probably missing the opportunity for a cure.

Now, if we're not lucky that we can get a patient to surgery, eventually, either at diagnosis or after we have done preoperative treatment, the things that we discussed before about being able to analyze the tumor in great detail. Pancreas cancer is not like lung cancer or leukemia or some other tumors where we do identify often targets, but sometimes we do. And there's about 10, 15% of the patients that by doing this very deep analysis of their tumor, we can identify alterations that are vulnerabilities that we can treat. So the expertise to do that is of course not trivial. And you need a team that does that for a living. And we have that.

And then the immunotherapy component, as we said before, having the opportunity to participate and to be involved in clinical trials with new medicines is crucial. So to me, the reason why these diseases, and pancreas cancer is an example, many other tumors are the same, are better managed tertiary academic centers because you have the clinical expertise on one side, but then the opportunity to participate in research studies on the other. And the combination of these two is what I think offers the best possibilities for cure or at least for prolonged and sustained palliation.

Dr. Leonard: So before we wrap up, I think that many in our audience may have recently been diagnosed with cancer or have loved ones that have been diagnosed with cancer, obviously and unfortunately, this comes up all the time. As chief of the Division of Hematology and Medical Oncology here, what advice do you give to those who might be facing a cancer diagnosis as they try to sort through what their next steps are?

Dr. Hidalgo: My advice is to seek medical attention in a center that has the expertise and the team to address their diseases. It's of course a very tough time for patients and their families when someone gets diagnosis of cancer. The good news is that many of these diseases can be treated and can be cured. But it's very important that things are done properly, particularly in the early days and the early months after a diagnosis.

So my advice is it's not good news to be diagnosed with a cancer, but it's not the end of the world and seek medical attention in a center like ours, like some others around the country where you can get this very expert treatment and advise because and more patients can be cured. And think that patients and their families should need to maintain hope that these days, it is possible. So seek good medical attention and be hopeful.

Dr. Leonard: Well, thank you very much, Dr. Hidalgo. This has been a great discussion and I know that our audience certainly appreciates your insights into these important areas. I want to invite our listeners to download, subscribe, rate, and review CancerCcast on Apple podcasts, Google Play Music or online at WeillCornell.org. We also encourage you to write to us at CancerCast@med.cornell.edu with questions, comments, and topics you'd like to cover more in depth in the future. That's it for CancerCast, conversations about new developments in medicine, cancer care and research. I'm Dr. John Leonard. Thanks for tuning in.