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GEN Protocols Expert Exchanges: Patient-Derived Organoids Predict Response to Therapy
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GEN Protocols Expert Exchanges: Patient-Derived Organoids Predict Response to Therapy
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ANJALI SARKAR: Hello, fellow scientists and science lovers. This is Anjali Sarkar, senior editor at GEN and GEN Protocols, welcoming you to this GEN Protocols Expert Exchange. Today, I will be talking to Matthew Weiss, who is Professor at the Institute of Cancer Research at the Feinstein Institutes and the Deputy Physician in Chief and Surgical Director in the Cancer Institute at Northwell Health. Before we begin, I'd like to introduce you to GEN Protocols.
ANJALI SARKAR: The need for access to reliable and reproducible technical know-how in the biosciences inspired us at Genetic Engineering and Biotechnology News to develop GEN Protocols, a freely accessible digital hub for scientific methods where researchers from academia and industry can share and showcase their technical expertise, nurture collaborations, and discuss technical challenges and solutions. GEN Protocols is open for submissions year-round.
ANJALI SARKAR: Together with a rich resource of up-to-date protocols and applications, Gen Protocols brings you expert exchanges, where experts in key areas of biosciences and biotechnology talk about method-focused developments, advances, challenges, and visions. So in today's expert exchange, we will be talking to Matthew Weiss about patient-derived organoids, or PDOs, that are being used to predict responses to chemotherapy in patients with pancreatic adenocarcinoma.
ANJALI SARKAR: Welcome, Dr. Weiss.
MATTHEW WEISS: Thank you so much. I appreciate your time.
ANJALI SARKAR: So could we start off by explaining to us what PDOs exactly are?
MATTHEW WEISS: Sure, so this is an exciting time. And thank you so much for allowing me to share some of this news with you and some of our research. Patient-derived organoids are basically, to simplify it-- basically taking a patient's own tumor, putting it in a Petri dish, growing that tumor, and then enabling the ability to both do pharmacotyping-- basically testing different chemotherapeutic agents against the patient's own tumor, as well as genotyping-- predicting which patients may respond, which chemotherapeutic agents, based upon the genetics.
MATTHEW WEISS: So it's essentially a way that we can try to predict what chemotherapy to give patients-- and in this case, pancreatic cancer patients.
ANJALI SARKAR: What makes it critical to be able to predict patient responses to chemotherapy?
MATTHEW WEISS: So it could be more important, especially in pancreatic cancer-- so it's true for all cancers. But if you think about pancreatic cancer, the big news a couple of years ago was that we had improved long-term survival for pancreatic cancer. We had gone from 5% five-year survival to 9% five-year survival. That's really poor, if you think about it.
MATTHEW WEISS: That gets you an F on pretty much any science exam you've ever taken in your career. If you can only cure 9% of patients, we need to do something dramatically differently. So there's been somewhat of a revolution occurring in the cancer space recently. There's the focus on what I would call precision cancer care, meaning-- don't treat all cancers the exact same way.
MATTHEW WEISS: Don't even treat all pancreatic cancers the same way. We need to find ways that we can treat every pancreatic cancer differently because, truthfully, I like to say that not all pancreatic cancers are the same. But really, I would say, no two pancreatic cancers are the same. And if you look at our current approach to pancreatic cancer, it's almost a shotgun approach.
MATTHEW WEISS: We have two large chemotherapeutic regimens that we use that we know are effective. But we have no real way of predicting which patients or which tumors are going to respond to which chemotherapeutic agents. So you could imagine that, if you present with pancreatic cancer, unfortunately, you see your medical oncologist or your surgical oncologist, like me, and it's determined that you're going to be started on chemotherapy.
MATTHEW WEISS: And the way we decide which chemotherapy we're going to start you on might as well be a flip of the coin between two regimens. We have no way of predicting whether you're going to respond to one over the other. The ability to predict who's going to respond to which chemotherapy, or maybe, perhaps even more importantly, who's not going to respond to a certain regimen is incredibly important and is a focus of our area of research related to pancreatic cancer patient-derived organoids.
ANJALI SARKAR: So according to your recent publications, these patient-derived organoids-- PDOs cultures-- can be established through either fine needle aspirations or fine needle biopsies or even surgical resections. So what are the differences between these procedures to establish PDO cultures using these methods?
MATTHEW WEISS: Yeah, so I think that's a really important point. So we're very fortunate here at Northwell and at the Feinstein Institute because, right here on Long Island, we have a world-renowned pancreatic cancer and pancreatic organoid program at the Cold Spring Harbor Lab. And one of the interesting things-- or one of, I think, the key components of this research that's been done is the fact that we really have teamed up with Dave Tuveson and his lab.
MATTHEW WEISS: Dave Tuveson was the president of the AACR, the American Association of Cancer Research, last year, and he is a world-renowned organoid development expert. And he, like I, have an interest in eradicating pancreatic cancer. That's probably why Dave and I get along so well. But we're very fortunate because we teamed up for this research project, and it was really to try to determine-- not only can we determine who responds to what chemotherapy, but there was a lot of technical modifications during this project that-- really, I give all the credit to Dave Tuveson and his team for because, in order for this to be truly clinically applicable-- in order for it to really impact our patients' lives, we need a way that we can get tissue and we can grow an organoid right from the onset of a patient's disease.
MATTHEW WEISS: So over time, we've shown that you can pretty reliably develop organoids from surgical specimens where there's a lot of tissue. I remove an entire tumor. You can take a lot of tissue. And you can develop organoids on it. We're successful-- in this paper, we showed about 70% to 75% of the time in surgically-resected specimens.
MATTHEW WEISS: But perhaps equally, if not more, important, if we're going to predict who's going to get what chemotherapy before they have surgery, then we need a reliable way that we can grow the organoids from less tissue. So patients that have pancreas cancer frequently have endoscopic procedures done. And to have endoscopic-- either fine needle biopsies or they have core biopsies, with just a little larger bore needle-- And in this project what we were looking at was, how reliably can we predict organoid development if it's less tissue from an FNA or a core biopsy?
MATTHEW WEISS: And although it was slightly less, we were still able to achieve organoid development in over 50% of samples. And remember, this was a trial, meaning that, for the trial, basically, patients got one pass of the needle for diagnosis and another pass of the needle for this research project. So in reality, if we were to use this clinically, you may have multiple passes of the needle, and we would anticipate that the success rate would go up if we were able to do that.
MATTHEW WEISS: So the other thing that we explored was, quite frankly, can you develop organoids when patients have already been on chemotherapy? So being on chemotherapy, in theory, changes the microenvironment of the tumor. And you may even be selecting for certain chemo-resistant cells or chemo-sensitive cells. So we were able to show that, even though patients had received chemotherapy beforehand, we still were able to pretty successfully develop organoids at Dave Tuveson's lab.
ANJALI SARKAR: Excellent. So from preclinical research on animal models, organoid and steroid cultures are often inside out, where the cells on the outside of the tumor are inside, in the organoid or the spheroid, and the outside cells are on the inside and vise versa. So is this the case for PDOs?
MATTHEW WEISS: Yeah, so I'm definitely more of the clinical arm of this study. And again, some of the true basic science is really done by Dave Tuveson and his team. But I will say, what's interesting about the organoids is that pancreatic cancer is unique in that it's characterized by cancer cells, but dense, dense, heavy stroma around the tumor, which we think actually makes it somewhat-- not only chemo-resistant but maybe immuno-resistant.
MATTHEW WEISS: It may be one of the reasons why our targeted therapies don't work as well in pancreatic cancer. So the way these organoids are developed, we take the tumor and, essentially, they do serial passages where they extract stromal cells to enrich for the tumor itself-- actual cancer cells. And each one of those organoids is basically-- encompasses all of the growth media and all the characteristics that are needed for it to continue to grow so that, after you do multiple passages, you essentially have an enriched tumor microenvironment.
MATTHEW WEISS: You have the tumor cells and the tumor microenvironment that we hope-- and multiple studies have demonstrated-- recapitulates the true tumor microenvironment so that it's a real life model that you can test chemotherapy in a real manner, that you can do genetic testing and genomic sequencing in an accurate manner. So it's basically a self-contained tumor microenvironment.
ANJALI SARKAR: That is interesting that you mentioned that, if I understand correctly, the stroma cells-- it goes through an enrichment process, if you will. So how does the cellular architecture and organization of the PDO-- final PDO that you achieve in culture-- affect its ability to recapitulate in-vivo tumor environment? You mentioned that it is-- there is a high degree of accuracy.
ANJALI SARKAR: But how is it measured, the ability of these PDOs to recapitulate in-vivo tumor environment and the ability of any biomarker assays on them to recapitulate the in-vivo tumor microenvironment and accurately predict the responses?
MATTHEW WEISS: Yeah, so that's really the crux of the question, and that's probably what we're asked the most. We do multiple scientific tests to determine whether the-- after multiple passages, the tumor cells look like they did in the beginning-- for instance, genomic sequencing and then comparing the sequencing upon multiple passages, showing that it doesn't change. And we've also done sequential tests of pharmacotyping to see if the profile of resistance or sensitivity to chemotherapy doesn't change.
MATTHEW WEISS: I was asked this question when I presented this work at the American Surgical Association meeting this past year. And the reality is that we're now doing prospective clinical trials. In this manner. For instance, there's a multicenter trial, which Northwell is participating in, called the past one trial, where patients with metastatic pancreatic cancer are undergoing-- they're randomized to the two different regimens of chemotherapy, and then they have organoids developed at the beginning.
MATTHEW WEISS: And then, basically, we look and see retrospectively whether the organoid accurately predicted what clinically was seen. So that's really at the stage where we are right now. What our paper showed was that, if you looked at patients that were receiving neoadjuvant chemotherapy before surgery, that we could predict which reagents they were going to respond to. But we certainly haven't done it in a prospective manner and a prospective, randomized manner, which I think really gets to the crux of your question.
MATTHEW WEISS: How do we know that, after six passages, nine passages, that it's really behaving like it did in the patient? And I think that's really where the future lies.
ANJALI SARKAR: Right, so these prospective studies are currently being done, is what you're saying?
MATTHEW WEISS: They are. So there's a multicenter prospective trial which we are a lead site in, called the PASS-01 trial. Dan King, who's a budding medical oncologist here, who specializes in pancreatic cancer-- is spearheading this for us. Dan, actually, not surprisingly, has a co-appointment in the Cold Spring Harbor Lab. But this trial is run through the clinical trials office at the Feinstein Institute, and it's doing exactly that.
MATTHEW WEISS: It's looking, in the metastatic setting, did the organoids predict the response that we saw? And the randomization is on which chemotherapy the patients receive, but then the retrospective analysis is looking at whether the organoids predicted the proper response. As you can imagine, there's a lot of other surrogate markers and such that are part of that study-- immunotherapy, immune endpoints, genomic sequencing endpoints.
MATTHEW WEISS: So there's a lot of science that's going to come out of that trial that I think is going to be very exciting in the next two to three years.
ANJALI SARKAR: Excellent. In the interest of other clinician scientists like yourself who are interested in using the PDO model, could you enlighten us a bit about what's involved in gaining IRB approval for recruiting patients, for establishing such a PDO-based trials or R&D and clinical testing purposes? Or how accepting are regulatory agencies for all of these PDO-based analysis for, say, drug testing?
MATTHEW WEISS: Yeah, so I think the key component is that, up until now, these patient-derived organoids are not being utilized to make clinical decisions. We're not, using them to say, OK, you're going to get this chemotherapy, just yet, because we need to do the further analysis and the retrospective analysis and the PASS-01 one trial to show that it is indeed the future. And in order to do those studies, they need to be done in a CLIA-certified lab.
MATTHEW WEISS: So currently, these organoids are really developed in a research environment. And patients obviously-- it's IRB-approved protocols. Patients are obviously consented to donate tissue. What I think is a key component is that, when the original research was set up, it was really set up as, can we develop these organoids? And now we've moved away from, can we develop the organoids to, can we predict response?
MATTHEW WEISS: And so that's a key component because what happens is patients have gone from, OK, I'm donating the tissue to, now, OK, I'm donating the tissue, and they're going to correlate it with my clinical information, which is a transition. But I have to tell you, as a clinician, I treat a lot of patients with pancreatic cancer. Patients are very excited about this research, and they really want to participate in it because-- let's be honest, they go online; they Google; they know what the prognosis is with pancreatic cancer; and they're looking to make a difference.
MATTHEW WEISS: They're looking to make a difference, not only in their own lives but in future patients that are unfortunately going to suffer from this disease. So the approval process has been standard internal IRB approval, consenting processes. These are all IRB-approved studies. The patients have been more than enthusiastic about joining. And our accrual rate has been very, very high. And interestingly enough, one of the other things that we've noticed-- because Northwell is such a, both, geographically and ethnically diverse health system-- is that one of the things that was interesting about our study was that more than 35% of the patients enrolled were actually minority patients, which is somewhat unique.
MATTHEW WEISS: If you look at a lot of, even, prospective, randomized trial or research trials out there, the accrual rate for underrepresented minorities is historically very low. And it's problematic because we know that those groups of patients actually frequently do worse, in particular with pancreatic cancer. And there's lots of reasons why that may be. There's certainly social issues, with access to care and insurance.
MATTHEW WEISS: But there's also the biological aspect. There's the genetic aspect. Maybe the tumors are different. We have an open trial right now looking at-- with a couple of other centers-- looking at the genetics of pancreatic cancer in African-American patients, sequencing their tumors, and looking for actual genetic differences. Maybe patients with pancreatic cancer that are African-American-- maybe they don't respond to the same chemotherapy because their tumor's genetically different and they haven't been enrolled in the randomized trials that we have out there thus far.
MATTHEW WEISS: So I think that's an interesting aspect of our study-- is that we're doing this, the organoids, in underrepresented minorities as well, meaning this is likely going to be broadly applicable.
ANJALI SARKAR: Coming back to the method of setting up these PDO cultures, you mentioned, a short while ago, that the tissue amount that you get from these aspirations or fine needle biopsies are smaller and stand a lesser chance of forming successful PDOs. But your recent poster abstract mentioned that PDOs from the surgical specimens were established with a higher success rate than those from the FNB and FNA samples.
ANJALI SARKAR: Could you talk a bit about this discrepancy and whether it's only due to the sample size or are there other genetic or inherent factors?
MATTHEW WEISS: Yeah, I think that's a great question. Truthfully, I think we don't know, definitively. I think it's probably multifactorial. You have to remember that these pancreatic cancers are heterogeneous, meaning you could have a lump of tumor that's a few grams or-- let's say it's centimeters in diameter, and not all of that is tumor. There's areas where there's high volume of tumor cells consolidated in an area, and there's other areas that may be very stroma-heavy.
MATTHEW WEISS: And so when you do an endoscopic ultrasound biopsy, an FNA, a core biopsy, you're essentially randomly sticking a needle in there. And it is it's possible you can miss the tumor altogether. Biopsies of these tumors by endoscopic ultrasound-- even for diagnostic purposes-- are not 100%. It's not uncommon to get a non-diagnostic biopsy. So you wouldn't expect that in FNA would have 100% organoid development because, number one, you don't even know you really got cancer cells in it.
MATTHEW WEISS: I was a math major in college. I got to believe it's a matter of just probability, that it's a smaller volume of tissue; it's a random biopsy. And my guess is, if you increase the size of the sample, you're going to have a much higher yield rate. I think the difference is, with a surgical specimen, not only do you have plenty of tissue, but let's be honest, you section it, and you can look under a microscope-- where the tumor cells are, and you can select for the areas that you want to grow.
MATTHEW WEISS: So I think it's a technical aspect that certainly will need to be addressed. That's the beautiful thing about working with brilliant people like Dave Tuveson and his team because some of these technical modifications, over time, are going to need to happen. It may require micro dissecting of even the biopsies. It may require technical modifications that people that do this all the time will be able to work out.
ANJALI SARKAR: So to put things in perspective, before the PDO culture is established as a normal clinical practice in the clinical workflow, what are some of the current methods in place that are used to predict patient responses, if any at all?
MATTHEW WEISS: So there's very few. There was a trial done in 2018 by a good friend of mine, Dr. Susai, at the Medical College of Wisconsin. It's one of the only true precision pancreatic cancer prospective trials that I'm aware of, whereby they use genomic sequencing of the tumor to try to predict which chemotherapeutic agents the patient should receive prior to surgery. It was a small number of patients, but it was a successful trial, meaning the median overall survival looked very good in that trial.
MATTHEW WEISS: There's been very few outside of that space. The reality is that, when you look at pancreatic cancer, of the known genetic, somatic mutations, how frequently do we find actionable somatic mutations in the tumor? Unfortunately, the number is relatively small. It's probably on the order of maybe 10% or so. So one aspect that's being explored by other groups is using the genetic signature to predict response to therapy.
MATTHEW WEISS: I think that's exciting. I think, as of right now with only 10% of the tumors having actionable mutations, I think we're going to need to develop more identification of more actionable mutations in order for that to come to fruition. There's other immunotherapy type trials that are ongoing right now. Pancreatic cancer, historically, is not very responsive to immune therapy, but there's a lot of work being done by labs across the country, trying to make it more sensitive to immunotherapy.
MATTHEW WEISS: But other than that, we're exploring some very, very explorative type stuff-- cutting edge, predictive of response, by injecting certain things like microchips into the tumor that may elicit multiple chemotherapeutic agents into the tumor. But really, there's nothing else out there, to be honest with you, that I'm aware of.
ANJALI SARKAR: Which makes it all the more important to work on this. You talked about the accuracy a short while ago. But compared to say blood biomarkers of pancreatic cancer, what degree of accuracy can PDOs have in predicting responses to neoadjuvant chemotherapy? Are there any studies that have been done or are being done on comparing these various predictive methods and models?
MATTHEW WEISS: Yeah, so that's an area of great interest to us right now, and that's what we're looking at. And Dan King, one of our-- as I mentioned before, one of our medical oncologists, is spearheading some of this effort. We all know that we need more sophisticated mechanisms to gauge response to therapy. And truthfully, currently, clinically, all we really have is crude measurements of response. We have CT scans, MRIs.
MATTHEW WEISS: OK, the tumor looks smaller; the tumor looks bigger; they responded; they didn't. Those are relatively unpredictable, to be honest. The tumor can look the same, and you can have a great response. Or the tumor can look the same, and you could have had a terrible response when you remove it. We utilize tumor markers classically for pancreatic cancer. There's the CEA level and the CA 19-9 level.
MATTHEW WEISS: These are proteins that we pick up in the bloodstream that are secreted by the tumors. If these tumors do secrete these substances, they are highly predictive of how a patient is going to do. They don't necessarily predict well. So for instance, CA 19-9-- we know by following a CA 19-9 level when someone's on chemotherapy-- if the level goes down, it's certainly a good sign.
MATTHEW WEISS: It seems that they're responding. But we know from several groups' studies, including-- I mentioned before, Susai from Medical College of Wisconsin-- that the actual decrease in CA 19-9 level may not be as important as if they normalize their CA 19-9 clinically. So one of the interesting things about our study that we just published was that many patients that had a decrease in their CA 19-9 level that didn't normalize but had a decrease in their CA 19-9 level actually showed very poor response-- both by organoid prediction but also by pathologic specimens.
MATTHEW WEISS: So yes, they had a decrease in their CA 19-9 while they were on chemo. But then we removed their tumor and we looked at it, and it didn't look like the tumor had responded really at all, despite having a decrease in their CA 19-9. The world of biomarkers is exploding right now. We're certainly looking for more and more biomarkers to predict response. We're looking at things like ctDNA, circulating tumor DNA, to predict response.
MATTHEW WEISS: You're seeing a lot of that in some of the other cancer spaces, like colorectal cancer. It's an area of research for pancreatic cancer, and there's still a lot of work to be done.
ANJALI SARKAR: So once these PDOs are established, you mentioned tests like genomic sequencing. But what other specific tests are these PDOs amenable to that give it the predictive value?
MATTHEW WEISS: Yeah, so, obviously, genomic sequencing. We know, for instance, in the last few years, that there's been the identification of different subtypes of pancreatic cancer that can be predictive of good response and poor response. There's something called the Moffitt classification system. And the Moffitt classification system essentially utilizes genotyping to predict who's going-- likely to respond to certain chemotherapeutic agents versus not.
MATTHEW WEISS: But I think other things that can be done-- obviously, RNA sequencing as well, the organoid development. And I think there's a lot of areas, truthfully, that can be utilized downstream once we have a reliable model.
ANJALI SARKAR: Right. You mentioned the identification of specific mutations related to pancreatic cancer that could even be used in the Moffitt system of classification that you just mentioned. But is the heterogeneity of the pancreatic cancer such-- to such a level that these mutations also differ largely between patients? Or can these mutations be used for, say, Moffitt classification or even predictive analyses?
MATTHEW WEISS: Yeah, I think we don't know. As I said before, I think no two pancreatic cancers are the same. Even within the same pancreatic cancer, there's probably subsets of cells that look differently. Clearly, trying to utilize what we know, in terms of actionable mutations-- for instance, we know that patients that have BRCA mutation-- somatic mutations in their tumors-- we know that they're more susceptible, more sensitive to certain chemotherapeutic agents like the platinum-based chemotherapy.
MATTHEW WEISS: Microsatellite instability-- now, in the oncologic space, we're starting to see drugs that are FDA-approved based upon the genetic signature of the tumor and not on the tissue of origin of the tumor. And that's true for microsatellite instability. I think, unfortunately, the repertoire of genetic initiating events for pancreatic cancer known to date is still relatively low. We see a lot of genetic changes in the tumor, but we sometimes don't know-- are those initiating events?
MATTHEW WEISS: Or are they more likely downstream events, meaning they may not be the right one to target? Truthfully, I don't know. I don't have a crystal ball. My guess is that you're probably going to have to target multiple of these to really completely eradicate the tumor and put surgeons like myself out of business.
ANJALI SARKAR: Right. So you mentioned chemotherapy-- even patients with chemotherapy are amenable to PDO cultures, to generating PDO cultures. But does the tumor stage affect-- or-- the tumor stage or the chemotherapy application affect the ability to predict chemotherapy responses from PDOs?
MATTHEW WEISS: Yes, I think that's a great question. After they receive chemotherapy, what does the organoid tell you? Does it tell you what it was like at the beginning? Or does it tell you what it's like now? And have you selected for cells-- excuse me-- that have become resistant? I think the beauty of being able to do this with FNAs-- with core biopsies-- that, in theory, you'd want to do the organoids longitudinally.
MATTHEW WEISS: You want to do them in the beginning; you'd want to do them while they're on therapy; and then you'll get the surgical specimen after. One of the shortcomings of our trial was that we had a low number of patients where we had a FNA or core biopsy of the tumor right in the beginning, before they received any treatment. Why is that? Well, honestly, it's usually an operational issue.
MATTHEW WEISS: Patients are coming to see Matt Weiss with pancreatic cancer, and they've already gotten a biopsy that's proven that they have pancreatic cancer before they see me. So to enroll them in a trial, I would almost have to do a separate procedure with a new biopsy, just to put them on the trial, which is somewhat logistically difficult. And honestly, you could question whether that makes sense.
MATTHEW WEISS: Ideally-- now we've made some operational changes. We get patients hopefully referred to us right in the beginning so that, from day 0, we can get that initial biopsy and we can compare it to what we see later on in the disease process. But I think that's a key that's a key point because, clearly, the tumor, after four months of chemotherapy or after six months of chemotherapy, could be starting to behave differently than they were after-- at day one.
MATTHEW WEISS: So I think it's a key point.
ANJALI SARKAR: Mm-hmm. Mm-hmm. You mentioned the application of PDO for precision individualized medicine. Could you tell us some instances of case studies, for example, that PDO-based analysis has promoted-- where PDO-based analysis has promoted precision or individualized approaches in clinical practice?
MATTHEW WEISS: Yeah, so I think-- I think we're still at the infancy of how the organoids are really going to be utilized clinically. Obviously, I live in the pancreatic cancer space, but there's a lot of work being done in other spaces. We're doing a fair amount of work in colorectal cancer. There is a very robust organoid development program at Cold Spring Harbor for breast cancer. So I don't have an example of, today, where, oh, yeah, I'm going to use this organoid to change this patient's therapy.
MATTHEW WEISS: But I think what's exciting about this is that you can clearly see the clinical applicability. And I think what you're going to see very, very soon is-- you're going to see these trials done in a prospective manner, that are going to answer the question, since we can do this. We actually are in the process-- Northwell Health is in the process of building a CLIA-certified lab we have the facility built, but we need to get the CLIA certification for organoid development.
MATTHEW WEISS: That's done as a combined effort with Cold Spring Harbor, as you can imagine. But that's the idea-- is that, once all these trials are done and we bring it into the clinic, we want to be ready to go.
ANJALI SARKAR: Excellent. In a recent press release, Dr. Kevin Tracey, President and CEO of the Feinstein Institute, mentions how you and your collaborators at Cold Spring Harbor Lab are developing new methods to personalize and optimize cancer care. So in addition to PDO-based analysis that we've talked about in today's session, are there any other novel methods in cancer precision medicine that you are working on now?
MATTHEW WEISS: Yeah, so it's an exciting time. I can't give away all my secrets. But one of the beautiful things, now, is that we-- I currently have, obviously, a research group. And I hire research fellows, which, really, are surgical residents spending two years doing research with us. And they spend half the time in the clinics with me, and they spend half the time in the basic science lab. And the beautiful thing is that this is truly, I think, a model for how to translate basic science into the clinics.
MATTHEW WEISS: So we're bouncing a lot of ideas on cutting edge basic science research that's being done at Cold Spring Harbor, as well as Feinstein, and how are we going to take that research get it into the clinics for four prospective trials. We're kicking around a lot of ideas. We're looking at potentially the idea that you could essentially insert a tiny microchip into a tumor and try to-- with multiple wells that emit different concentrations and different amounts of chemotherapy, try to put it in the tumor, then remove the tumor, and see if that predicted which chemotherapy you can respond to, so almost like an in-vivo test in the patients.
MATTHEW WEISS: So our research fellows are doing that currently in an animal model, and the idea is maybe we could think about doing it in a prospective way in a clinical setting. Lots of innovative thinking going on. So I think the future's bright in this space, for sure.
ANJALI SARKAR: Thank you so much, Dr. Weiss. That brings us to the end of today's GEN Protocols Expert Exchange Thank you for a very illuminating discussion. And a reminder to all scientists among our viewers-- GEN Protocols is open for submission, and we welcome your protocols in all aspects of biotechnology. This is Anjali Sarkar. Until next time, good luck in your research, and goodbye from all of us at GEN Protocols. [MUSIC PLAYING]
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ANJALI SARKAR: Hello, fellow scientists and science lovers. This is Anjali Sarkar, senior editor at GEN and GEN Protocols, welcoming you to this GEN Protocols Expert Exchange. Today, I will be talking to Matthew Weiss, who is Professor at the Institute of Cancer Research at the Feinstein Institutes and the Deputy Physician in Chief and Surgical Director in the Cancer Institute at Northwell Health. Before we begin, I'd like to introduce you to GEN Protocols.
ANJALI SARKAR: The need for access to reliable and reproducible technical know-how in the biosciences inspired us at Genetic Engineering and Biotechnology News to develop GEN Protocols, a freely accessible digital hub for scientific methods where researchers from academia and industry can share and showcase their technical expertise, nurture collaborations, and discuss technical challenges and solutions. GEN Protocols is open for submissions year-round.
ANJALI SARKAR: Together with a rich resource of up-to-date protocols and applications, Gen Protocols brings you expert exchanges, where experts in key areas of biosciences and biotechnology talk about method-focused developments, advances, challenges, and visions. So in today's expert exchange, we will be talking to Matthew Weiss about patient-derived organoids, or PDOs, that are being used to predict responses to chemotherapy in patients with pancreatic adenocarcinoma.
ANJALI SARKAR: Welcome, Dr. Weiss.
MATTHEW WEISS: Thank you so much. I appreciate your time.
ANJALI SARKAR: So could we start off by explaining to us what PDOs exactly are?
MATTHEW WEISS: Sure, so this is an exciting time. And thank you so much for allowing me to share some of this news with you and some of our research. Patient-derived organoids are basically, to simplify it-- basically taking a patient's own tumor, putting it in a Petri dish, growing that tumor, and then enabling the ability to both do pharmacotyping-- basically testing different chemotherapeutic agents against the patient's own tumor, as well as genotyping-- predicting which patients may respond, which chemotherapeutic agents, based upon the genetics.
MATTHEW WEISS: So it's essentially a way that we can try to predict what chemotherapy to give patients-- and in this case, pancreatic cancer patients.
ANJALI SARKAR: What makes it critical to be able to predict patient responses to chemotherapy?
MATTHEW WEISS: So it could be more important, especially in pancreatic cancer-- so it's true for all cancers. But if you think about pancreatic cancer, the big news a couple of years ago was that we had improved long-term survival for pancreatic cancer. We had gone from 5% five-year survival to 9% five-year survival. That's really poor, if you think about it.
MATTHEW WEISS: That gets you an F on pretty much any science exam you've ever taken in your career. If you can only cure 9% of patients, we need to do something dramatically differently. So there's been somewhat of a revolution occurring in the cancer space recently. There's the focus on what I would call precision cancer care, meaning-- don't treat all cancers the exact same way.
MATTHEW WEISS: Don't even treat all pancreatic cancers the same way. We need to find ways that we can treat every pancreatic cancer differently because, truthfully, I like to say that not all pancreatic cancers are the same. But really, I would say, no two pancreatic cancers are the same. And if you look at our current approach to pancreatic cancer, it's almost a shotgun approach.
MATTHEW WEISS: We have two large chemotherapeutic regimens that we use that we know are effective. But we have no real way of predicting which patients or which tumors are going to respond to which chemotherapeutic agents. So you could imagine that, if you present with pancreatic cancer, unfortunately, you see your medical oncologist or your surgical oncologist, like me, and it's determined that you're going to be started on chemotherapy.
MATTHEW WEISS: And the way we decide which chemotherapy we're going to start you on might as well be a flip of the coin between two regimens. We have no way of predicting whether you're going to respond to one over the other. The ability to predict who's going to respond to which chemotherapy, or maybe, perhaps even more importantly, who's not going to respond to a certain regimen is incredibly important and is a focus of our area of research related to pancreatic cancer patient-derived organoids.
ANJALI SARKAR: So according to your recent publications, these patient-derived organoids-- PDOs cultures-- can be established through either fine needle aspirations or fine needle biopsies or even surgical resections. So what are the differences between these procedures to establish PDO cultures using these methods?
MATTHEW WEISS: Yeah, so I think that's a really important point. So we're very fortunate here at Northwell and at the Feinstein Institute because, right here on Long Island, we have a world-renowned pancreatic cancer and pancreatic organoid program at the Cold Spring Harbor Lab. And one of the interesting things-- or one of, I think, the key components of this research that's been done is the fact that we really have teamed up with Dave Tuveson and his lab.
MATTHEW WEISS: Dave Tuveson was the president of the AACR, the American Association of Cancer Research, last year, and he is a world-renowned organoid development expert. And he, like I, have an interest in eradicating pancreatic cancer. That's probably why Dave and I get along so well. But we're very fortunate because we teamed up for this research project, and it was really to try to determine-- not only can we determine who responds to what chemotherapy, but there was a lot of technical modifications during this project that-- really, I give all the credit to Dave Tuveson and his team for because, in order for this to be truly clinically applicable-- in order for it to really impact our patients' lives, we need a way that we can get tissue and we can grow an organoid right from the onset of a patient's disease.
MATTHEW WEISS: So over time, we've shown that you can pretty reliably develop organoids from surgical specimens where there's a lot of tissue. I remove an entire tumor. You can take a lot of tissue. And you can develop organoids on it. We're successful-- in this paper, we showed about 70% to 75% of the time in surgically-resected specimens.
MATTHEW WEISS: But perhaps equally, if not more, important, if we're going to predict who's going to get what chemotherapy before they have surgery, then we need a reliable way that we can grow the organoids from less tissue. So patients that have pancreas cancer frequently have endoscopic procedures done. And to have endoscopic-- either fine needle biopsies or they have core biopsies, with just a little larger bore needle-- And in this project what we were looking at was, how reliably can we predict organoid development if it's less tissue from an FNA or a core biopsy?
MATTHEW WEISS: And although it was slightly less, we were still able to achieve organoid development in over 50% of samples. And remember, this was a trial, meaning that, for the trial, basically, patients got one pass of the needle for diagnosis and another pass of the needle for this research project. So in reality, if we were to use this clinically, you may have multiple passes of the needle, and we would anticipate that the success rate would go up if we were able to do that.
MATTHEW WEISS: So the other thing that we explored was, quite frankly, can you develop organoids when patients have already been on chemotherapy? So being on chemotherapy, in theory, changes the microenvironment of the tumor. And you may even be selecting for certain chemo-resistant cells or chemo-sensitive cells. So we were able to show that, even though patients had received chemotherapy beforehand, we still were able to pretty successfully develop organoids at Dave Tuveson's lab.
ANJALI SARKAR: Excellent. So from preclinical research on animal models, organoid and steroid cultures are often inside out, where the cells on the outside of the tumor are inside, in the organoid or the spheroid, and the outside cells are on the inside and vise versa. So is this the case for PDOs?
MATTHEW WEISS: Yeah, so I'm definitely more of the clinical arm of this study. And again, some of the true basic science is really done by Dave Tuveson and his team. But I will say, what's interesting about the organoids is that pancreatic cancer is unique in that it's characterized by cancer cells, but dense, dense, heavy stroma around the tumor, which we think actually makes it somewhat-- not only chemo-resistant but maybe immuno-resistant.
MATTHEW WEISS: It may be one of the reasons why our targeted therapies don't work as well in pancreatic cancer. So the way these organoids are developed, we take the tumor and, essentially, they do serial passages where they extract stromal cells to enrich for the tumor itself-- actual cancer cells. And each one of those organoids is basically-- encompasses all of the growth media and all the characteristics that are needed for it to continue to grow so that, after you do multiple passages, you essentially have an enriched tumor microenvironment.
MATTHEW WEISS: You have the tumor cells and the tumor microenvironment that we hope-- and multiple studies have demonstrated-- recapitulates the true tumor microenvironment so that it's a real life model that you can test chemotherapy in a real manner, that you can do genetic testing and genomic sequencing in an accurate manner. So it's basically a self-contained tumor microenvironment.
ANJALI SARKAR: That is interesting that you mentioned that, if I understand correctly, the stroma cells-- it goes through an enrichment process, if you will. So how does the cellular architecture and organization of the PDO-- final PDO that you achieve in culture-- affect its ability to recapitulate in-vivo tumor environment? You mentioned that it is-- there is a high degree of accuracy.
ANJALI SARKAR: But how is it measured, the ability of these PDOs to recapitulate in-vivo tumor environment and the ability of any biomarker assays on them to recapitulate the in-vivo tumor microenvironment and accurately predict the responses?
MATTHEW WEISS: Yeah, so that's really the crux of the question, and that's probably what we're asked the most. We do multiple scientific tests to determine whether the-- after multiple passages, the tumor cells look like they did in the beginning-- for instance, genomic sequencing and then comparing the sequencing upon multiple passages, showing that it doesn't change. And we've also done sequential tests of pharmacotyping to see if the profile of resistance or sensitivity to chemotherapy doesn't change.
MATTHEW WEISS: I was asked this question when I presented this work at the American Surgical Association meeting this past year. And the reality is that we're now doing prospective clinical trials. In this manner. For instance, there's a multicenter trial, which Northwell is participating in, called the past one trial, where patients with metastatic pancreatic cancer are undergoing-- they're randomized to the two different regimens of chemotherapy, and then they have organoids developed at the beginning.
MATTHEW WEISS: And then, basically, we look and see retrospectively whether the organoid accurately predicted what clinically was seen. So that's really at the stage where we are right now. What our paper showed was that, if you looked at patients that were receiving neoadjuvant chemotherapy before surgery, that we could predict which reagents they were going to respond to. But we certainly haven't done it in a prospective manner and a prospective, randomized manner, which I think really gets to the crux of your question.
MATTHEW WEISS: How do we know that, after six passages, nine passages, that it's really behaving like it did in the patient? And I think that's really where the future lies.
ANJALI SARKAR: Right, so these prospective studies are currently being done, is what you're saying?
MATTHEW WEISS: They are. So there's a multicenter prospective trial which we are a lead site in, called the PASS-01 trial. Dan King, who's a budding medical oncologist here, who specializes in pancreatic cancer-- is spearheading this for us. Dan, actually, not surprisingly, has a co-appointment in the Cold Spring Harbor Lab. But this trial is run through the clinical trials office at the Feinstein Institute, and it's doing exactly that.
MATTHEW WEISS: It's looking, in the metastatic setting, did the organoids predict the response that we saw? And the randomization is on which chemotherapy the patients receive, but then the retrospective analysis is looking at whether the organoids predicted the proper response. As you can imagine, there's a lot of other surrogate markers and such that are part of that study-- immunotherapy, immune endpoints, genomic sequencing endpoints.
MATTHEW WEISS: So there's a lot of science that's going to come out of that trial that I think is going to be very exciting in the next two to three years.
ANJALI SARKAR: Excellent. In the interest of other clinician scientists like yourself who are interested in using the PDO model, could you enlighten us a bit about what's involved in gaining IRB approval for recruiting patients, for establishing such a PDO-based trials or R&D and clinical testing purposes? Or how accepting are regulatory agencies for all of these PDO-based analysis for, say, drug testing?
MATTHEW WEISS: Yeah, so I think the key component is that, up until now, these patient-derived organoids are not being utilized to make clinical decisions. We're not, using them to say, OK, you're going to get this chemotherapy, just yet, because we need to do the further analysis and the retrospective analysis and the PASS-01 one trial to show that it is indeed the future. And in order to do those studies, they need to be done in a CLIA-certified lab.
MATTHEW WEISS: So currently, these organoids are really developed in a research environment. And patients obviously-- it's IRB-approved protocols. Patients are obviously consented to donate tissue. What I think is a key component is that, when the original research was set up, it was really set up as, can we develop these organoids? And now we've moved away from, can we develop the organoids to, can we predict response?
MATTHEW WEISS: And so that's a key component because what happens is patients have gone from, OK, I'm donating the tissue to, now, OK, I'm donating the tissue, and they're going to correlate it with my clinical information, which is a transition. But I have to tell you, as a clinician, I treat a lot of patients with pancreatic cancer. Patients are very excited about this research, and they really want to participate in it because-- let's be honest, they go online; they Google; they know what the prognosis is with pancreatic cancer; and they're looking to make a difference.
MATTHEW WEISS: They're looking to make a difference, not only in their own lives but in future patients that are unfortunately going to suffer from this disease. So the approval process has been standard internal IRB approval, consenting processes. These are all IRB-approved studies. The patients have been more than enthusiastic about joining. And our accrual rate has been very, very high. And interestingly enough, one of the other things that we've noticed-- because Northwell is such a, both, geographically and ethnically diverse health system-- is that one of the things that was interesting about our study was that more than 35% of the patients enrolled were actually minority patients, which is somewhat unique.
MATTHEW WEISS: If you look at a lot of, even, prospective, randomized trial or research trials out there, the accrual rate for underrepresented minorities is historically very low. And it's problematic because we know that those groups of patients actually frequently do worse, in particular with pancreatic cancer. And there's lots of reasons why that may be. There's certainly social issues, with access to care and insurance.
MATTHEW WEISS: But there's also the biological aspect. There's the genetic aspect. Maybe the tumors are different. We have an open trial right now looking at-- with a couple of other centers-- looking at the genetics of pancreatic cancer in African-American patients, sequencing their tumors, and looking for actual genetic differences. Maybe patients with pancreatic cancer that are African-American-- maybe they don't respond to the same chemotherapy because their tumor's genetically different and they haven't been enrolled in the randomized trials that we have out there thus far.
MATTHEW WEISS: So I think that's an interesting aspect of our study-- is that we're doing this, the organoids, in underrepresented minorities as well, meaning this is likely going to be broadly applicable.
ANJALI SARKAR: Coming back to the method of setting up these PDO cultures, you mentioned, a short while ago, that the tissue amount that you get from these aspirations or fine needle biopsies are smaller and stand a lesser chance of forming successful PDOs. But your recent poster abstract mentioned that PDOs from the surgical specimens were established with a higher success rate than those from the FNB and FNA samples.
ANJALI SARKAR: Could you talk a bit about this discrepancy and whether it's only due to the sample size or are there other genetic or inherent factors?
MATTHEW WEISS: Yeah, I think that's a great question. Truthfully, I think we don't know, definitively. I think it's probably multifactorial. You have to remember that these pancreatic cancers are heterogeneous, meaning you could have a lump of tumor that's a few grams or-- let's say it's centimeters in diameter, and not all of that is tumor. There's areas where there's high volume of tumor cells consolidated in an area, and there's other areas that may be very stroma-heavy.
MATTHEW WEISS: And so when you do an endoscopic ultrasound biopsy, an FNA, a core biopsy, you're essentially randomly sticking a needle in there. And it is it's possible you can miss the tumor altogether. Biopsies of these tumors by endoscopic ultrasound-- even for diagnostic purposes-- are not 100%. It's not uncommon to get a non-diagnostic biopsy. So you wouldn't expect that in FNA would have 100% organoid development because, number one, you don't even know you really got cancer cells in it.
MATTHEW WEISS: I was a math major in college. I got to believe it's a matter of just probability, that it's a smaller volume of tissue; it's a random biopsy. And my guess is, if you increase the size of the sample, you're going to have a much higher yield rate. I think the difference is, with a surgical specimen, not only do you have plenty of tissue, but let's be honest, you section it, and you can look under a microscope-- where the tumor cells are, and you can select for the areas that you want to grow.
MATTHEW WEISS: So I think it's a technical aspect that certainly will need to be addressed. That's the beautiful thing about working with brilliant people like Dave Tuveson and his team because some of these technical modifications, over time, are going to need to happen. It may require micro dissecting of even the biopsies. It may require technical modifications that people that do this all the time will be able to work out.
ANJALI SARKAR: So to put things in perspective, before the PDO culture is established as a normal clinical practice in the clinical workflow, what are some of the current methods in place that are used to predict patient responses, if any at all?
MATTHEW WEISS: So there's very few. There was a trial done in 2018 by a good friend of mine, Dr. Susai, at the Medical College of Wisconsin. It's one of the only true precision pancreatic cancer prospective trials that I'm aware of, whereby they use genomic sequencing of the tumor to try to predict which chemotherapeutic agents the patient should receive prior to surgery. It was a small number of patients, but it was a successful trial, meaning the median overall survival looked very good in that trial.
MATTHEW WEISS: There's been very few outside of that space. The reality is that, when you look at pancreatic cancer, of the known genetic, somatic mutations, how frequently do we find actionable somatic mutations in the tumor? Unfortunately, the number is relatively small. It's probably on the order of maybe 10% or so. So one aspect that's being explored by other groups is using the genetic signature to predict response to therapy.
MATTHEW WEISS: I think that's exciting. I think, as of right now with only 10% of the tumors having actionable mutations, I think we're going to need to develop more identification of more actionable mutations in order for that to come to fruition. There's other immunotherapy type trials that are ongoing right now. Pancreatic cancer, historically, is not very responsive to immune therapy, but there's a lot of work being done by labs across the country, trying to make it more sensitive to immunotherapy.
MATTHEW WEISS: But other than that, we're exploring some very, very explorative type stuff-- cutting edge, predictive of response, by injecting certain things like microchips into the tumor that may elicit multiple chemotherapeutic agents into the tumor. But really, there's nothing else out there, to be honest with you, that I'm aware of.
ANJALI SARKAR: Which makes it all the more important to work on this. You talked about the accuracy a short while ago. But compared to say blood biomarkers of pancreatic cancer, what degree of accuracy can PDOs have in predicting responses to neoadjuvant chemotherapy? Are there any studies that have been done or are being done on comparing these various predictive methods and models?
MATTHEW WEISS: Yeah, so that's an area of great interest to us right now, and that's what we're looking at. And Dan King, one of our-- as I mentioned before, one of our medical oncologists, is spearheading some of this effort. We all know that we need more sophisticated mechanisms to gauge response to therapy. And truthfully, currently, clinically, all we really have is crude measurements of response. We have CT scans, MRIs.
MATTHEW WEISS: OK, the tumor looks smaller; the tumor looks bigger; they responded; they didn't. Those are relatively unpredictable, to be honest. The tumor can look the same, and you can have a great response. Or the tumor can look the same, and you could have had a terrible response when you remove it. We utilize tumor markers classically for pancreatic cancer. There's the CEA level and the CA 19-9 level.
MATTHEW WEISS: These are proteins that we pick up in the bloodstream that are secreted by the tumors. If these tumors do secrete these substances, they are highly predictive of how a patient is going to do. They don't necessarily predict well. So for instance, CA 19-9-- we know by following a CA 19-9 level when someone's on chemotherapy-- if the level goes down, it's certainly a good sign.
MATTHEW WEISS: It seems that they're responding. But we know from several groups' studies, including-- I mentioned before, Susai from Medical College of Wisconsin-- that the actual decrease in CA 19-9 level may not be as important as if they normalize their CA 19-9 clinically. So one of the interesting things about our study that we just published was that many patients that had a decrease in their CA 19-9 level that didn't normalize but had a decrease in their CA 19-9 level actually showed very poor response-- both by organoid prediction but also by pathologic specimens.
MATTHEW WEISS: So yes, they had a decrease in their CA 19-9 while they were on chemo. But then we removed their tumor and we looked at it, and it didn't look like the tumor had responded really at all, despite having a decrease in their CA 19-9. The world of biomarkers is exploding right now. We're certainly looking for more and more biomarkers to predict response. We're looking at things like ctDNA, circulating tumor DNA, to predict response.
MATTHEW WEISS: You're seeing a lot of that in some of the other cancer spaces, like colorectal cancer. It's an area of research for pancreatic cancer, and there's still a lot of work to be done.
ANJALI SARKAR: So once these PDOs are established, you mentioned tests like genomic sequencing. But what other specific tests are these PDOs amenable to that give it the predictive value?
MATTHEW WEISS: Yeah, so, obviously, genomic sequencing. We know, for instance, in the last few years, that there's been the identification of different subtypes of pancreatic cancer that can be predictive of good response and poor response. There's something called the Moffitt classification system. And the Moffitt classification system essentially utilizes genotyping to predict who's going-- likely to respond to certain chemotherapeutic agents versus not.
MATTHEW WEISS: But I think other things that can be done-- obviously, RNA sequencing as well, the organoid development. And I think there's a lot of areas, truthfully, that can be utilized downstream once we have a reliable model.
ANJALI SARKAR: Right. You mentioned the identification of specific mutations related to pancreatic cancer that could even be used in the Moffitt system of classification that you just mentioned. But is the heterogeneity of the pancreatic cancer such-- to such a level that these mutations also differ largely between patients? Or can these mutations be used for, say, Moffitt classification or even predictive analyses?
MATTHEW WEISS: Yeah, I think we don't know. As I said before, I think no two pancreatic cancers are the same. Even within the same pancreatic cancer, there's probably subsets of cells that look differently. Clearly, trying to utilize what we know, in terms of actionable mutations-- for instance, we know that patients that have BRCA mutation-- somatic mutations in their tumors-- we know that they're more susceptible, more sensitive to certain chemotherapeutic agents like the platinum-based chemotherapy.
MATTHEW WEISS: Microsatellite instability-- now, in the oncologic space, we're starting to see drugs that are FDA-approved based upon the genetic signature of the tumor and not on the tissue of origin of the tumor. And that's true for microsatellite instability. I think, unfortunately, the repertoire of genetic initiating events for pancreatic cancer known to date is still relatively low. We see a lot of genetic changes in the tumor, but we sometimes don't know-- are those initiating events?
MATTHEW WEISS: Or are they more likely downstream events, meaning they may not be the right one to target? Truthfully, I don't know. I don't have a crystal ball. My guess is that you're probably going to have to target multiple of these to really completely eradicate the tumor and put surgeons like myself out of business.
ANJALI SARKAR: Right. So you mentioned chemotherapy-- even patients with chemotherapy are amenable to PDO cultures, to generating PDO cultures. But does the tumor stage affect-- or-- the tumor stage or the chemotherapy application affect the ability to predict chemotherapy responses from PDOs?
MATTHEW WEISS: Yes, I think that's a great question. After they receive chemotherapy, what does the organoid tell you? Does it tell you what it was like at the beginning? Or does it tell you what it's like now? And have you selected for cells-- excuse me-- that have become resistant? I think the beauty of being able to do this with FNAs-- with core biopsies-- that, in theory, you'd want to do the organoids longitudinally.
MATTHEW WEISS: You want to do them in the beginning; you'd want to do them while they're on therapy; and then you'll get the surgical specimen after. One of the shortcomings of our trial was that we had a low number of patients where we had a FNA or core biopsy of the tumor right in the beginning, before they received any treatment. Why is that? Well, honestly, it's usually an operational issue.
MATTHEW WEISS: Patients are coming to see Matt Weiss with pancreatic cancer, and they've already gotten a biopsy that's proven that they have pancreatic cancer before they see me. So to enroll them in a trial, I would almost have to do a separate procedure with a new biopsy, just to put them on the trial, which is somewhat logistically difficult. And honestly, you could question whether that makes sense.
MATTHEW WEISS: Ideally-- now we've made some operational changes. We get patients hopefully referred to us right in the beginning so that, from day 0, we can get that initial biopsy and we can compare it to what we see later on in the disease process. But I think that's a key that's a key point because, clearly, the tumor, after four months of chemotherapy or after six months of chemotherapy, could be starting to behave differently than they were after-- at day one.
MATTHEW WEISS: So I think it's a key point.
ANJALI SARKAR: Mm-hmm. Mm-hmm. You mentioned the application of PDO for precision individualized medicine. Could you tell us some instances of case studies, for example, that PDO-based analysis has promoted-- where PDO-based analysis has promoted precision or individualized approaches in clinical practice?
MATTHEW WEISS: Yeah, so I think-- I think we're still at the infancy of how the organoids are really going to be utilized clinically. Obviously, I live in the pancreatic cancer space, but there's a lot of work being done in other spaces. We're doing a fair amount of work in colorectal cancer. There is a very robust organoid development program at Cold Spring Harbor for breast cancer. So I don't have an example of, today, where, oh, yeah, I'm going to use this organoid to change this patient's therapy.
MATTHEW WEISS: But I think what's exciting about this is that you can clearly see the clinical applicability. And I think what you're going to see very, very soon is-- you're going to see these trials done in a prospective manner, that are going to answer the question, since we can do this. We actually are in the process-- Northwell Health is in the process of building a CLIA-certified lab we have the facility built, but we need to get the CLIA certification for organoid development.
MATTHEW WEISS: That's done as a combined effort with Cold Spring Harbor, as you can imagine. But that's the idea-- is that, once all these trials are done and we bring it into the clinic, we want to be ready to go.
ANJALI SARKAR: Excellent. In a recent press release, Dr. Kevin Tracey, President and CEO of the Feinstein Institute, mentions how you and your collaborators at Cold Spring Harbor Lab are developing new methods to personalize and optimize cancer care. So in addition to PDO-based analysis that we've talked about in today's session, are there any other novel methods in cancer precision medicine that you are working on now?
MATTHEW WEISS: Yeah, so it's an exciting time. I can't give away all my secrets. But one of the beautiful things, now, is that we-- I currently have, obviously, a research group. And I hire research fellows, which, really, are surgical residents spending two years doing research with us. And they spend half the time in the clinics with me, and they spend half the time in the basic science lab. And the beautiful thing is that this is truly, I think, a model for how to translate basic science into the clinics.
MATTHEW WEISS: So we're bouncing a lot of ideas on cutting edge basic science research that's being done at Cold Spring Harbor, as well as Feinstein, and how are we going to take that research get it into the clinics for four prospective trials. We're kicking around a lot of ideas. We're looking at potentially the idea that you could essentially insert a tiny microchip into a tumor and try to-- with multiple wells that emit different concentrations and different amounts of chemotherapy, try to put it in the tumor, then remove the tumor, and see if that predicted which chemotherapy you can respond to, so almost like an in-vivo test in the patients.
MATTHEW WEISS: So our research fellows are doing that currently in an animal model, and the idea is maybe we could think about doing it in a prospective way in a clinical setting. Lots of innovative thinking going on. So I think the future's bright in this space, for sure.
ANJALI SARKAR: Thank you so much, Dr. Weiss. That brings us to the end of today's GEN Protocols Expert Exchange Thank you for a very illuminating discussion. And a reminder to all scientists among our viewers-- GEN Protocols is open for submission, and we welcome your protocols in all aspects of biotechnology. This is Anjali Sarkar. Until next time, good luck in your research, and goodbye from all of us at GEN Protocols. [MUSIC PLAYING]
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