Anirban Maitra, M.B.B.S. Hi, I'm Anirban Maitra. I'm a professor of Pathology and

Translational Molecular Pathology and scientific director of the Pancreatic Cancer

Research Center here at MD Anderson Cancer Center. I'm here today with my colleague,

Dr. Shubham Pant, who is professor of GI Medical Oncology and Investigational Cancer Therapeutics. And together, we welcome you to the Cancerwise Podcast. So, Dr. Pant, it's great to have you here. We've been working for over a decade together in the arena of pancreatic cancer and exploring ways of improving care for our patients. Our shared focus on advancing treatments and research has led to many important conversations, just like the one we're having today. So, let's first talk about what makes pancreatic cancer so challenging to treat.  

Shubham Pant, M.D., M.B.B.S. Thank you, Dr. Maitra. I know we've been doing this together for a long time, treating patients. And I think over the last decade, we definitely have improvements in therapy for pancreatic cancer patients. And I thing more are to come. But to your question, what it makes a challenging is, about 80 percent of pancreatic cancer are advanced stage disease. That means they either cannot be resected or they've already spread beyond the pancreas to the liver, to the lungs. So, when you have stage IV disease, the treatment, when we say is more palliative, that means to control the disease, it's not curative. It cannot cure the disease. That's what makes it so hard. The second thing is even in the patients who have resected disease, pancreatic cancer, little cells can metastasize very early. So, that means they run away from the pancreas and they form a home in the liver, or the lungs or the lymph nodes. And that can blossom over time, even after we resect the pancreatic cancer out, and we give patients chemotherapy, it can blossom later. So, it's like a tough disease that way. The third thing is that pancreatic cancer is run by a mutation called RAS. About 90 percent of pancreatic cancer patients have a mutation call RAS, and that's been something called the "undruggable mutation." That means it's a target that we cannot latch any drugs onto. So, it has been fairly challenging. But I know you've done a lot of research in this setting also, so I want to throw the same question back to you. In your mind, why is it so challenging for pancreatic cancer?  

Anirban Maitra, M.B.B.S. So, I think you hit the nail on the head in terms of most patients, unfortunately, presenting with advanced disease. That is a real challenge. More than 80 percent of our patients, when they come to MD Anderson, have disease that has unfortunately spread beyond the pancreas, and therefore our surgeons cannot take the disease out. They have to see someone like you, an oncologist. For a long time, the treatments that we had available, or I should say, you had available for our patients, were somewhat limited because the disease was not responsive to many of these treatments. For the first time now, we have a remarkable armamentarium of drugs that actually can hit this particular abnormal gene that you talked about, KRAS, that is kind of like, sort of, your pedal-to-the-floor accelerator on pancreas cancer, right? And we knew that it was there, but we didn't have a way to block it. Now, finally we have drugs that hit KRAS, that can block it. And I'm very excited by the clinical trials that are happening at MD Anderson, many of them led by you. You are treating patients with these absolutely newly-available compounds. But at the same time, we know from the early clinical data that while patients will respond, they will unfortunately progress. The disease will become what is called resistant to the treatment, and so a large effort in my lab and other labs at MD Anderson, many scientists at MD Anderson are working on this, which is to figure out how do we overcome this resistance by developing more effective combination therapies. And once we know what these effective combinations are that can sustain the response to RAS inhibitors, either with two drugs or three drugs, in addition to this particular RAS inhibitor, then we can go back to you and say, "Dr. Pant, run this trial, because we really think this is an effective trial to run." So, I love this part about the back and forth between the lab.  

Shubham Pant, M.D., M.B.B.S. The bench to the bedside.  

Anirban Maitra, M.B.B.S. Exactly. Exactly. And it's a circle. It's not just one-way street. You come back to us and say, "This drug is a really good drug, but I think it would benefit from having more research done on it." And then we do that and we go back to you and say, "This is the trial you need to run." So, it goes both ways.  

Shubham Pant, M.D., M.B.B.S. No, that's fantastic. You're exactly right. So, you know, I'm going to talk a little bit about, you know, currently what are we doing. So, we talked a little about the research, but currently majority of the patients who come to us, we treat them with chemotherapy. So, there are two different big types of chemotherapy. Recently, a newer chemotherapy has been introduced, which is something called 5-fluorouracil liposomal irinotecan and oxaliplatin. We also use something called 5-fluorouracil irinotecan and oxaliplatin, another chemotherapy called gemcitabine Abraxane®. So, those are the most of the chemotherapies we use in advanced setting. And we'll talk a little bit about, you know, all these newer therapies which are coming, all these exciting clinical trials that we are running right now, that we hope to change this curve of pancreatic cancer. But you know we talked a little about the lab, right, Anirban? So, what are you seeing in the lab that you think impacts current treatment strategies?  

Anirban Maitra, M.B.B.S. So, I think, you know, one of the biggest challenges we have in pancreas cancer is many of these wonderful drugs called immunotherapies that have been, actually it arose out of work by our own Dr. Jim Allison here at MD Anderson. He actually received the Nobel Prize for one of first immunotherapies that has really transformed melanoma from a lethal disease to something that is incredibly manageable. Those drugs unfortunately have not worked in pancreas cancer. And so again, there's a lot of effort going on in our lab and labs all across MD Anderson trying to figure out how can we make immunotherapies more effective. And I think it's really exciting because we talked about these new RAS drugs that have come that you are testing in the clinic. We are starting to see that when you combine these immunotherapies with RAS inhibitors, now you start seeing effects that were not visible previously. So, I think there is a great opportunity here to now leverage these sort of combinations of targeting RAS and throwing in immunotherapy in there, drugs that previously did not work, but now we have an opportunity to use them. So, this is something that, again, there's a lot of exciting research going on. We are also very interested in the field of early detection. And again, we've had substantial efforts at MD Anderson in terms of identifying blood-based markers, a blood test, so to speak, for pancreatic cancer. Currently, there really isn't a blood test. One of the reasons why patients present so late with these diseases is that unlike colon cancer, where you can get a colonoscopy done, or breast cancer, where you can get mammograms done, or a PSA test for prostate cancer, there really isn't a test for pancreas cancer. So, you kind of walk off the street with this disease in most instances. So, we've been very interested at MD Anderson in identifying a blood test that works in identifying: 1. Who is at risk for this disease? And 2. If they are carrying a tumor that is still small, contained in the pancreas and can be surgically resected because that is your best shot at cure. Long-term cure is really coming in those, is really seen in those patients who were able to get the tumor out. Right now, that number is 15 to 20 percent of patients. But if we can increase that number of patients who are able to get surgery from 15 to 20 to 50 to 75 percent, then we will impact the trajectory of the disease and totally transform survival better than anything. So, there's obviously a lot of research we're doing in early detection as well.  

Shubham Pant, M.D., M.B.B.S. That's great because when you catch it early, it's curable. You catch it late. Yes, we're trying to improve the outcomes, but we really want to catch it early. So, we're really able to change the trajectory. I think that's very important, Anirban, what you said. And I just want all our listeners to know that it all begins in the lab. So, it kind of begins in a lab where great scientists like you kind of figure it out. And then we take it to the clinic. Anirban, you talked about immunotherapy a little bit. A lot of patients come to me and they're like, "Hey, why can't you give us immunotherapy?" Because it's kind of a buzzword for lung cancer and melanoma, and all these ads are there on television, but tell me why is it, why does immunotherapy not work in pancreatic cancer?  

Anirban Maitra, M.B.B.S. That's a great question, and again substantial work has been done here at MD Anderson in the research labs, as well as through the clinical trials where we have you know under, where we have undertaken biopsies on our patients who have not responded to see why is immunotherapy not working. It's a really vexing question but over the last decade we have really come to understand a little bit about this this recalcitrance to immunotherapy that is so prevalent in pancreas cancer. So, it turns out that pancreas cancer does not exist in isolation. It's not a ball of cells, of cancer cells. It exists in this unique, what we call microenvironment. It is surrounded by other cell types that form like a sheath around those cancer cells, think of it like a chocolate chip cookie. And the chocolate chips are the cancer cells.  

Shubham Pant, M.D., M.B.B.S. I'll never be able to eat a chocolate chip cookie, you know.  

Anirban Maitra, M.B.B.S. Well, it is what it is, you know.  

Shubham Pant, M.D., M.B.B.S. I love chocolate chip cookies.  

Anirban Maitra, M.B.B.S. Well pathologists, one of the things about pathologists, which is what I am, is we have a penchant for having a food analogy for everything, you know, like.  

Shubham Pant, M.D., M.B.B.S. No, no, no more. No more food analogies. I still love my food.  

Anirban Maitra, M.B.B.S. I'll stop with food analogies, but let's talk about the chocolate chip cookie. So, it's important because the chips are the tumor cells and the chocolate, the dough around it, that's your microenvironment. So, the drug has to go through that dough and get to the chocolate chips for that chip to be affected. And that's where

immunotherapy gets hindered because: 1. It doesn't reach the tumor cells. And 2. Even if it reaches, these tumor cells make a lot of signals that actually impact your immune cells in a deleterious way. So, even if they get there, they're not able to function the way they would, for example, in melanoma or lung cancer. So, a huge part of what we're trying to do, and this is where the RAS drugs come in and some great work from one of our colleagues at MD Anderson has shown that if you block RAS, you can block some of these deleterious signals that make T cells not function, and now you can get T cells to start working. So, again, the research has been pivotal here. Thank you for bringing that up, that it all starts in the lab. But here at MD Anderson, one of the great things is it's always a continuous cycle. 

 Shubham Pant, M.D., M.B.B.S. Yeah, it's a great ecosystem, it is a great ecosystem.  

Shubham Pant, M.D., M.B.B.S. You're coming to me and I'm going back to you, so I think that...  

Shubham Pant, M.D., M.B.B.S. And we have long conversations when I'm driving back home, you know, talking about, "Hey, what do you think about this?" If I saw something that I think can be improved or I read something and you, it's vice versa. So, that's great because there's like back-and-forth information that we do. And thank you for the chocolate chip cookie analogy. I'm hungry now, but we'll do that after the podcast. But Anirban, you also, you know, patients always ask me, you know once they get it, their family members, they always ask me, "What can I do to decrease my risk of pancreatic cancer?" So, what are some of the risk factors for pancreatic cancer? What can our patients, caregivers, family members look out for?  

Anirban Maitra, M.B.B.S. That's a great question, and I think one that is foremost on the minds of somebody who's just been diagnosed, because you're always thinking, what about my children? What about my siblings? And again, in the last decade or more, we have learned a lot about what constitutes risk for pancreas cancer. Who is at risk? So, for example, if you have just one family member with the disease, as tragic as that is, in general, that does not increase your risk too much. But if you now start having two family members, especially if they're first-degree relatives, a sibling and a parent, now you start getting into what we call a high-risk category for this disease. Or there are some patients, some individuals, who have certain conditions that make them more prone to getting pancreas cancer. So, for example, there are these fluid-filled sacs in the pancreas called cystic lesions. And if you have a cystic lesion, while most cystic lesions will not become cancer, it's still a higher risk of becoming cancer than somebody who doesn't have a cystic lesion. So, then there are some genes that can predispose you to getting pancreas cancer. So, for example, this might come as a surprise to our listeners, but the breast and ovarian cancer gene, BRCA1 and BRCA2, also increase the risk of pancreas cancer. And it always comes as a surprise to me that there are physicians out there who don't know this. They think of BRCA because BRCA stands for breast cancer, that it's only for breast and ovarian cancer in women. But if you have a BRCA mutation, if you have a family where there is a BRCA mutation that's carried among family members, those individuals also need to be screened for the risk of pancreas cancer. So, again, multiple family members, certain genes, having these cystic lesions in the pancreas, all of these increase the risk of pancreas cancer over the lifetime. The good news is, here at MD Anderson, and you know this, we have a high-risk clinic that is dedicated to pancreatic cancer families. So, if you have somebody who has a family with multiple pancreatic cancers or has one of these genetic mutations that increase your risk, you can come and enroll in this clinic, and we will offer you personalized surveillance strategies. By surveillance I mean we can do imaging studies, you have a multidisciplinary clinic made up of gastroenterologists, geneticists, you know, oncologists who will make sure that your surveillance is tailored for your family. We have a cyst clinic here run by one of our surgeons. So, if you have a cyst in the pancreas and you're worried that cyst is becoming cancerous, you can come and get imaging studies done. So, all of that is available. Just pick up the phone and call.  

Shubham Pant, M.D., M.B.B.S. That's one thing Anirban, like at MD Anderson, people think, oh, we're coming here, treatment, and there are great treatments, newer innovations, but there's all this other stuff there, right? There's all the things for family members, high risk, all these other things. And I saw a patient recently, you know, had breast cancer 10 years back, BRCA1, and then saw me like 10 years later, had pancreatic cancer. So, you now, we do see this in real life, and having these resources, which you won't know about until you actually came here, are amazing.  

Anirban Maitra, M.B.B.S. Yeah, I think it's very important for us to emphasize that even though we are called MD Anderson Cancer Center, you don't need to have cancer to come here. In fact, a huge part of the effort that we have here is preventing cancer from happening. So, I think that's important for me to sort of emphasize. Well, let me flip back a question to you. Again, one of the unfortunate things about the natural history of this disease is even patients who do undergo surgery, we know that many of them have a very high risk of the disease coming back for a term that we call relapse of disease. And that's why you follow patients after our surgeons remove the tumor for the risk of relapse. So, what are the sort of treatments that are now available for preventing or delaying recurrence of disease?  

Shubham Pant, M.D., M.B.B.S. Yeah, thank you so much, Anirban. So, what normally happens is patients who have a resectable disease that the surgeons can take out, we normally give them chemotherapy after that. And that differs according to the patient. But after that, there's really no standard of care. Normally we wait and watch, we do scans at regular intervals, labs for patients. But now we have this whole generation of cancer vaccines which are being introduced. So, these are vaccines against the KRAS mutation that we talked about. And what we are trying to do is, we're trying to get that immune system really revved up. So, remember you talked about the chocolate cookie, right? So, what I want to tell my patients is when you have micrometastatic disease potentially, that means small cells running around that nobody can see, those are the little chocolate chips, right, they're not the cookies. The cookie has not been formed, that means the cancer has not be formed, those little chocolate tips are running around, and then they're easier to target because they do not have that shield around them, right? So, I think that's what we are trying to target. So, these vaccines, by boosting your immune response, what you talked about, your T cells, against the RAS mutation specifically. So, it's very personalized technically to the patient against that RAS mutation. What we are trying to do is kind of nip it in the bud before really it can form, these little chocolate chips can form the little dough around it and everything. We're trying to nip in the bud, and that's what we're trying do. And we presented some data last year, a couple of years back and we are doing these trials for patients. These are not FDA-approved. But we definitely have trials which are actually showing us in early times that if you really rev the immune system in the patients, those patients tend to have a longer time survival. But right now, we don't know who those patients are. That's the challenge. That's why we're doing these clinical trials. But it's amazing that we are trying to target in a different way, that using these vaccine therapies, which we have ongoing. So, more, more, watch this space, more in the future, but I think this is a very interesting and exciting time for drug development in pancreatic cancer.  

Anirban Maitra, M.B.B.S. So, you mentioned a word that I want to come back to for one second, because I think it's important for our listeners to understand that. So, for those of you who don't know Dr. Pant, he started his career in something called Phase I Program, which is basically how newest drugs are tested in patients for the first time. So, what we call first in-human studies. So, you mentioned the term "clinical trials." Can you talk a little bit about the importance of clinical trials and why it's so important to at least consider one as your therapy?  

Shubham Pant, M.D., M.B.B.S. Yeah, 100 percent. So, clinical trials are very important for any cancer, but I think really a lot for pancreatic cancer. Less than 5 percent of patients with pancreatic cancer go on clinical trials, and it can be due to different reasons why they don't go on, but the number is small. And what I want our listeners to know is that every drug which is approved has gone through a clinical trial. It's not magically appeared. So, it goes through this thing called Phase I, Phase II and Phase III clinical trials. So, it's very important. And you know, we have trials for patients who have not started any treatment for their stage IV disease. We have trials for patients in the adjuvant treatment. So, it's really important that, you know, when you're diagnosed with pancreatic cancer, you know, where you go first really does matter because there may be a trial that you could be eligible for if you meet all the eligibility criteria. So, those are important because we have a lot of trials now coming in pancreatic cancer. Like you were talking about RAS. So, RAS mutation is just not one thing. It's different mutations inside RAS, so you really get into the weeds here. There's something called KRAS G12D, D as in delta, V as in Victor, R as in Romeo. And why I say that is because we have newer drugs targeting KRAS G12D. And though they're all in clinical trials, Phase I to Phase III, we have different trials going on. So, we have clinical trials for patients who are newly diagnosed pancreatic cancer, never received therapy. We have trials for patient who went through the first line of therapy, but unfortunately maybe it did not work. And we have trials or second line. We also have trials of something called maintenance therapy. That means once patients get the initial therapy about six months, the chemotherapy toxicities keep showing up, so we can do something called maintenance therapies, something kind of gentler, but still to delay the cancer from growing. So, right now in pancreatic cancer, and I'm saying in the next half a decade or decade is going to be the really, I think we're going to see an explosion of newer therapies for our patients with pancreatic cancer. I have true belief that, you know, there is hope, which is here now, and it's there on the horizon. Like I, you know, like they say, you can see the light at the end of the tunnel. Really in pancreatic cancer, it's been so tough, so tough over the decades. But now, you know, I think the curve has shifted and the way I look at it is for lung cancer, when I was a fellow, long back, I'm not going to say when, but a long back when I was fellow, you know melanoma, we used to treat with these chemotherapies or these really tough therapies called IL-2. Lung cancer, we used to treat with only chemotherapy. And then completely change, right? Melanoma with the immunotherapy, lung cancer with the targeted therapy. And I truly believe we're on the cusp of these changes in pancreatic cancer because I see the excitement out there. We have newer therapies, but obviously we have to caution that they have to go through the clinical trial process. You know, we are realistically optimistic. So, I'm really optimistic for the future of pancreatic cancer. And I really think we've come to the point where we are going to make a difference in our patients' lives, because that's what it's all about. It has to be patient-centered care. We really have to think about how we can improve outcomes for these patients. And pancreatic cancer patients, it's targeting with chemotherapy, but also supportive care, which we have, right? They need pancreatic enzymes to improve the digestion, pain control. It's a whole kind of a, it's truly a village which helps take care of this patient. And like, a shout out to the caregivers who kind of, you know, who are there with the patients, really taking them, bringing them to appointments, being with them all the time. So, I think there's a lot going on in the field of pancreatic cancer. There's something on cachexia, patients cannot eat. So, there's newer therapeutics which are being developed for that. So, it's coming from all directions. I'm really excited about the future for our patients. And I truly believe in the next coming years and decades, we are going to see improvement in survival, in stage IV disease, improvement in cures for patients who have been resected. And with amazing scientists, brilliant scientists like you, doing more early detection and hopefully doing the curative therapies early. So, caught early is curative. So, I'm really hopeful for the future.  

Anirban Maitra, M.B.B.S. Yeah, I mean, that that was that was really well put. And again,

I want to emphasize that, you know, you brought up something really important, which is not just about drugs. You know, it is also about supportive care, about taking care of you know appetite and pain. That is so important and really takes a village. So, you know, an optimistic GI oncologist I have not seen one.  

Shubham Pant, M.D., M.B.B.S. They will make the glasses always half-full.  

Anirban Maitra, M.B.B.S. Yes, fantastic. No, but there is real cause for optimism, real cause for hope. And I think, you know, having done this for a quarter century, I have to say that it's a whole different renaissance era to be living in. Well, thank you Dr. Pant for being with us today and thank you to our listeners. For more information or to request an appointment at MD Anderson, please call 1-877-632-6789 or visit MDAnderson.org.