Dr. Samuel Achilefu PhD Dr. Ravi Vij, MD Dr. Monica Shokeen, PhD, MBA Washigton University Interview Date: May 6, 2016 

 Nanotechnology is the study of very small things, down to the atom and molecule level. Based on the award-winning expertise of Dr. Samuel Achilefu and other experts, the Center for Multiple Myeloma Nanotechnology has now opened at Washington University in St. Louis and is considered a Center of Cancer Nanotechnology Excellence (CCNE).This group is one of six centers to receive a prestigious NIH grant to study nanotechnology in cancer and is the only center to study it in multiple myeloma. In this show, the doctors share that nanotechnology can be used to deliver existing or new drugs in a more targeted and more concentrated way, that it can also be paired with an imaging contrast agent to "light up" the cancer cells and target exactly where the treatment should go, and that it can kick out hiding myeloma cells into the blood so that it can be found and killed. This is a fascinating show that explores an exciting and completely new potential treatment for multiple myeloma. 

Jenny: Welcome to today’s episode of Myeloma Crowd Radio. Today’s show is unique in that we have three guests covering an up and coming topic, nanotechnology. For those of you like me who are new to nanotechnology, it’s best described as the ability to study very small things, or to see and control individual atoms and molecules. I’m here in St. Louis at the Washington University Center for Multiple Myeloma Nanotherapy, a new center that will apply nanotechnology to bone cancers and multiple myeloma specifically. They are one of a very select group of researchers who have been awarded a coveted NIH grant to explore the use of nanotechnology in cancer. They were selected because they have enormous institutional resources and support, diverse expertise in myeloma, participation of patient advocates and industry partners, both basic and clinical investigators, and most importantly nanotechnology expertise. Their goal is to improve myeloma treatment outcomes using these very small atoms and molecules, to deliver myeloma drugs with better impact and minimal off-target toxicity, as well as other things that you’ll hear about later. With me today are three specialists, Dr. Samuel Achilefu, a pioneer in the development of molecular imaging probes, and nanomaterials for imaging in the treatment of cancer. He currently leads the translation of innovative imaging technologies and molecular probes from the bench to the bedside. We also have Dr. Ravi Vij, a myeloma expert who is Professor of Medicine at the Washington School of Medicine in the bone marrow transplant section. He leads many clinical trials, and has established a large myeloma tissue bank at Washington University with a strong focus on setting the genomics of the disease, which are critical to understanding what causes myeloma and how to cure myeloma. We also have with us Dr. Monica Shokeen, an expert in imaging technologies like MRIs and PET/CT scans and in developing macromolecular agents that will improve the accuracy of these imaging tests. Her goal is to find myeloma cells using imaging technology, no matter where they reside in the body, no matter how young or old the cells are, and no matter how much they like to hide in the bone marrow niche. I welcome you all. Dr. Achilefu, let’s start by you helping us understand how a technology that has been using chemistry, physics and engineering is now coming to cancer and how you’re doing that with your projects at Washington University.

Dr. Achilefu: So this is one of six centers funded by the NCI to introduce nanotechnology to cancer research, and the focus is to bring a multidisciplinary team of investigators that can bring their expertise to solving a common problem. And of all these six centers, in fact this is the first NCI funded nanotechnology-based center to look at multiple myeloma. So in a nutshell, what we’re trying to do is to ask key questions that I’ll answer today and take advantage of the power of nanomedicine to apply it to cancer research. So we have projects, three projects, that are looking at ways of addressing critical issues in multiple myeloma therapy. The first one is looking at a protein oncogene that’s highly upregulated in multiple myeloma cells and the problem before now is people do not know how to deliver inhibitors to where they should work inside cancer cells. So our team members, led by Greg Lanza, discovered a very nice way that nanoparticles we grow everywhere using VLA-4 were discovered and championed by one of our team members here, Monica Shokeen, that can latch on to these cancer cells. And then once it’s there, it fuses with the membrane in a way that then it empties the content directly into the cells. That way they’re not degraded. They go to these targets. They only treat the cancer cells and make sure they die.

Jenny: So you were using nanotechnology to specifically deliver the right treatment to only the cancer cells. What other projects are you working on?

Dr. Achilefu: The other project is asking a different question: what about these cancer cells that relapse all the time, which is what patients worry about. Can we prevent relapse? Can we treat them independent of the tumor resistant phenotype that is there or treatment resistant phenotypes? So, in that way we are applying a type of therapy, previously used only for skin diseases. What we discovered is a way to take light and this small molecule, a drug, but at a dose that’s so low that it will have no effect on normal healthy tissue. When they come together, the radiopharmaceutical that’s used to know you’re in remission or if somebody has cancer relapsing, we use radiopharmaceuticals. If we take those two and bring them together in cancer cells, then they are described as cancer cells independent on whether it’s resistant or not. With that method, the nanotechnology allows us to do a special type of treatment that’s never been done before, and that’s what we’re excited about, too. That project is looking at where cancer cells hide in the bone marrow. We know that they go in there, the bone marrow niche allows them to sequester themselves in a way that you can’t find them. Then they relapse at a later time. When you see a remission, it doesn’t mean necessarily they have nothing in there. So the whole goal is to say, can we find a way to mobilize these cancer cells, kick them out into the bloodstream, sending out particles that are very efficient in killing them, to get to them before they go back into their hiding place again? So that project is led by John DiPersio to help us make sure that indolent cancer cells, the resistant ones hiding in the bone marrow can be kicked out and then treated. So the whole synergistic event we hope to accomplish here is that with the different therapeutic methods we have, by combining the nanotherapy, with light-based therapy, with chemotherapy, cancer cells have no chance to survive at all. So that’s what this is all about and we’re so glad to have leaders like Dr. Vij who is now giving us guidance into the clinical arenas, access to patients and interacting with them. So we learn everyday how to do this much better.

Jenny: It sounds like those two projects have specific goals. The first is you want to overcome drug resistance and the second is you want to get rid of leftover myeloma cells that like to hide in the bone marrow by kicking them out into the blood so the myeloma drugs can find them and kill them appropriately. With those goals, maybe you want to back up a little and give us an overview of what nanotechnology is all about. I, for one, am not familiar with it at all especially in medicine.

Dr. Achilefu: Nanotechnology, nanoparticles -- just think about a strand of your hair. It’s like 1000 times smaller in diameter. So basically, you can’t see it with your naked eyes, but think about it like an association of atoms, and they put them together in a way that they create these nice pocket surface areas that allow us to add a lot of materials into them. Nanoparticles are very tiny, tiny things we can’t see, but they can do so much more, ten times better, a hundred times better than single molecules. For example, in new airplanes today they are beginning to make them based on nanomaterials, and the essence of that is if you can pack so many tiny things with different surface areas within a small volume of tissues and for us in medicine, the advantage of the nano is that it’s small, but we can’t construct it in such a way that we introduce multiple things at the same time. We can introduce drugs that kill cancer. We can introduce imaging agents that can allow us to see where they’re going. We can introduce a monitoring device that allows us to know what’s happening over time. So the nano platform is a new way that people now are looking into, tackling these resistant genotypes that before now, a single molecule would not get there. So a final illustration is thinking of soldiers that march in a straight line, and they are walking into war. Of course, then you see them and take them out in series, but imagine putting all those 1000 battalion soldiers into a small place, all pointing their guns at the same person, all of a sudden there's really mass in number to get to the target by shooting from different directions but getting to the same target. That’s what a nanoparticle does for us, it amplifies the effect that you can have, and prevents the escape of cancer cells.

Jenny: So when I think about small molecule medication, I think about Velcade or other myeloma drugs. Is that what you mean? I think I may be confused when you’re talking about small molecules.

Dr. Achilefu: Nanoparticles, think about molecules, drugs that you have taken. Each time you take a pill, you have thousands of the same molecule inside the pill, and they formulate it into a tablet and give it to you to take. And in formulating each one, what’s being done right now is that they use something like chalk to put them together and you take that. It dissolves. It does what it wants to do. We are asking a different question altogether. Why not we take that whole big pill you’re taking in? Reduce it a million times smaller. Now, we can put one million times more in that tube you are going to take, to have efficient delivery into your body, and we then make them to be released over a longer period of time in the body. So the nanomaterials are like taking so many small molecules, put them together in such a way that you package them so well that they stick together but only get released to do the work as you want them to go through slow release. There’s another type. The other type is one you take some materials that themselves can become drugs, and when you put them together again, the advantage you have is that when they come in contact with tumor cells, they can now release their property effect right there. So think of nanoparticles not as a machine that’s different with a big device. It’s the same type of drug you are taking, except that now they are packaged differently to go to a given area and not randomly anymore and then have the effects selectively where you want them to have that effect. So there will be no need for giving a long IV introduction of chemo drugs for minutes or I don’t know how long you spend doing that, but more you can just give a little bit amount of this and still have more than 100 times efficiency than what you would normally have done. So they are still molecules. They are still like small drugs, but now packaged in a way that they’re going to have an effect on the target area.

Jenny: Okay. So you’re saying that using this technology can make the medications maybe a hundred times more effective and significantly more specific, only hitting the cancer cells and not the healthy cells? That is completely amazing. Now in immunotherapy, these approaches target certain proteins like CS1 or BCMA or other targets on the surface of the myeloma cells. Does nanotechnology work in the same way?

Dr. Achilefu: So we have two questions—there are two issues there. One is targeting. The other one is therapy effect. For us to target, we are looking at the new agent altogether, which is really not part of the center right now but we hope to bring it in, that can go to different types of cancer. It doesn’t matter what type it is. So we’re excited about that. That’s coming. What we have now is we are looking at treatments. You asked the question about light. I talked about light therapy and other rays. Let me explain that. It’s an amazing point. There’s a type of therapy that’s known as photodynamic therapy, and that involves the use of some drugs that are sensitive to light and if you apply them to the skin, you allow them to absorb in the area that’s injured, then you shine light onto the skin, giving wavelengths band of light and then it generates reactive oxygen species inside here that then allows your cells to die. It’s being used in the hospitals to treat a lot of surface lesions. The problem with that is that for multiple myeloma, it’s not on the surface. It’s spread everywhere; where do we apply that, where will we shine the light? So what this project has done is that we found out that radiopharmaceuticals like FDG, that a lot of patients take, they are not good I’ve found in PET scans. The molecule that helps you see the cancer can actually give out light, and so what if we then make the tumor cells take up this material and give out light? So we no longer need to shine the light from outside. The light now will come from inside the cancer cells themselves.

Jenny: So most patients are familiar with the contrast they get either with the PET CT scan or sometimes an MRI can be done with contrasts. These contrasts take the radioactive glucose and then light up the scans. Doctors can see where they myeloma still is in the body and if it’s progressing or not. You’re saying that these contrast agents can actually shine light on the cancer cells so that drugs can target them specifically, right?

Dr. Achilefu: Yes, but then we take that light when we deliver small drugs that naturally will not be toxic but only when they see that light from cancer cells then they generate this reactive oxygen that allows you to kill them selectively. So we’ve taken away that limitation that you need to spring the light to find where the cancer is shined and treated to the point where we’re saying, “We don’t care where the cancer cells are anymore.” They are going to take all these radiopharmaceuticals. We’re going to deliver these nice drugs that are light sensitive and the only place that they will come together to become toxic is inside the cancer cells. So now the light is coming from within, instead of from outside, and the drug is having an effect with it instead of in the whole vascular system. So it has the light based for a few we’re having.

Jenny: That is completely amazing. How exactly does it work to kill the myeloma cells?

Dr. Achilefu: The good thing then about it when you think is not dependent on the type of multiple myeloma. The way it kills cancer cells is there are multiple ways. First of all, it goes through this reactive oxygen that makes them toxic and allows us to then start killing them, or stress the cells. In that process, some cells will die, but some that are not dying will express antigens on the surface that now allows immune cells to come in and take care of them down the line. So you have immediate response and downsream response where your immune system will kick in to now remove the remaining part of it. So it’s not when we say it’s independent of the genotype or myeloma type, that’s what we mean by that; that we can get to it, we can stimulate it, we can kill it directly, we can disturb the blood vessels that feed into there through the single therapeutic approach. So that’s an innovative aspect we are looking at right now.

Jenny: There are some myeloma researchers I’ve spoken with who say there are precursor cells or myeloma stem cells that are early cells and maybe one reason myeloma keeps coming back, that they can hide and then they can develop in the plasma cells later, and that they might be different than more mature plasma cells. So that’s one question, can this technology bind and kill those early cells?

Dr. Achilefu: So that’s actually a very good question because, how do you know the cancer stem cells are the precursor cells and become cancerous down the line? If they would actually do that, do you want to start treating all of that in anticipation that they will transform into cancer or not, whatever healthy people have in the sense that they have not manifested the disease yet and we never get the disease down the line because the immune system will be able to walk through that or not. So the goal for us, which is another major area of research we hope to get the funding to do, is that there’s a new molecule that we believe is telling us which of those cells will become cancerous and which ones will not, and we’ve used it in pancreatic cancer model, where we have the precursor cancer cells and then it’s pointing to us: these are the ones that will become cancerous, these are the ones that will not. We now like to take into breast cancer, multiple myeloma and other areas to ask that question: can we predict which population of cells, that are suspicious, would become cancerous and which ones may not be. The fear is always that of overtreatment—if you start going after everything that’s suspicious then the patient may die of overtreatment and Dr. Vij will explain that better to you. But those are the things, issues we consider as we move down the line, to optimize for it in such a way that we are getting after those that will relapse down the line. The way we are proposing to do it, and this is down the line and Dr. Vij will be helping us with that later on is the preventive care that we hope to establish through this therapy. Where a patient that is in remission can go once a year. It can be an outpatient or primary care, just have a dose of this treatment that make sure if there’s anything coming up down the line. We as well just get rid of them before they develop into anything significant down the way. So that way we are not over-treating a patient and it’s creating something bad that is going to happen, but instead we are preventing something bad from happening by just having an annual visit to the doctor and use that as preventive care. That’s the approach we hope to establish at the end of this study with this center to move forward.

Jenny: So your goal is to prevent relapse using a once a year maintenance therapy. That would be fabulous.

Dr. Achilefu: And for the high-risk population, one of the suggestion is that if it works well -- we hope it’s going to work, then those in high-risk population can always go ahead and do that. The advantage being that both the drug and the radiopharmaceuticals who can give them at a sublevel, sub-therapeutic dose, then the worries that you will have by using current preventive care methods may not be an issue anymore, and because this therapy does not induce resistance, you would not see cancer cell resistant for that kind of dynamic therapy device then repeat treatment is not going to be problematic. You are looking at the new onset of your disease that’s coming from somewhere and you will still be able to respond but the treatment, even if it’s in a preventive care mode, it’s not going to stimulate -- become a therapy resistance down the line. So that’s our hope.

Jenny: That would be amazing. You mentioned pancreatic and breast cancer, has this been used already in other solid tumor cancers?

Dr. Achilefu: Yes. We may be fortunate actually to get one of the biggest awards in breast cancer to look at that using this approach as well, where we are looking at the types of cancer especially the spread of cancer, metastatic breast cancer. That’s an area we’re excited about looking at the indolent cells that do not really respond well to treatment, and predicting which patients will — DCIS will now go on to become real malignant tumors down the line versus those that will not progress and be able to eradicate them that way. So we’re excited to look at it because sometimes we see cancer as different types and we address them there, but at times when it comes to treatment, looking that’s not the current molecular pathway people are using. We can then expand it if we are successful with multiple myeloma. Dr. Vij may now be calling his colleagues in all the areas and say, “Do you want to try this therapy in your case or not because we can still deliver them and have similar effect.” So this center is going to set this stage, the platform that we now open it up for us just by looking at different types of malignancies that are around today, but we are starting with the first one in the country that’s looking at multiple myeloma as an entity to the disease to take care of.

Jenny: We are so excited that you chose multiple myeloma. How long has this therapy been around? You’re the first center to do this in myeloma and the recipient of this NIH grant. How did you get involved with that?

Dr. Achilefu: Officially, our centers that did — that was last September. So we are not even up to a year yet, but we made good progress, thanks to everybody here. The way we started was that NIH required us, they asked and they’re looking for centers of excellence in nanotechnology that we apply that knowledge to cancer therapy. So we’re looking at — we said, “Well, we should be one of the centers.” It was highly competitive. They already had nine/ ten centers before now and they are reducing everything to only six. The question became, how do we do it? We look at different types of cancer and we’re looking at solid tumors, blood cancers and everything. We have the technologies that can go through all of that but the question became where do we have an edge? Is there an area we can really focus and make an impact? Fortunately for us, there was Michael Thomas and Monica Shokeen, all of who were working on multiple myeloma and Dr. Ravi Vij has this huge patient population he treats all the time here. So we have the clinical center of excellence for that. We have topnotch researchers that can do multiple myeloma. We have technologies that can be applied to multiple myeloma, and so we ask ourselves, what if we put those three pieces together to create a center that will now be looking at it from a holistic point of view? And that’s how we came about that.

Jenny: Dr. Achilefu, thank you so much for joining us today and explaining this program. Your work is completely amazing and we just hope you keep going. Dr. Vij, you see myeloma patients all day long. In the context of myeloma, how do you see this being used?

Dr. Vij: So nanotechnology is obviously disease agnostic. It is just a method of a drug delivery and it’s even wider than that. Nanotechnology, as you’ve heard from Sam, can be used in wide industrial applications, things like that. So as far as where we stand with it in terms of a patient application, we’re still probably at least a couple years off. You have to test this technology in pre-clinical models first. Then you have to do pre-clinical work which is going to form the basis of an IND that will then be submitted to the FDA wherein they will permit what are going to be sort of first in human trials and like any drug, it will go through Phase I, Phase II, Phase III development. So I think that not many people realize in some ways one of the drugs that is out there, Doxil, is also based on nanospheres, and encapsulated Doxil. That is a form of nanotechnology, but the kind of nanoparticles being explored here are totally novel and much better in the preclinical realm to deliver the drugs and do some of the very fancy things as you saw Sam say about being activated by light, targeting things that are very specific to the cancer cell, whereas Doxil is just going to be a drug that is encapsulated in these liposomes that are not really truly specific for a cancer cell. So it is using nanotechnology to be much more targeted to the cancer cell and in terms of when we bring it to patients, it will obviously be something that we will have to tread very carefully, because this is absolutely new technology. It is something that we hope will be a true pharmaceutical product one day but I think we’re probably several years away from it being a commercially available product.

Jenny: What I hear you saying is that it has to go through the regular process of clinical trials. So why myeloma? What makes myeloma an attractive target?

Dr. Vij: I think that as they say, the technology is actually disease agnostic and cancer agnostic. I think the way it has come about as Sam told you is because we had a critical mass of research people who had research background in myeloma. They had mouse models. They had petri dishes full of myeloma cells that they had been working with already. They had produced data independent of nanotechnology researchers and then those two groups met and based on what they saw, the nanotechnology group had already been happening, they felt that it was a prime area because of the strength of the scientists that are already engaged in the basic science research in the realm of myeloma, to then use technology that they were dropping to come and give patients hope in myeloma.

Jenny: It’s not often you have everything you need at one center to go after a specific disease with a full team and the 360-degree view of the disease from the research side to the clinician side with patients.

Dr. Vij: You have to realize a lot of the people in the nanotechnology world that are participating in the development here are by training cardiologists. Some of them are individuals that have a background in radiotherapy and imaging. There are others that are actually engineers. They work in the School of Bioengineering at Washington University. So it’s a multidisciplinary approach. The synthesis of these nanoparticles is done by people who have background in chemistry and engineering. So they obviously were already working independently on creating these materials. So it was a good synergy that came about and all the other things that played a role as Sam said, is the demonstration to the MCI that we do have a critical mass of patients where this technology can subsequently be developed and the transition can be made from the laboratory to the clinic. We're very glad that it is myeloma, but could it have been breast cancer or lung cancer or colon cancer, sure. That technology can be applied to any cancer but you need to have researchers that are like-minded with a focus, and that’s how it came about. I’m very happy—I’m a clinician and I will hopefully be able to utilize this for the good of patients but I have to rely on my basic science researchers like Sam and Monica here to be able to develop the technology to be able to make that transition.

Jenny: Well, I congratulate you on the depth you have here and the coordinated effort. What you’re doing is not an easy task.

Dr. Vij: I think that there are very few centers that have the ability to bring together a multidisciplinary scheme in any cancer type and I think that Washington University, we are fortunate that we have some of the leading researchers in various fields and each is a world-renowned figure in their own area and it is breaking down the barriers. People work in silos, and you don’t know that a technology being developed literally in the next room could be used by you, who is working on a totally different area to help patients, and I think that that is a challenge of science to often break the barriers. Often, the technology exists, it is just that you don’t know the person in the next room can utilize your technology and take it to the next level. So, yes I think that there are quite a few centers that have the capability to do so and there are other centers that are working from a multidisciplinary approach but yes, they are probably in the United States, perhaps half a dozen, definitely less than ten that have a programmatic approach wherein you have the critical mass of basic scientists and scientists in different areas that can come together to do it. Some people do the clinical piece very well, others do the basic science piece but lack the clinical ability to translate it to the clinic. We’re fortunate that we seem to have all the pieces here, and we hope to be able to utilize it to make it happen, to make the transition.

Jenny: So in today’s world of myeloma treatment, we always hear about combination therapies, a stem cell transplant added to a protease inhibitor or an IMID, a steroid and maybe an immunotherapy. How do you see this thing incorporated or is the hope that it replaces everything?

Dr. Vij: Well, I think we will have to see how it goes. Obviously, we’re learning more and more about the genetics and the genomics of myeloma. We are learning that these cancers don’t have a homogenous group of mutations, even within the same individual, and that at different times, different groups of cancer cells with certain mutations predominate. That has led to the realization that we need to give our drugs in combinations so that you can target different subsets of cells within the tumor. But the fact is that there’s also another countervailing paradigm that’s evolving with immunotherapy where it is felt that you may not have to perhaps target individual cell mutations, that you can eliminate cancer by just having the body’s immune system attack the cancer. So I think that where this battle or this hopefully in the future where there will be synergy leads to as an open question: will we need to develop drugs targeted to individual mutations, combine them and kill away individual clones of cells within the tumor to be successful, or could we have an approach where you can actually target the cell independent of the genetic makeup? And as I said, nanotechnology is a mode of delivery and it could possibly have applications involving those paradigms. You could considerably have Velcade attached to a nanoparticle and and Revlimid attached to a nanoparticle that will be much better, less toxic and be more able to kill the cancer cell better. On the other hand, you can have perhaps the Nano technology used to deliver a molecule that will kill the cell based on either an immune approach or a cell surface molecule that is present in all those cells, irrespective of its genetic makeup.

Jenny: I think I’m beginning to understand that this is a drug delivery method, not another type of drug or treatment in and out of itself.

Dr. Vij: It is a drug delivery method. It’s not only just a drug delivery method. Nanotechnology is useful in a lot of areas of as I said industry. It has so many wide applications just outside of medicine and it is used outside of medicine even. These are just using very small molecules as Sam was saying, 1000 times smaller than the breadth of a hair to then have a structure that can accommodate drug molecules for delivery in a very concentrated manner.

Jenny: You could even use it to deliver melphalan or something like that, right?

Dr. Vij: Veru true, you could possible attach melphalan to a nanoparticle, making it much more efficient and less toxic. But we also hope that we will not only use this technology to deliver drugs that are out there and people are already working with preclinically, but also to deliver drugs that are synthesized and are formulated here, which would take it to the next level. You have the delivery method and you have the nanomolecule like what Sam was talking about, the light activated system. That is something that is being explored here. It is something that is being developed here. So you have a nanoparticle developed here, delivering a drug method or new method of killing cancer cells developed here being combined.

Jenny: Dr. Vij, thank you for giving us a myeloma perspective. One thing about you and Dr. Achilefu talked about is using imaging on a PET-CT type of technology to actually deliver targeted drugs. Dr. Shokeen, you’re an expert in imaging. How did you get involved in this and in nanotechnology?

Dr. Shokeen: So I have a PhD in Chemistry, and I’ve been trained as a chemist from Washington University in St. Louis itself, and then I had a wonderful opportunity to do my post-doctoral work here at the medical school, entrusting under the Program of Excellence in Nanotechnology. So during my early years at postdoctoral work, I was exposed to nanotechnology and nanomedicine in particular and that’s where I developed interest in developing nanoparticle based imaging agents. So I found my passion into designing radio pharmaceuticals for cancer research and cardiovascular research. So the chemist, we could go to the drawing board and think of molecules that could target cancer cells more specifically, and use it as an imaging agent. But molecular imaging in the preclinical models and clinical imaging, it has the advantage of giving a whole body picture in real time. So we know that the person had a disease through a blood test, a urine test, but molecular imaging and imaging in general gives us the power to see where the disease is located, if it has spread, how widely it is spread and which lesions are more active and which lesions are less active and benign and could be left untreated. So I started working with nanoparticles in an attempt to design the drug delivery, and initially I started working with breast cancer, targeting nanoparticles, and I worked with a collaborator, Katherine Weilbaecher, who is world-renowned breast cancer clinician here at Washington University. So we looked at targeting breast cancer and then I had the opportunity to work with the myeloma group here at Washington University with Michael Thomas and Ravi Vij and John DiPersio. What intrigued me at that time as I was starting my own independent research group was that at that time in 2012 there were no targeted molecular imaging agents for multiple myeloma or leukemia in general.

Jenny: So most patients are familiar with the PET scan where they have this glucose radioactive material and the glucose goes to the active myeloma cells and that’s what shows up on their scan.

Dr. Shokeen: FDG PET has been workhorse, the gold standard for oncologic imaging and provides very good value. So it has served the patient community and continues to do that in terms of detecting disease and then monitoring therapeutic response. But FDG is looking at one aspect of the cancer proliferation. The cancer cells love glucose to survive and proliferate and that’s where FDG comes in. However, I was interested in looking at how about the lesions in the bone marrow that do not express the Glut-1 transporter, which is needed for the FDG uptake. So can we have something more specific for myeloma cells? Can we learn more about the biology of maybe the resistant phenotypes of myeloma? So with that motivation, I started designing radiopharmaceuticals for the targeted imaging of myeloma initially in preclinical annual models. I was fortunate at early on right after I joined the optical radiology lab under the mentorship of Professor Sam Achilefu. I was awarded an R01 grant by NCI to develop receptor targeted imaging agents for multiple myeloma because NCI saw the need that in the portfolio of imaging agents, what was missing was a good imaging agent for multiple myeloma. The challenge there was the disease in the blood, in leukemia, how do you see focal points. But myeloma, one of the characteristics of myeloma is that you have multiple focal lesions within the bones. So there’s bone imaging and then there can be functional imaging to look at the proliferating cells. And can we target those cells and help in the early diagnosis and more efficient diagnosis of myeloma patients? There is a subset of myeloma population, which are oligosecretory. So those myelomas that are missed by the traditional tests, urine test or blood test. Ravi Vij used to tell me, that's the population, which really needs imaging because we cannot see it by our routine tests and that’s a false negative, and so imaging can be part of that.

Jenny: These are patients who essentially lost M spike, right? So they’re called non-secretors or they’re no longer making an M-protein, so it’s tough to test their blood or urine and you really have to do a biopsy, which everybody wants to avoid. What you’re saying is you can use imaging instead?

Dr. Shokeen: Looking at the resistant cells following therapy with FDG-PET, FDG sometimes can have a higher background uptake in the bone marrow. So I’ve started working on the agents that can be more specific, bring in more specificity, while retaining the sensitivity of PET, which is positron emission tomography, a technique used in oncologic imaging, which gives us a high signal to noise and it does not have to deal with the barriers of light because it can be easily detected. These are high energy gamma rays that can which be detected by the camera around the patient. So with my grant and now my group is actively working at looking at different molecular imaging modalities to more effectively diagnose, image and monitor multiple myeloma. I’ve been very fortunate to be part of the Center for Multiple Myeloma Nano therapy because here, I’m working with the different projects to monitor the therapeutic response more effectively in addition to the SPEP or the free light chain assay. Can we look at which cells escaped the therapy? Can we identify those and then target those? And as Sam explained that we need a good source of light. FDG is a fantastic source of light of getting to most of the cells but can we have something different in addition to FDG, more effective, targeted. In my case, I’m looking at VLA-4.

Jenny: And what is FDG? I think you may have to explain that. Now this is the contrast we get when we get imaging done?

Dr. Shokeen: So basically it’s, a glucose molecule. So what chemists realized early on, well cancer cells love glucose molecules. So what we did decades ago and FDG was one of the very first FDA approved imaging agent used in clinics, was to replace one of the set of atoms on the glucose molecule with a fluorine, a radioactive fluorine atom. So with radioactive fluorine, it’s a PET radionuclide. Radioactive fluorine gives out positrons. So it's a positron radionuclide. So what it does is that we have changed regular, nonradioactive glucose molecule into a radioactive glucose molecule, which is now—so cancer cells take it up as they would take up glucose. They think it is the same sugar molecule, it’s sugar to them, so once it’s taken up by the cancer cell. Since we have not replaced one of the set of atoms in the glucose molecule with the fluorine, they don’t know how to use it up. It’s pretty much trapped in the cancer cell. So the more they take it up, it’s just trapped and then you get a more higher signal. It’s a light bulb, which is getting brighter and brighter as it’s taken up because of the radioactive fluorine, which is now part of this molecule and here at Washington University, we have a world class cyclotron facility. So we are leaders in making FDG a clinical grade FDG, which we give to patients all the time.

Jenny: Is FDG the same as MRI contrast?

Dr. Shokeen: These are two different things. In MRI also, the contrast you get is a gadolinium based contrast. So MRI is definitely one of the star imaging platform for multiple myeloma patients because of its very high resolution and specifically giving the soft tissue contrast in the bone marrow. So if we’re looking at bone marrow imaging, gadolinium-enhanced MRI. So that’s the contrast you get. However, that is not specific. It’s basically looking—it’s useful for looking at the different anatomical parts of the cortical bone, trabecular bone, pelvic bone and also can be bone marrow. When there are tumor cells, the way water diffuses in and out, there is a difference. So you’re essentially measuring the change of water diffusion as magnetic resonance imaging is basically looking at water molecules, which we have plentiful in us. So we try to create an effective contrast by giving gadolinium. So that’s one imaging platform. PET is considered a more functional platform where we’re looking -- so MRI gives a great anatomical contrast and often we are picking up a lot of more functional bio markers based on MR. PET is very sensitive and so the cool thing now is that now we have more combined systems of PET/MR. So usually if a patient goes, gets a PET CT, so CT scan gives a very nice snapshot of the bone. So it helps you localize a PET signal. It gives the location that okay, so this is close to the arm, upper arm or leg. So you have a very nice co-registration and now we are doing here at Washington University, we have a -- I think we were the third one in the whole US to get a clinical PET MR scanner and we are screening a lot of myeloma patients using this platform. So we are using the power of MRI and the PET but all together.

Jenny: That is fantastic to get them both done at the same time, very efficient.

Dr. Shokeen: Otherwise you would have two independent scans. So for MR you have one and you will be given a gadolinium contrast and then for PET you will be given an FDG PET. So that’s a different contrast. They have different modes of action - PET is more high energy. It uses ionizing radiation but it’s given in—the contrast is given in such low doses that it does not cause any harm. So it basically—it’s called non-invasive imaging in the sense that it’s an innocent bystander taking a picture of the tumor but not really interfering with the tumor and that’s what we want. Jenny: So now you’re trying to apply those lessons you learned about imaging to nanotechnology?

Dr. Shokeen: Rather than shooting in the dark, we are giving the clinicians a real time snapshot of where the lesions are located, and then some lesions would respond and then you could see a PET image using FDG or any other molecularly targeted contrasted agents. And then you can hopefully manage the disease more effectively and identify the responders from the non-responders at an early stage rather than waiting several weeks or months before we realize a therapeutic change would have taken place much earlier to help the patients. So basically, helping with the management in addition to early diagnosis and also as part our center, the center is looking at effective ways of treating multiple myeloma cells and the pilot center is also using nanoparticles. So like Sam and Ravi mentioned, nanoparticles are multifunctional molecules and we can attach different drugs. We can encapsulate different drugs into the core of the nanoparticle and then have more targeting agents around it, and those targeting agents could target like you mentioned CS1, VLA-4 or CD38 on cancer cells so they can chaperon these nanoparticles to where those tumor cells are and have it retained there, and then we can attach imaging agents to these nanoparticles. So in addition to delivering therapy and using light also as part of the therapy, we get image as—how well our therapy is working, if it’s reaching the target. So it’s pretty much giving it a flashlight to our therapy.

Jenny: And you’re saying how well is this working?

Dr. Shokeen: Exactly. Is it going to the tumor cells, and did we make an impact? If there was reduction in the lesion, in the bone or inside of the bone?

Jenny: Where do you see this new technology headed?

Dr. Shokeen: I believe nanoparticles and nano medicine in general has evolved a great way. I was involved with nanomedicine almost a decade ago, and I have seen through all the years the progress researchers across the world have made. So the technology is ready for the next step where it’s ready to be help patients. Now, it’s more biocompatible. It’s more bioavailable in vivo. So that translates into effective delivery, effective targeting and I believe it’s going to impact the disease and hopefully help eradicate or manage multiple myeloma more effectively. As a chemist and as a scientist, I believe in this technology. 

Jenny: Dr. Achilefu, Dr. Vij and Dr. Shokeen, thank you so much for taking time to talk with us so we can learn about this ground breaking new approach to treating myeloma. I congratulate you again for your creation and funding by the NIH of this exceptionally innovative program that we hope will help cure this disease. We know we’ll be hearing much more about your project in the future and we look forward to your updates. So thank you for listening to another episode of Myeloma Crowd Radio. Join us for future shows to learn more about the latest in myeloma research and what it means for you.