Dr. Sadhana Jackson — Breaking Through the Blood-Brain Barrier

>> Diego (narration): If you listened to our last episode, you heard about the President Biden’s goal to reduce cancer rates by 50% over the next 25 years. It’s an ambitious goal against a formidable foe. Billions of dollars are spent each year in research labs across the world racing to find a cure or development new treatments for cancer. And some exciting stuff is on the horizon; there’s buzz around therapeutic cancer vaccines that could rally the body’s own troops against the rogue cancerous cells. New nanotech promises to better target and deliver anticancer drugs to tumor sites. And with the flood gates of AI now open, new screening methods could improve early detection and prevention.

Each of these avenues promises a higher degree of precision. Because that’s the thing about cancer, it can turn up in many different ways and in different parts of the body. So the more targeted a treatment can be the better chances it has of eradicating the danger without harming healthy tissue in the process.

Broadly speaking, we currently fight cancer in four ways. Surgical resection, that’s going in and physically cutting out the cancer [SOUND OF SCISSORS OPENING AND CLOSING]. Chemotherapy, which basically entails poisoning cancer cells [SOUND OF CHEMICAL SINGE] to stop them from rapidly growing and reproducing. Radiation therapy, where doctors zap cancerous cells [SOUND OF LASER BEAMS] with focused beams of high-energy radiation to destroy them. And most recently, immunotherapies, that boost the body’s defense systems so that they’re better prepared to fight cancer [BATTLE CRY].

However, alone or in combination, these methods can’t guarantee success. And they can be more effective against some cancer than others. For example, the survival rate five years after diagnosis for breast and prostate cancers caught in the early stages is in the upper 90s. But unfortunately, the number dwindles to the low thirties for brain cancer. Part of the reason is because treating brain cancer comes with the added hurdle of the blood-brain barrier.

>> Dr. Jackson: The blood-brain barrier is a collection of cells that come together through tight junctions that form the blood vessel and act as the barrier for letting bad things get into your brain, like toxins, bacteria, and viruses.

>> Diego (narration): That’s Dr. Sadhana Jackson.

>> Dr. Jackson: I am Sadhana Jackson, I am a physician scientist and tenure-track investigator at the National Institute of Neurological Disorders and Stroke or NINDS as well as at the National Cancer Institute which is NCI. And I conduct research having to do with the blood-brain barrier and malignant glioma.

>> Diego (narration): Dr. Jackson likens the brain to an exclusive night club [SOUNDS OF CLUB AMBIANCE FADES IN] where different types of cells each have their specialized role, just like bartenders, club promoters, and club security each have their distinct jobs to make sure things run smoothly.

Manning the entrance to the club are…

>> Dr. Jackson: …the pericytes, P-E-R-I-C-Y-T-E-S, astrocytes, we call them astrocytes because the cells actually look like stars, and then endothelial cells.

>> Diego (narration): These cells make up the blood-brain barrier. They’re the bouncers that keep bad actors from coming in.

>> Clip from “Lord of the Rings (2001)”: You shall not pass!

>> Diego (narration): That’s all good and well when you’re keeping viruses, bacteria, and toxins from coming inside the brain and potentially wreaking havoc. But if the danger is already inside…

>> Clip from “When a Stranger Calls (2006)”: We traced the call. It’s coming from inside the house. Did you hear me? It’s coming from inside the house.

>> Diego (narration): …the BBB—blood-brain barrier—can actually work against a person’s health by shutting out the medications meant to eliminate the threat.

>> Dr. Jackson: Where the BBB is closed it will not allow for chemotherapy to effectively get there. And so, sadly, that's why these patients do so poorly because the tumor cells start to regrow.

>> Diego (narration): And therein lies Dr. Jackson’s work. She is working to figure out ways to selectively get cancer treatments through the blood-brain barrier to treat patients with certain types of brain tumors, known as gliomas.

>> Dr. Jackson: Our studies really look at how can we transiently open this blood-brain barrier and understand why, at some aspects it's open versus it's closed in the context of these fully aggressive tumors.

>> Diego (narration): In this episode, I talked with Dr. Jackson about what makes the BBB so selective, how she’s chipping away at it, and the impact breakthroughs in the blood-brain barrier could have against these aggressive brain tumors.

[TRANSITION MUSIC]

>> Diego (narration): As I said at the top of show, not all cancers are the same, even when we’re talking about cancers in the brain. Gliomas, the type of brain tumors Dr. Jackson studies, occur when the cells surrounding and supporting our nerves turn malignant and grow uncontrollably.

>> Dr. Jackson: When a patient actually is diagnosed with these type of high grade gliomas, glioblastomas, very aggressive type tumors, we'll get an MRI and these patients will see on the MRI this bright, kind of white spot of where the tumor is.

And so, as a neurosurgeon or as a radiation oncologist, or as an oncologist like myself, we'll start to plan what type of therapies are best for these patients. And so, in the context of surgery, the neurosurgeon will go in and they'll excise, or take out, this white area that is seen on the MRI and they usually will not touch what is not bright or lighting up.

>> Diego (narration): That was the case with Brenna Davis, a patient who came into Dr. Jackson’s care at the tender age of 13.

>> Brenna: the summer that I turned 13, I went to NIH to get tested to see if I had LFS.

>> Diego (narration): LFS stands for Li-Fraumeni syndrome, a rare genetic condition that increases a person’s chances of developing cancer.

>> Brenna: I’m more likely to get cancer than your average everyday person because of a genetic mutation that my family has. My mom and my grandpa and my aunt all had LFS. And I knew that everybody who had LFS had had cancer. My aunt, unfortunately, passed away when I was eight from an osteosarcoma of the skull, actually. So, I knew that, like, my aunt had died from cancer, and I knew that my grandpa had cancer and that my mom had cancer.

>> Diego (narration): Brenna’s family was already part of ongoing NIH study on LFS. And given their history, Brenna’s mom thought it was best to enroll her in the study as soon as she was eligible.

>> Brenna: the usual screening protocol for that study is to go ahead and get a full-body MRI and a dedicated brain MRI. And I wasn't super excited to go ahead and get that baseline scan because I was, like, “Oh, my gosh, you're telling me that the reason that all y'all were sick, that I have the same thing that y'all have”—because I didn't understand all of it at all, just that I had the potential to get very sick. So I was a little nervous, but my mom was like, “No, no, no, we'll just go ahead and get it done.” So I get tested. We finish up the stay. And about a week and a half, two weeks later, we'd gone back home to Tennessee and we get the call that I actually had an astrocytoma in the right frontal lobe of my brain.

>> Diego (narration): The mass was the size of a golf-ball. And although she knew she was at higher risk for cancer, the news didn’t come easy.

>> Brenna: The couple of days after that was honestly just disbelief. I was pretty shocked. I didn't feel sick. I didn't look sick. I knew what sickness looked like at least. And I was like that's not me. I was, like, getting straight A's, I was swimming. I was playing basketball. Like, there were no symptoms that would have really given any of us any indication. I just knew that we had to go back.

>> Diego (narration): Despite being asymptomatic, there was still a sense of urgency.

>> Brenna: I ended up having my initial surgery just a couple of weeks after that scan that they had. So not a whole lot of time to dwell on what was going on, just action because I was so young and they wanted to make sure that they got it out as quick as possible.

>> Diego (narration): So, Brenna went back to the Clinical Center where the surgery took more out of her than just the tumor.

>> Brenna: It was a long recovery time. Especially the first surgery, I went from, like, just perfectly fine and okay to you get wheeled back and you take a nice little nap and then you wake up. And my head was completely bandaged. I was wrapped like a mummy. The intubation tube that was in my mouth, it rubbed like a blister on my mouth. So, I looked like a monster. And it took a while to shake out of like the fogginess. I was very, like, light-sensitive and sound-sensitive, so I was pretty much in my bedroom, blinds shut, door closed, very quiet environment. So, like, I didn't have a lot of interaction until about nine or so weeks after surgery with anyone outside of my family, really. I just took that long to kind of be a person again. My brain was, like, resetting essentially.

>> Diego (narration): During that time of confusion and hardship, Brenna came into the care of Dr. Jackson, who was studying cases like Brenna’s to understand the mechanics of these gliomas and explore ways to improve drug delivery.

>> Dr. Jackson: She had what we call a low-grade glioma so not so much on the aggressive side of the tumor. But there’s a lot to be learned about high-grade glioma from low-grade glioma, because under the microscope low grade-glioma very much looks like high-grade glioma or the glioblastoma tumor.

>> Diego: Dr. Jackson continued to monitor Brenna’s condition, and fortunately after a second surgery her glioma is now in remission.

>> Brenna: After I recovered from that, it's been a really smooth progression of life. I graduated from high school first off, third in my class, which is absolutely hilarious considering I had two brain surgeries. But that was something that I never thought that I would get to do after that initial diagnosis. So that was in 2019. And this past May, just graduated from college with a chemical engineering degree. And I got married, and now I'm living in Johnson City, Tennessee. It's amazing. I am such a success story when it comes to childhood cancer diagnosis. And I am so thankful to all of the nurses at NIH and Dr. Jackson and that team specifically.

>> Diego (narration): But not every glioma patient is as lucky as Brenna. When they're particularly aggressive, these types of cancers can have low survival rates, less than 50% two years after diagnosis even after patients have undergone chemotherapy, radiation, surgical resection and that’s because cancer cells are particularly invasive.

>> Dr. Jackson: These very smart, aggressive brain tumors don't just start to grow and they stay in one spot. They communicate with all these kind of normal brain cells and they tell these normal brain cells, "Sshh, don't tell anybody we're here. Don't try to kill us. We just want to just live and continue to invade into your normal environment." They don't necessarily metastasize, these are primary brain tumors. But what they do is they invade into normal tissue and they're so infiltrative. They look and act like normal cells, originally, but then over time, they start to be a lot more aggressive.

>> Diego (narration): That brings us back to the blood-brain barrier, because these undercover cancer cells are largely protected by the BBB. You might remember, Dr. Jackson talked earlier about how neurosurgeons will excise areas in the brain that light up in white in an MRI scan. The white glow is the result of a chemical dye, called contrast agent, that’s delivered intravenously and helps visualize tumors and evaluate the extent of malignancy. But the thing is, contrast is usually locked out by the blood brain barrier. It can only get through to the core of the tumor because that’s where cancers cells are densely populated and cause so much chaos and disruption that the BBB is compromised.

>> Dr. Jackson: We know that the core of the tumor—the BBB, is open and so the neurosurgeon goes after what we can see on the MRI. However, we know microscopically there are still tumor cells left.

>> Diego (narration): This difference in the permeability of the BBB makes it a problem not just treatment, but for diagnosis as well, since the interlopers remain undetected.

>> Dr. Jackson: They are around where the tumor cell was just taken out and that is where the BBB is closed and not allowing for contrast to get there, will not allow for the chemotherapy to effectively get there. And so, sadly, that's why these patients do so poorly because the tumor cells start to regrow despite radiation and chemo and surgery first being taken to treat that tumor.

>> Diego (narration): So, I asked Dr. Jackson how scientists like her are designing drugs that will have an easier time travelling through the barrier.

>> Dr. Jackson: Yeah. So, there are certain qualities about a drug that allow it to cross the blood-brain barrier. So, if the drug is really rich with fats, we call it hydrophobic because it's very fatty and the brain is very fatty. And so, the brain will let in things that look like it.

There are a lot of great researchers now and in the past that have looked at using drugs that are encapsulated or surrounded by more fats or lipids. And also nanoparticles. So, the size of the drug really makes an impact of how much can get across the BBB. So, if you have a smaller sized drug, so less than 600 Daltons, so that's kind of our sizing of things.

>> Diego (narration): For reference, the mass of a water molecule is about 18 Daltons. Meaning a molecule can’t be larger than 30 or so water molecules to cross the barrier. To put that in perspective, there are over 1.5 sextillion molecules in a drop of water, that’s 1.5 followed by 21 zeros, or a billion trillion.

>> Dr. Jackson: So 400 to 600 Dalton, we can get into the brain as long as it's lipid-filled and not charged that is getting across. But if you're larger than 600 Dalton, that's not getting across. So, there's just various qualities that these drugs have to have in order to allow them—allow the bouncer to let them be into this cool club of the brain.

So, when you think of an ideal drug that can get across the BBB, it's small, it's fat, it can move through and not have another bouncer that are called the efflux transporters. These are the certain proteins that even though the drug can get in, these transporters can push it right on back out. So, you also don't want to have a drug that's an active agent or a substrate of these type of proteins that will push it right on back out even if it does get into the brain.

>> Diego (interview): Wow. That's a lot of levels to get through.

>> Dr. Jackson: A lot of bouncers.

>> Diego (interview): It's very complicated.

>> Dr. Jackson: A lot of regulation, yes.

>> Diego (interview): So have found any contenders that check off all the boxes? Or are there ways you’re changing chemotherapy drugs so they can pass through the BBB and get where they need to go?

>> Dr. Jackson: So, I can talk to you about a previous study where we went from the bench to the bedside back to the bench. So this is a neat exploration where we use a drug that is actually specifically used in a heart or cardiac setting. So, we use the drug called regadenoson. Regadenoson is a cardiac-stress drug where if you were to go to your doc and say, "Doc, I'm having some chest pains," the doc would say, "OK, I need you to walk on a treadmill and we'll see if you start to show that you have some blockage around the vessels in the heart." Well, if, for some reason, you were unable to walk on that treadmill, you would get this drug called regadenoson and it does just the same thing. It makes your heart beat really fast, it makes it seem as if you just walked on a treadmill. And then your physician is able to see whether or not there's a blockage around the heart. Well, a good 26, 30% of patients who received this regadenoson medicine also experienced headaches. And the headaches were thought to be because of the vasodilation or the increased enlargement of the vessels around the heart. You also see that vasodilation in the brain of these patients. Well, there's a group out of Cornell that said, "Hmm, there's vasodilation in the brain, there's headaches,” maybe that's causing some increased BBB drug delivery. And so, they were able to show that they could increase the BBB drug delivery of this large drug that -- like a 70 kilodalton. So, if you can recall, I said 400 to 600 Dalton is what gets into the brain but they show that if they get this cardiac stress drug, they could give a 70 kilodalton agent. And so, I said, "Well, I don't really care about the 70 kilodalton but what if I can get more chemotherapy and the chemotherapy that we were interested in, that's the standard of care, chemotherapy for adults with glioblastoma or high-grade glioma is called temozolomide.

So, we looked at rats, gave them temozolomide, gave them regadenoson, and found that we could see a good 60, 70% increase in the amount of temozolomide that got into the brain of these rats. And we said, "That's cool. What if we could see it in human beings who had these ugly, aggressive glioblastoma tumors?" And so, we opened the trial where we looked at about five patients, we gave them regadenoson, we gave them temozolomide after they had had a surgical resection of the tumor. And then, we used this cool catheter that got placed by neurosurgeons to measure the drug concentration over time, how much of the temozolomide gets in the brain versus how much is in the rest of the body. We wanted to see that 60 to 70% increase that we saw with the rats in these human beings who had glioblastoma. Unfortunately, only two out of the five patients showed an increase and it was more of a 40% increase and not that 60 to 70 that we saw in the rats. So, then, that led us to say, "Well, why only two out of five?" Interesting, those two that did have the increased concentration of temozolomide in the brain that we saw, those two patients did have headaches. So, we said, "Well, maybe, that was a kind of indicator for that medicine working but not working for all five," made us go back into the rodent models and looked to see, "Well, what if we gave regadenoson with rats who had brain tumors and then looked at the BBB?" So, looked at the endothelium, looked at the pericytes, looked at the astrocytes, looked at what was going on in terms of the environment. And we actually found that when you give regadenoson in rats who have brain tumors, you see this level of disruption of the endothelial cells, so they're not touching or they're not kissing, yet when you gave repeat dosing of regadenoson with temozolomide, we could not see prolong survival.

So, that was kind of a whirlwind of a good six years where we looked at bench to bedside back to bench and really understand how this one drug works on the brain and interesting enough, it was a cardiac or heart-stress drug but allowed us to be able to say, "What other agents are out there, either FDA approved or not FDA approved, that have an impact on the brain and could actually cause some level of disruption, either microscopically or macroscopically, to affect drug delivery and drug concentrations?" And so, our lab is looking at other drugs, not regadenoson any further because we've kind of deaded that in the water in the context of the BBB story. But other drugs that can transiently open the BBB to increase drug delivery and to see what effect that has on the endothelium as well as what effect that has on the tumor cells.

I would definitely just like to put out a shameless plug. I have a open trial for young-adult patients where we really look at how much drug gets across in the context of these fully aggressive tumors that are in the cortex of the brain but also what we call the midline location of the brain. And so, I am asking for any patients that have these really aggressive type tumors and that are in this age range of 18 to 39 to really think about coming to the NIH for evaluation and being a part of the study so that we can really think about more drug delivery and drug permeability and really enhance more the personalized aspect of care for these patients.

>> Diego (interview): Well, now, a question that you probably get a lot, is there a danger to keeping the blood-brain barrier open considering that, you know, it also keeps up the bad stuff that we don't want to reach our brain?

>> Dr. Jackson: That's a good question because I have various friends who are infectious doctors and they say, "Well, what if you cause meningitis or encephalitis?" But there's temporal changes that happen with your BBB. So, normally, during the day, our BBB is closed. Interesting, at night, our BBB is a little bit more permeable as we dream, as we actually get rid of toxins within our brain at night time and really have a reset. And then, by the morning time, it starts to close and is kind of back to normal and has good integrity. So, there's more information we need to know and use that information to exploit how we think about providing treatments and care to our patients.

I'd love—now that we're talking about it—I’d love to get some involvement from some other collaborators to really look at the BBB and permeability for our chemotherapy agents. What if we gave therapy for our patients who have these aggressive tumors, in the nighttime or the evening instead of during the day? And maybe our therapies would do a little bit better. Now, each person is different—like I told you, we had five patients and two out of the five respondents. So, this is more and more to think about the personalized medicine aspect.

So, what if there was a way where we could screen patients and say, "We know that the BBB is going to be open more at the nighttime hours, but for this patient specifically, it's really open so let's definitely give her or him or their chemotherapy in the evening where as another person, we need to give it at dusk. So, that would be future technologies and future thinking, but I think it's be awesome to get more personalized in providing therapy as we know more about the blood-brain barrier, a blood-tumor barrier.