A New Attack on Brain Cancer
Glioblastoma—it’s one of the most deadly forms of cancer. About 10,000 Americans are diagnosed each year with this aggressive brain tumor. Now, there’s a new treatment that may offer hope.
Burhan and Renee Oral know moments like these are precious. Burhan has glioblastoma – an aggressive brain cancer.
“They told me I had three to six months to live,” Burhan told Ivanhoe.
“Never ever, ever give up. That’s what I tell him,” Renee told Ivanhoe.
Five surgeries and 2 ½ years later—Burhan is still here, but his cancer came back a few months ago.
“It’s very much like we are playing chess with the tumor cells. For every drug we give it, the tumor cells could make a move,” Clark Chen, MD, PhD, Vice Chairman of Neurosurgery, University of California, San Diego, told Ivanhoe.
Dr. Clark Chen told Burhan about a clinical trial testing a new, minimally invasive treatment for glioblastoma. First—he makes a small hole in the skull. Using MRI to guide a catheter to the brain, he then injects a virus directly into the tumor, which lights up on scans.
“So, we can actually see in real-time where the virus is as we inject it,” Dr. Chen said.
The patient then takes a powerful anti-fungal drug that goes into every cell in the body. The virus activates the drug, telling it to attack the tumor.
“What we are able to see is that the area where the viruses are injected, the tumor is melting away,” Dr. Chen said.
Since the treatment, scans show no signs of cancer growth and Burhan continues to hope for the best.
The treatment is given as part of a phase one clinical trial. It’s considered a minimally-invasive brain procedure, and patients are discharged one day after having it. Because it’s a targeted approach, Dr. Chen says there are fewer side effects. In fact, he hasn’t observed any unwanted side effects in his patients.
BACKGROUND: Glioblastoma is an aggressive, malignant brain tumor; also known as grow-and-go tumors, they grow very quickly in their original site and they move quickly to new sites in the body. These tumors develop in cerebral hemispheres, but may also appear in other parts of the brain, spinal cord, or brain stem. They stem from glial cells from tissue surrounding the spinal cord and brain. (Source: http://www.braintumor.org/patients-family-friends/about-brain-tumors/tumor-types/glioblastoma-multiforme.html?gclid=CPrK1KHT3boCFUPl7AodewoAbQ)
SYMPTOMS: Symptoms of glioblastoma depend on the location of the tumor, but typical symptoms include: headache, nausea, memory loss, confusion, change in vision, change in speech, change in mood, nerve pain or numbness, and seizures. (Source: http://www.gliadel.com/gbm-treatment/symptoms/)
NEW TREATMENT: Neurosurgeons at the University of California, San Diego School of Medicine are among the first in the world to utilize real-time magnetic resonance imaging (MRI) guidance for delivery of gene therapy as a potential treatment for brain tumors. Using MRI navigational technology, neurosurgeons can inject Toca 511, an investigational gene therapy, directly into a brain malignancy. This new approach offers a way to precisely deliver a therapeutic virus designed to make the tumor susceptible to cancer-killing drugs. “With chemotherapy, just about every human cell is exposed to the drug’s potential side-effects. By using the direct injection approach, we believe we can limit the presence of the active drug to just the brain tumor and nowhere else in the body,” Clark Chen, MD, PhD, chief of stereotactic and radiosurgery and vice-chairman of neurosurgery at UC San Diego Health System, was quoted as saying. “With MRI, we can see the tumor light up in real time during drug infusion. The rest of the brain remains unaffected so the risk of the procedure is minimized.”
Toca 511 is a retrovirus engineered to replicate in cancer cells, like glioblastomas. It produces an enzyme that converts an anti-fungal drug, flucytosine (5-FC), into the anti-cancer drug 5-fluorouracil (5-FU). After the injection of Toca 511, the patients are treated with an investigational extended-release oral formulation of 5-FC called Toca FC. The cancer cells begin to die when 5-FX comes into contact with cells infected with Toca 511. To ensure that the adequate amount of Toca 511 is delivered to the region of the tumor, neurosurgeons use state-of-the art MRI guidance, called ClearPoint, to monitor the delivery and injection processes in real time. It provides visual confirmation that the desired amount of drug is delivered into the tumor and provides physicians the ability to make adjustments to optimize the location of drug delivery. (Source: http://ucsdnews.ucsd.edu/pressrelease/southern_californias_first_real_time_mri_guided_gene_therapy_for_brain_canc)
Clark Chen, MD, PhD, Vice Chairman of Neurosurgery at University of California at San Diego, talks about a new way to treat patients with glioblastoma.
How many glioblastomas do you treat in a day, a week, a year?
Dr. Chen: Glioblastoma is a fairly rare disease. There is an estimated 10,000 cases in the entire U.S. and it’s in large part because of its rarity that it’s considered an orphan disease. We tend to work on diseases that our loved ones are inflicted by and because glioblastoma is such a rare disease, it’s not being worked on as much as the other tumors. On average, at UCSD, we treat somewhere between 150 and 200 tumors of this nature per year.
So, glioblastomas are very hard to treat, right?
Dr. Chen: They are extremely difficult to treat. It is one of the most resistant tumors to radiation and chemotherapy. Many, very prominent public figures have been inflicted with this disease and have gotten really the best possible care and without fail, all of them died within a year of diagnosis; people like Senator Kennedy, Siskel of Siskel and Ebert, Johnny Cochran of the O.J. Simpson trial.
Is that because glioblastoma has what I call fingers? It just grows through the brain?
Dr. Chen: That’s exactly right. The tumor is extremely infiltrative. What you are referring to are, are finger-like projections that send out little colonies, little colonies of tumor, apart from where we can see them. So, it is very difficult to remove the tumor in its entirety by surgery. Chemotherapy is absolutely warranted. In addition, there is a challenge that’s unique to glioblastomas, which is that there is this barrier that protects our brain, called the blood brain barrier, and normally it protects our brain from the effect of viruses and certain drugs. The problem is when you have this barrier and you have a tumor in there, the tumors are also protected from the drugs. So, when we give a drug to the patient, it’s never clear whether the drug got to the tumor at all.
So, now you have a new way to try to get drugs to that tumor, correct?
Dr. Chen: That’s right. Essentially, what we are leveraging on in this strategy is for the neurosurgeon, there is no blood brain barrier. When we actually go in and remove the tumor, we are right there with the tumor. So, with surgery, we could directly infuse drugs into the tumor so that we make sure that the drug gets into the tumor without the hindrance of the blood brain barrier.
So, before this, with the MRI-guided gene therapy, you couldn’t tell if you were actually getting all of the tumor?
Dr. Chen: That’s exactly right. What we are doing with this MRI-guided technology is we are mixing the drug, in this case, a virus, with a material that lights up. So, wherever the virus is injected, that area lights up. We couldn’t do this with any other reagent, and we can’t do this in any other way.
What kind of virus is it?
Dr. Chen: It’s a virus that is engineered to convert a benign drug into a drug that will kill the tumor. The virus encodes for an enzyme and this enzyme converts an antifungal drug, which is otherwise completely benign. It doesn’t do anything to your body at all, but when the drug touches the virus, the virus converts it into a drug that would then be toxic to the tumor. So the basic idea is, it’s a two-step process. You inject a virus, and the virus into the tumor. The virus is engineered in a way so that they only replicate in the tumors, not in normal cells. After that’s done, you give the patient a drug, this antifungal drug called 5-FC. This drug gets through every single cell in your body, including the brain. However, without contact with the virus, it doesn’t really do anything, so only in the area where the tumors are infected with the virus, that comes in contact with this antifungal drug do you produce an effect that will kill the tumor.
How does the MRI-guided part of this help you do this?
Dr. Chen: The MRI allows us to see the tumor in real time so that we know; when we put a catheter in the brain, the skull is opaque; we don’t know where it is. The MRI allows us to know exactly where the catheter is in real time and the reason that’s important is twofold. First, it avoids the risk of the catheter ripping a blood vessel causing a stroke. So, that makes the surgery safe. The second reason, this is very important, is by virtue of seeing where the catheter is in real time, we’ll know that the area that we deliver the drug is precisely within the tumor.
It lights up the tumor where you can actually see it, correct?
Dr. Chen: Right. The way that’s done is that the virus is mixed with an agent called gadolinium. That agent is bright on MRI.
Does this allow you to track what it’s doing to the tumor?
Dr. Chen: For us to follow what it’s doing to the tumor, we have get MRIs a few months after the procedure, after the patient has gone to therapy. In fact, we had recently gotten several images of patients who are treated and what we are able to see is that the area where the virus is injected, the tumor is melting away.
How many people have you tried this on and are all the results shrinking the tumor?
Dr. Chen: Well, I don’t know of all of the results. I know that in my hands, the patients I have treated have responded very favorably.
Is this drug FDA approved?
Dr. Chen: This is a clinical trial, which means that this drug has been reviewed by the FDA and deemed it to be safe to be delivered in a trial basis to the patients.
Is it a 2-part type of trial where you are testing the drug, but then also the MRI guided part of the delivery system?
Dr. Chen: The MRI-guided part of the surgery has been approved as a medical device. That is, the accuracy has been proven and it has been used extensively in a number of other types of surgery, but not in tumors. We have adapted that technology so that we could use it to deliver drugs specifically to a tumor in a patient.
Do you see this curing these glioblastomas or do you see them buying the patients months, years?
Dr. Chen: Well, I think this technology will be a part of a larger tool set that we have. When we treat tumors, it’s very much like we are playing chess with the tumor cells. For every drug we give it, the tumor cells could make a move; they could adjust in some way. The tumor is like an organism and so we have to have a number of different tools in order for us to be able to cure a cancer. The problem with glioblastoma is that right now, we have two tools: radiation and chemotherapy, none of which works very well. So, the gene therapy concept and this technology allows us to have another tool so that we can make the next move against the tumor. My personal belief is that to cure cancer, you have to have a wide range of options. The same way heart disease requires many different types of drugs.
Is this a more targeted therapy?
Dr. Chen: Absolutely. I think that because the virus replicates only in the tumor, the effect of the drug would only be seen in the tumor. So in principle and in reality, this approach should be safer than chemo and radiation. That being said, I don’t think it’s going to completely replace chemo and radiation. Once again, I think that we have to have different tools in our armamentarium for us to make a meaningful impact on our patients with brain tumors.
Have you seen any side effects from this drug? And what’s the name of this drug?
Dr. Chen: The drug is called 5-FC. It’s converted by the virus, by this enzyme into something called 5-FU. The 5-FU is a well-established chemotherapeutic drug. 5-FC is a known antifungal drug. Have I seen any side effects? In my hands and in my patients, the answer is no. With every new investigational agent, we brace ourselves for potential side effects, but to my pleasant surprise, there hasn’t been any so we are quite pleased.
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