Novel Nanomedicine Development for Glioblastoma


We spoke with Dr. Priya Kumthekar and Dr. Alexander Stegh about their nucleic acid-based therapeutic development that targets glioblastoma.

Today we are speaking with Alexander Stegh, PhD, an assistant professor of neurology at Northwestern University Feinberg School of Medicine who, along with other colleagues at Northwestern, has developed a novel nucleic acid-based therapeutic that targets glioblastoma and we are also speaking to Priya Kumthekar, MD, an assistant professor of neurology and hematology-oncology also at Northwestern, who is the principle investigator of the trial with this novel agent that is called NU-0129.

-Interviewed by Anna Azvolinsky, PhD

OncoTherapy Network: Dr. Kumthekar, let’s start with you. Could you tell us briefly about the types of treatments currently used for patients with glioblastoma as well as the need for new therapies?

Dr. Kumthekar: There are only a handful of FDA [US Food and Drug Administration]-approved upfront therapies for glioblastoma as and there is no single standard of care for recurrent disease which is the population being studied in our clinical trial. The typical upfront therapy newly diagnosed glioblastoma or GBM involve surgery, chemotherapy, and radiation. And at recurrent disease, there are only a few FDA-approved therapeutics and there is no single standard of care. And despite treatment for these patients, and with treatment, the survival from diagnosis for these patients on average is about a year and a half, so there is definitely a need for improvement in the therapies that we offer. And there is also a need for new therapies.

There are a lot of challenges for treating brain tumors, particularly glioblastoma. One of those challenges Dr. Stegh and other colleagues worked to overcome is the blood-brain barrier. This is a physical barrier that is usually a protective mechanism for us that can help from different toxins from getting into the brain. But what it also can do is to prevent certain therapies from getting into the brain, so there is a need for therapies that are not only effective, but that effectively can get to the brain tumor.

OncoTherapy Network: Dr. Stegh, can you tell us about NU-0129, what is the drug, how does it work, and what does it target?

Dr. Stegh: NU-0129 is in essence a novel nanomedicine. We refer to this class of nanomedicines as spherical nucleic acids or SNAs. In essence we are looking at a gold nanoparticle core that we can use as a scaffold and to this gold nanoparticles small interfering RNAs and these small interfering RNAs (siRNAs), once they are inside the cell, have the ability to regulate gene expression. What they can do is they can bind to endogenous messenger RNAs and can recruit the help of many different proteins and once there is a complex that is assembled, that leads to the cleavage and inactivation of this messenger RNA.

What we have is an individualized medicine at hand that really allows us to target genes that we think are critically important for the progression of a disease and in our case, for the progression of glioblastoma multiforme. And NU-0129 specifically is an SNA that uses siRNAs that are specific for an oncogene that we have identified a while back and this oncogene is called BCL2L12, and we think that BCL2L12 is important for GBM progression in that it can regulate the susceptibility of cancer cells towards therapy and that it can regulate the growth of tumors. We think that by taking out BCL2L12, that by suppressing the expression of BCL2L12, we can slow down tumor progression and we can increase susceptibility of tumors towards therapies and in particular, standard of care therapies.

OncoTherapy Network: Dr. Stegh, what do we know about the potential activity of this drug from preclinical testing?

Dr. Stegh: When we injected these SNAs specific for BCL2L12 into tumor-bearing mice, we saw that number one, and Priya alluded to this, that these SNAs can actually cross the blood-brain tumor barrier and can actually accumulate within intracranial tumor sites. And once they are in the brain, they have the ability to infiltrate tumor tissue and what we found is that this very high level of tumor infiltration resulted in a significant reduction of tumor progression. The tumors were four to five times smaller in animals that were treated with BCL2L12-targeting SNAs with NU-0219, and we also saw that this reduction and slowing down of progression resulted in a significant increase in animal subjects that are viable so we see an increase in survival by approximately 20%.

OncoTherapy Network: Dr. Kumthekar, how is NU-0129 now being tested in patients? Can you tell us about the glioblastoma clinical trial?

Dr. Kumthekar: Right now NU-0129 is being used in the recurrence setting, for those patients who have gone through first-line treatment and have had their tumors come back. These are patients who have planned surgery for their recurrent tumor, they are given the drug intravenously the day prior to their surgery, and then a day later they are undergoing surgery. We are taking out the tumor and essentially looking for the presence of the compound, NU-0129, within the tumor tissue and seeing how much is actually getting to the tumor, confirming that it is in fact crossing the blood-brain and blood-tumor barrier. In that same period we are also drawing blood and checking serum levels of the presence of drug as well and looking at the pharmacokinetics of the drug.

The other important thing that we are looking at in this study, and like all early-stage studies, safety is of course of utmost importance to us. We are looking to see if patients have any side effects, any issues with tolerability because of course quality of life for our patients during whichever treatment they are going to receive is very important to us. Essentially, we are looking that the drug gets to the right place and that patients are tolerating it. 

OncoTherapy Network: Is there anything else to highlight about this novel therapeutic agent or glioblastoma in general?

Dr. Stegh: One of the critical challenges is to have drugs available that are able to cross the blood-brain, blood-tumor barrier and with SNAs, you really have a novel class of drug that can regulate gene expression and has this enormous ability to actually infiltrate intracranial tumor sites. That is really a very exciting activity for us and where we felt that it’s really worthwhile evaluating this activity not just in rodent models, but also in human beings.

Dr. Kumthekar: We are planning on accruing a total of six to eight patients on this study and our first patient is planned to be treated today, but we are still open for patients to join. If there are potential patients, you can go to to find out more about the trial and how you can potentially get a patient on the trial.

OncoTherapy Network: Thank you both for joining us today.

Dr. Stegh: Thank you for having us.

Dr. Kumthekar: Thanks.