Janina Baranowska-Kortylewicz, PhD, is a professor in the Department of Pharmaceutical Sciences. She has conducted translational and clinical research at UNMC since arriving here from Harvard University in the 1990s. She has used her expertise in synthetic chemistry and radiochemistry to facilitate many investigations into cancer therapy with novel radioactive molecules. She has prepared radiolabeled experimental drugs (antibodies and small molecules) for over 400 patients in nearly 40 trials. Her current projects with collaborators in Pediatric Hematology/Oncology are exploring a new class of radioactive compounds that can deliver radiation directly to the nuclei of neuroblastoma tumor cells, minimizing damage to healthy cells and tissues.
SPECIAL CONCERNS FOR PEDIATRIC CANCER THERAPY
Dr. Baranowska-Kortylewicz points out important facts to consider in designing cancer therapies for pediatrics. Twenty percent of children and adolescents diagnosed with cancer die from their disease despite intensive, multi-modality treatments , which shows there is much room for improved efficacy. Among childhood cancer survivors, about 95% suffer at least one chronic health condition by age 45 , showing there is also much room for improvement in safety. Children’s developing bodies make them especially vulnerable to long-term toxicities. Furthermore, technological interventions that would modify transcriptional pathways or epigenetic functions have the potential to disturb every cell in a child’s body – with potential consequences that are very difficult to predict.
“When we work on drug design, for me the guiding principle is ‘minimize the long term morbidities.’ So if we can make a drug that can be less toxic, can be administered in small doses more than once, rather than mega-doses, and allows us to monitor the tumor responses. If you see with imaging that the tumor is coming back, you give another small dose. It is somewhat analogous to insulin for diabetics. If there is a problem, you treat it, and you treat it with a drug that, at the end, doesn’t produce those co-morbidities.”
This concept of pairing a highly targeted therapy with an image-guided diagnostic test that monitors the tumor’s response to treatment is an example of a new field called “cancer theranostics.” Dr. Baranowska-Kortylewicz’s research aims to design and test radioactively tagged molecules that furnish therapeutic and diagnostic tools for a safe and effective pediatric cancer intervention. Her team’s recent work takes the sophistication of theranostics a step further with a “dual targeting” strategy that further ensures the radioactive medicine won’t leak out of the cancerous cells.
DUAL TARGETING STRATEGY
One theranostic drug already has a track record of use in pediatric cancer patients: meta-[131I] iodobenzylguanidine (MIBG), a radioactive molecule that resembles the neurotransmitter norepinephrine. Why is this structure relevant? Since neuroblastoma tumor cells express a high level of the norepinephrine transporter (NET), they soak up MIBG. Then the radioactive energy brought by the radioactive 131I iodine atom (called a “radionuclide”) kills the tumor cells. However, tumor remission brought about by MIBG treatment turns out to be short-lived. One specific drawback: MIBG is poorly retained in the neuroblastoma cells. This reduces the cumulative radioactive dose received by the tumor and allows resistance to build.
Dr. Baranowska-Kortylewicz and colleagues have designed a series of theranostic guanidine compounds with the same backbone structure as MIBG, so they still enter neuroblastoma cells through NET. Then, inside the cell, each molecule is cleaved, producing a thymidine analogue with two important characteristics:
- It incorporates into replicating cells’ DNA, ensuring radioactivity will not leak out. (Uptake through NET is the initial drug delivery target; retention in the DNA provides the “dual target”.)
- The radionuclide is 125I, which has different properties than the 131I found in MIBG. As summed up by Dr. Baranowska-Kortylewicz, this radionuclide goes directly to the tumor’s nucleus, where it “shatters” the DNA, yet within such a small sphere of energy deposition that nearby cells are not affected and the side effects are kept to a minimum.
Finally, it is important that the compounds are stable enough in human serum to arrive at a patient’s neuroblastoma cells in the first place. One of the new compounds has a half-life of 2.3 hours in human serum, which is suitable for diagnostic imaging, but rather short for effective therapeutic delivery. One more creative structural modification in the lab – at the inspiration of Janina’s husband and recently retired collaborator, Paul Kortylewicz – produced a new version with a half-life of 7.5 hours.
Dr. Baranowska-Kortylewicz explains, “So we now have an ideal pairing for theranostic approaches: a drug that shows shorter half-life for imaging and a drug with a longer half-life for therapy. That’s what’s so nice about this approach. You only want to treat a child who has a neuroblastoma overexpressing NET. So, you give them a small dose of the first drug to get an image to make sure that the tumor takes it up. If you can figure that out, then on the basis of the imaging you can calculate the precise dose of that second drug that you need to give to deliver therapeutic doses.”
She and her team hope to be able to treat children with the candidate drug at 10-fold lower doses than the doses currently required for the older drug, MIBG. With successful pre-clinical experiments in mice already complete, they will submit the IND application to the US FDA and seek to begin human Phase I trials with these novel theranostic agents in the near future.
CAREER STEPPING STONES
Dr. Baranowska-Kortylewicz earned her PhD at the University of Kentucky, while designing platinum-based chemotherapy drugs that insert into the replicating DNA in cancerous cells, damage the DNA, and cause the cells to die.
Next, in 1986, she joined a radiation biology lab at Harvard Medical School, where she spearheaded research to develop therapeutics based on radioactive molecules. Dr. Baranowska-Kortylewicz reflects, “It was a wonderful experience. I loved the challenges. I loved the fact that we were collaborating with nuclear medicine. That’s when I started finally working with a lot of nuclear medicine people and oncologists. That was where we for the first time administered a therapeutic radioactive drug to a patient with glioblastoma.”
After 7 years at Harvard, in search of a faculty position, Dr. Baranowska-Kortylewicz was approached by Margaret Tempero, MD, David Colcher, PhD, and the late Glenn Dalrymple, MD, who were developing a radioimmunotherapy program at UNMC. Dr. Baranowska-Kortylewicz explains, “They needed someone with my set of skills, so Dr. Dalrymple invited me to join the faculty at UNMC.
“Dr. Dalrymple was probably the best educator I ever had. He didn’t deny a PhD investigator access to the clinic. When I was bringing the doses to the patient, initially there was always a reluctance to have a non-clinician in the room. But he put me on all of his IRB protocols, so I was able to not only be the two hands that made the drug, but I was able to bring it to the patient. The patient was able to ask me questions: ‘So how does this work? Why did you do it this way?’ And the whole team was incredible – it was the best experience you can imagine.”
In those earlier years at UNMC, Dr. Baranowska-Kortylewicz worked exclusively on adult oncology projects, ranging from pancreatic to prostate cancer. Now, most of her clinical research is in collaboration with Don Coulter, MD, in Pediatric Hematology/Oncology. Dr. Baranowska-Kortylewicz remarks, “I met Dr. Coulter and when we started talking I realized that this dual targeting approach is probably even better suited for pediatric patients than for anybody else.”
- Robinson LL and Hudson MM. Survivors of childhood and adolescent cancer: life-long risks and responsibilities. Nature Reviews Cancer. 2014 Jan;14(1):61-70.
by Matthew Sandbulte, CHRI Grant & Scientific Writer | March 11, 2020