In a groundbreaking collaboration between researchers at UConn and Yale, promising work in the treatment of glioblastoma multiforme (GBM), the most common and deadly form of brain cancer, is underway. The research, coming from the laboratories of Raman Bahal at UConn and W. Mark Saltzman at Yale, uses nanoparticles to inhibit expression of miR-21 – an oncogenic (tumor-causing) microRNA that is overexpressed in GBM.
Raman Bahal is assistant professor of Pharmaceutics in the Department of Pharmaceutical Sciences at UConn. W. Mark Saltzman is Goizueta Professor of Biomedical Engineering, Chemical & Environmental Engineering and Physiology at Yale. The two began their collaboration when Bahal was completing his post-doc in the department of therapeutic radiology at Yale, in the lab of Peter M. Glazer, which centered on gene therapy and gene targeting.
In describing their work, Bahal says, “We have active collaboration with Mark at Yale where we are working on targeting GBM by using novel approaches involving nucleic acid chemistry and nanotechnology interface. Our recent study is published in Biomaterials and now we are working together to move this technology to the next level to target this dreadful disease.”
The article, which appears in the May 2019 issue of the journal, is titled “Nanoparticle-mediated intratumoral inhibition of miR-21 for improved survival in glioblastoma.” In this article, the authors highlight a new approach for localized therapy involving the use of two types of miR-21 inhibitors with efficient intracellular delivery resulting in miR-21 suppression, upregulation of the target protein, tumor growth inhibition and apoptosis or death of the target cancer cells.
Currently, surgery is the first course of action when GBM is diagnosed in order to alleviate pressure in the brain and to remove as much of the tumor as possible. However, these tumors consist of star-shaped cells called astrocytes that make their own blood supply and enable them to spread rapidly. Their diffuse structure and finger-like tentacles make it difficult to remove cancerous cells completely, thus necessitating follow-up with chemotherapy and radiation.
Bahal says that one of the biggest problems with current methods for treating GBM is that eventually the tumors develop resistance to chemotherapy and grow back. The miR-21 inhibitors being developed by the UConn-Yale researchers should eliminate that complication.
He says, “Our paper shows that we have successfully completed the proof of concept stage of our research. We have demonstrated that our concept of targeting microRNA involved in GBM with nucleic acid analogues and delivering them to specific areas of the brain is feasible and has definite clinical potential.”
Like all drug development, the research takes time, and the next step is to further advance this technology. Bahal is working with graduate student, Shipra Malik, in his lab at UConn to create the next generation molecules to target GBM using the new delivery system Saltzman’s lab developed. Ultimately, human studies will be required before this promising treatment protocol can be put into practice, but Bahal is optimistic.
“New treatments don’t happen overnight,” he says, “but we have some important things in our favor. One is that the US Food and Drug Administration (USFDA) is aware of the value of personalized medicine and has an expedited approval process for truly novel treatment approaches. Our research meets that parameter because, rather than killing the existing cancer cells or providing primarily symptomatic relief, we are targeting the root cause that plays an important role in the development of GBM. If we can target microRNAs involved in GBM, that would mean long-term survival and would have a major effect on prolonging a patient’s life. We now see people who have had breast cancer or HIV living normal lives, and that’s my hope for the future of people diagnosed with GBM.”
Bahal is further encouraged because of the interdisciplinary effort supporting the fight against GBM. “It’s more than just two universities working together,” he says. “Science is all about individual dedication. Cancer cells are smart and you have to come up with a smarter way of beating them. It’s a battle, actually, and you can’t give up. That’s why we have chemists and cancer biologists and biomedical engineers working together in our team.
“I guess you could say that we’re on a mission and I think the outcome will eventually mean that glioblastoma will fall into the category of a treatable disease.”