Steven S. Rosenfeld, M.D., Ph.D., is a neurologist whose research focuses on identifying novel and effective therapeutics to treat glioblastoma, the most common and lethal of primary brain tumors. In particular, Dr. Rosenfeld's laboratory team is developing treatment approaches that target molecular motors — intracellular enzymes that move cells, driving tumor cell invasion, and chromosomes, driving tumor cell proliferation. Dr. Rosenfeld's team has shown that targeting molecular motors with genetic and pharmacologic means in animal models of glioblastoma is well tolerated and effective in prolonging survival, key first steps in getting new therapies into the clinic. Dr. Rosenfeld is also examining how to improve on this therapeutic approach by combining it with established anticancer drugs and radiation therapy.
- Molecular motor targeting. Dr. Rosenfeld is focusing on small molecule inhibitory strategies that block glioblastoma invasion and proliferation by targeting mitotic kinesins and myosins that are involved in driving tumor cell invasion and proliferation. He is also interested in understanding how tumor resistance to these therapies develops, and his team has uncovered a novel mechanism for this process that can be reversed with drugs already approved by the U.S. Food and Drug Administration (FDA). He and his team are now exploring how to most effectively combine a molecular motor therapeutic with a drug regimen designed to prevent development of treatment resistance in animal models of glioblastoma.
- Enhancing the efficacy of other cytoskeletal targeting therapies. Microtubule-targeting drugs have been successful in treating a variety of other cancers but disappointing for glioblastoma. Dr. Rosenfeld's team has determined that this is partly due to the fact that glioblastomas can enhance the stability of their microtubules through a single post-translational modification — acetylation of a single lysine residue in the alpha tubulin subunit. Dr. Rosenfeld has shown that glioblastoma cells with high levels of tubulin acetylation are resistant to the effects of FDA-approved microtubule depolymerizing drugs, including vinca alkaloids. He has also shown that suppressing the one enzyme that acetylates alpha tubulin — tubulin acetyl transferase (ATAT1) — restores sensitivity to these drugs. His lab is now exploring how to take advantage of this ATAT1 dependency for a therapeutic effect.
- Approaching glioblastoma heterogeneity from a therapeutic perspective. The intratumoral heterogeneity that characterizes glioblastoma also provides an obstacle to effectiveness for a second set of tumor therapeutics — kinase inhibitors. Dr. Rosenfeld's lab has shown that glioblastomas consist of subpopulations of tumor cells that depend on different oncogenic kinases, with each subpopulation sensitive to a limited set of kinase inhibitors. Consequently, his lab has found that treatment with one such inhibitor simply allows the other, insensitive tumor cell subpopulations to continue to grow. Dr. Rosenfeld's lab is now studying genetically engineered mouse models of glioblastoma and using a novel ex vivo platform for studying freshly resected human glioblastomas to see how to target each subpopulation in a glioblastoma simultaneously, using kinase inhibitors in combinations or dosing schemes that are individualized to each specific tumor.
Significance to patient care
The general focus of Dr. Rosenfeld's research laboratory is to develop novel therapeutics to treat glioblastoma. This disease remains a death sentence for patients despite more than 50 years of intensive clinical and basic research on glioblastoma. Novel approaches are desperately needed to make an impact on this disease, particularly approaches that are guided by the unique biology of glioblastoma. Dr. Rosenfeld's goal is to introduce the novel therapeutic approaches his lab is developing into phase 0, phase 1 and phase 2 clinical trials for patients.