Our understanding of the causes of cancer informs our efforts to develop effective therapies. Mutations of the BRAF gene that result in an aberrant KIAA1549-BRAF fusion protein and subsequent dysregulation of the RAS/RAF/MEK signaling pathway occur in a large number of pediatric low-grade gliomas. This pathway is therefore a good candidate pathway for therapeutic targeting. There are currently numerous clinical trials for many cancers that examine the effectiveness of small molecule inhibitors of the MEK kinases. Some MEK kinase inhibitors work better than others, but it is not clear why. Michael Eck, MD, PhD uses structural biology approaches to examine the physical interactions between MEK inhibitors and MEK kinases to determine what physical features affect bioactivity. This will help us design better candidate inhibitors.
Nathanael Gray, PhD is a medicinal chemist who develops novel small molecule inhibitors to signaling pathway components involved in cancer development, notably protein kinases. Clinical and preclinical inhibitors of downstream signaling pathways of BRAF are evaluated for their potential to be ‘re-purposed’ as targeted PLGA therapy according to a flowchart of in vitro and in vivo assays. In addition, his group is using medicinal chemistry techniques and high-throughput screening to improve potency and in vivo pharmacokinetic parameters of novel kinase inhibitors for cancers that are BRAF inhibitor resistant.
In parallel work, Sara Buhrlage, PhD is spearheading an approach to circumvent the problem of drug resistance that frequently develops with prolonged drug treatments. While inhibited by drugs, oncogenic proteins often remain in cells and can contribute to additional cellular processes underlying resistance. An approach to circumvent this problem involves the selective degradation of oncogenic proteins. Ubiquitin mediated degradation is a fundamental cellular process. Designated proteins are “tagged” by ubiquitin ligases and consequently recognized and degraded by cellular proteolytic machinery. In opposition, deubiquitylating (DUB) enzymes remove ubiquitin tags countermanding degradation. Dr. Buhrlage’s lab is developing ways to manipulate this cellular system to selectively remove oncogenic drivers in transformed cells.
In addition to drug development, it is also important to find out if the small molecules can pass through the blood:brain barrier (BBB). The BBB acts like a physiological wall to protect the central nervous system from toxins and pathogens, but also impedes drugs designed to treat brain disease. Using a new methodology of matrix assisted laser desorption ionization mass spectrometry imaging (MALDI MSI), Nathalie Agar, PhD, is able to visualize drug penetration in brain blood vessels to build a temporal/spatial map of multiple drug treatments without using radiolabeling or cerebrospinal fluid sampling.
Once drug candidates have been discovered, they are tested at both the in vitro and in vivo level by researchers from the laboratory of Roz Segal, MD, PhD. Specifically, investigators are looking for a drug to inhibit the growth of tumors in mice, and have been able to screen sixteen different compounds this past year alone. Further testing on each candidate is then done in collaboration with Nathalie Agar, PhD to determine brain penetrance and possible candidacy for inclusion in our own investigator-initiated clinical trials.