Drug Development

In addition to understanding the causes of cancer, we are also focused on developing small molecules to inhibit aberrant intracellular signaling pathways. Nathanael Gray, PhD is a medicinal chemist who develops novel small molecule inhibitors to signaling pathway components involved in cancer development, notably kinases.  He uses two approaches, preclinical evaluation of known inhibitors and identification of novel inhibitors.  Clinical and preclinical inhibitors of downstream signalling 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.

Currently, researchers from Dr. Gray’s laboratory are profiling intracellular kinase inhibitors; key findings from the effort include several new compounds that inhibit molecules of important targeted signaling pathways.   Both of these inhibitors exhibit high brain: blood plasma drug ratios following oral dosing in mice.  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.

Our investigators are collaborating with Neal Rosen, MD, PhD of Memorial Sloan-Kettering Cancer Center in New York, to expand and enhance the drug discovery portion of the Program.  Using cell lines developed in Dr. Stiles’ laboratory, the PLGA Program supports a postdoctoral fellow and technician to screen these lines for growth inhibitors from Dr. Rosen’s library of small molecules.

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 Charles Stiles, 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.

Selected Publications