Nicolas Nassar, PhD

Biography

The major focus of our laboratory is to understand the regulation and signaling of the GTP-binding protein Ras and other Ras-like GTPases and to find small molecules that inhibit their activity in human cancers. Signaling by Ras-like GTPases is key to almost every cellular process and Ras is among the most mutated genes in human cancer. Despite this, a small molecule specifically targeting Ras activity has yet to enter clinical trials. Our research efforts encompass several methodologies, including protein crystallography, biophysical and biochemical studies, cellular functional assays, and ultimately, high throughput screenings of chemical libraries of small compounds that bind to and modulate GTPase signaling in cell line models.

We have identified several compounds that bind in vitro to Ras, inhibit cell proliferation of lung and other Ras-transformed cell lines, and decrease the activation of Erk-1/-2 and PI3K/AKT. Several ongoing questions stem from this finding: (i) we want to establish the mechanism of action(s) of these compounds. What gene or cellular process do they activate or silence downstream of Ras? Do they bind to Ras in cells and how specific is their binding? (ii) We are in the process of translating our findings to several disease models where Ras is hyperactivated, including both solid tumors such as lung adenocarcinomas, and MPNSTs and leukemias such as B-ALL.

We are also interested in the structure/function relationship of the multidomain protein tyrosine phosphatase (PTP) UBASH3B/Sts-1. Sts-1 was shown to be a target in triple negative breast cancer (TNBC). Our research is geared towards identifying small molecule inhibitors of the phosphatase activity of Sts-1. We have identified one such compound that inhibits the phosphatase activity of Sts-1 in vitro, decreases TNBC cell proliferation and decreases overall levels of phosphorylated proteins. We are currently testing structural analogs of our lead compound to further improve its potency.