Oncology
Development of OST Inhibitors for the Treatment of Lung Cancer
2021 Harrington Scholar-Innovator
A new concept for an oncology drug that has the potential to cure non-small cell lung cancer (NSCLC) is being pursued by Dr. Contessa and his colleagues.
Cell surface receptor tyrosine kinase (RTK) signaling is known to drive NSCLC initiation, proliferation, and tumor cell survival. Its correlation with the development and progression of numerous cancers has made RTKs an attractive therapeutic target. Dr. Contessa and his colleagues have studied RTK glycosylation as a new vulnerability for blocking RTK activity. Their work identified a first-in-class glycosylation inhibitor that targets the oligosaccharyltransferase (OST). This small molecule, called N-linked glycosylation inbibitor-1, causes OST to “skip” discrete cellular glycosylation sites. Using OST inhibitors in mouse models caused NSCLC tumors to regress.
“We looked at mechanisms of tumor cell resistance to other therapies, and they frequently rely on other receptors that require glycans for function,” Dr. Contessa says. “So we just asked the question, ‘Can we block addition of the glycans?' At first the answer was no, because there was no small molecule that had that ability. So we performed high-throughput screening of chemical libraries to identify compounds that do have that effect.”
Dr. Contessa's team, along with New England Discovery Partners, has synthesized hundreds of new analogs of N-linked glycosylation inhibitor analogs to enhance the potency and solubility of this drug class. With the assistance of Harrington Discovery Institute, they hope to expedite the move into clinical trials.
“This pathway has never been investigated in oncology before,” Dr. Contessa says. “We're in a completely new space.”