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2027 Scholar-Innovator and ADDF-Harrington
Oncology, Cardiovascular
Development of LSS Inhibitors for the Treatment of Glioblastoma
2024 Harrington Scholar-Innovator
There are many facets to drug discovery in cancer, the most important being efficacy (how well a drug stops tumor growth) and toxicity (a drug’s ability to kill cancer cells without causing prohibitive side effects in the patient). When targeting glioblastomas, however, there is an additional challenge: the drug must be able to cross the blood-brain barrier and get into the brain in sufficient quantities to be effective.
Glioblastomas are lethal, non-metastatic tumors that exist exclusively in the brain. As Dr. Nijhawan explains, glioblastoma cells need cholesterol to survive. They must produce their own cholesterol or scavenge it from other cells. Knowing this, Dr. Nijhawan and his colleagues began investigating the mechanism of MM0299, a member of a class of organic compounds that can disrupt cholesterol synthesis.
In essence, MM0299 fights glioblastomas by tricking cancer cells into making a “decoy” cholesterol. It does this by inhibiting lanosterol synthase (LSS), a key enzyme in the cholesterol biosynthesis pathway. When LSS is inhibited, glioblastoma cells behave as if they have plenty of cholesterol, when in reality the cholesterol they need to survive has been diverted into a shunt pathway.
The researchers are now seeking ways to get MM0299 into the brain.
Dr. Nijhawan says he and his colleagues are advancing their research by “letting the science guide them.”
“We saw that there was a molecule that was very potently toxic to glioblastoma cells,” he says. “So, we just followed that molecule to see what it was doing and how it was doing it, and it has led us to this very promising approach.”
"We really don't overlap with traditional pharmaceutical targets and discovery. Our goal is to have an independent approach and Harrington's support has helped us in that effort."