Targeting Lipid Synthesis Efficacious in Glioblastoma Mouse Models

Glioblastoma is notoriously resistant to conventional therapies, partly because glioblastoma stem-like cells (GSCs) can metabolize multiple nutrients. They convert carbohydrates to fats (de novo lipid synthesis, DNLS), which supports their energy demands and sustains tumor growth and proliferation.

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Massachusetts General Hospital researchers have observed in patient-derived GSCs and mice that YTX-7739, a drug that interferes with DNLS, increased glioblastoma cells' sensitivity to anticancer therapy and delayed tumor growth in mice.

Katharina M. Eyme, MD, Alessandro Sammarco, PhD, a research fellow in the Department of Neurology, Christian E. Badr, PhD, principal investigator of the Badr Lab in the Department, and colleagues published their findings in Science Translational Medicine.

Background

Stearoyl coenzyme A desaturase 1 (SCD) converts saturated fatty acids to monounsaturated fatty acids. In previous work published in Stem Cell Reports, a Mass General team found that intranasal CAY10566, an SCD inhibitor, led to long-term depletion of monounsaturated fatty acids and impaired tumor initiation in mice bearing primary glioblastoma tumors.

However, CAY10566 has a poor ability to penetrate the blood–brain barrier (BBB). Recently, reports in Molecular Neurobiology show that YTX-7739, an SCD inhibitor that's orally available, was able to cross the BBB in rats and monkeys, was safe and had favorable pharmacokinetics. YTX-7739 is currently in phase 1 trials to treat Parkinson's disease.

Efficacy of YTX-7739

In this new study, YTX-7739 triggered lipotoxicity in patient-derived GSCs—when SCD was inhibited, the cells accumulated too many saturated fatty acids. Whether administered as a single agent or in combination with temozolomide, YTX-7739 was also effective in GSCs grafted onto mice, due to both its lipotoxicity and ability to interfere with DNA damage repair.

In most cases, though, YTX-7739 had only a transient effect and failed to eradicate tumors. Combination regimens with radiation, temozolomide, or other agents will probably be necessary.

Genetic Drivers

The researchers used an astrocyte-based model of gliomagenesis to explore what oncogenic signaling makes cells susceptible to DNLS-targeted therapies:

• Vulnerability to YTX-7739 and other pharmacologic inhibitors of lipogenesis was primarily driven by aberrant MEK/ERK signaling and its repression of AMP-activated protein kinase (AMPK)
• Conversely, AMPK activation diminished lipotoxicity, making GSCs resistant to YTX-7739

Toward Development of Novel Therapies

Identifying the genetic drivers of vulnerability to DNLS inhibitors is of major clinical importance. The new understanding that AMPK protects glioblastoma tumors and contributes to lipid metabolism adaptability provides a framework for rationally developing DNLS-targeted therapies.

Furthermore, MEK/ERK and AMPK activity, detected by immunohistochemistry of tumor biopsies, could be predictive biomarkers to guide patient selection. For instance, some widely used drugs, such as salicylates and metformin, are potent activators of AMPK and could interfere with DNLS inhibitors.

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