Overcoming drug resistance remains a primary goal in cancer treatment. Researchers at Cincinnati Children’s discovered they could overcome it in a mouse model of glioblastoma, a notoriously refractory tumor type. They discovered that inhibiting the enzyme Stearoyl Co-A Desaturase (SCD) reduced the expression of the protein FBJ murine osteosarcoma viral oncogene homolog B (FOSB); tumors were then unable to develop resistance to a SCD inhibitor and the mouse survived longer.
The SCD enzyme plays an important role in tumor lipid metabolism and membrane architecture; it is often up-regulated in cancer cells. Because of this, a number of drugs have been developed targeting SCD. Many glioma cell lines express low levels of SCD compared to normal healthy brain cells. A few, however, evolved along a different path and were highly dependent on SCD for survival.
To study the effects of SCD inhibition, the team treated glioma-bearing mice with temozolomide (TMZ) — a currently used agent against glioblastoma — against SCD inhibition with the agent CAY10566 and TMZ.
While TMZ alone initially produced significant tumor reduction, all of the mice relapsed and 80% had died by 50 days post treatment. In contrast, 80% of mice treated with TMZ/CAY 10566 survived past 50 days.
“CAY10566 and TMZ combination improved survival relative to either drug alone,” the authors write. “We expect that an alternative drug scheduling where TMZ is delivered in multiple cycles may yield even better results.”
This means that although most glioblastomas survive without SCD, those that retain SCD expression are exquisitely sensitive to SCD inhibitors.
The researchers discovered that the FOSB protein plays a central role in regulating SCD levels. Silencing the FOSB protein improved the efficacy of SCD-inhibiting drugs like CAY 10566.
In related studies, the researchers produced similar favorable outcomes when testing the combination therapy to treat melanoma, a severe form of skin cancer.
