Treatment for diffuse intrinsic pontine glioma
20 September 2018
Diffuse intrinsic pontine glioma (DIPG) is a lethal, high-grade, paediatric glioma that accounts for up to 85% of all brainstem gliomas and 100-150 new cases are recorded each year in the USA. DIPG is difficult to treat due to the heterogeneity generated from the various mutations associated with the disease, as well as its sensitive location in the brainstem. Chemotherapies have proved ineffective and new treatments are urgently required.
Palbociclib is a novel DIPG treatment that restricts the proliferation of rapidly dividing cancer cells via selective inhibition of cyclin-dependent kinase (CDK) 4 and CDK6. However, implementing it as a monotherapy for DIPG is unfeasible, as CDK4/6 inhibitor resistance is commonplace and palbociclib does not readily cross the blood–brain barrier (BBB) or persist in the central nervous system. To inhibit the growth of DIPG cells, a team from the Functional Neurosurgery Research Group in the Bristol Medical School aimed to use palbociclib in combination with the rapamycin analog temsirolimus, which is known to ameliorate resistance to CDK4/6 inhibitors and inhibit BBB efflux. They tested palbociclib and temsirolimus in three patient-derived DIPG cell lines.
Analyses revealed palbociclib and temsirolimus inhibited CDK4/6 and mammalian target of rapamycin (mTOR) signalling through perturbation of phosphorylation of the retinoblastoma (RB) and mTOR proteins, and demonstrated that palbociclib and temsirolimus inhibited cell proliferation in all three DIPG cell lines, acting synergistically in combination to further restrict cell growth.
Asby DJ et al. (2018). Combined use of CDK4/6 and mTOR inhibitors induce synergistic growth arrest of diffuse intrinsic pontine glioma cells via mutual downregulation of mTORC1 activity. Cancer Management and Research. 10, pp. 3483-3500.