New clinical trial for recurrent glioblastoma
Novel anticancer therapy targets cell signaling pathway often dysregulated in brain tumors
Current therapies for glioblastoma are not effective at stopping disease progression – particularly once the brain tumor recurs.
A clinical trial led by the UCSF Brain Tumor Center is now recruiting people with recurrent glioblastoma. This phase I/Ib trial is evaluating RMC-5552 – a drug inhibiting a protein that scientists believe drives tumor growth and resistance.
The mTOR cellular signaling pathway normally regulates cell growth and metabolism through two distinct protein complexes. But many patients with glioblastoma have mutations in proteins that are part of this signaling pathway, which enhance its activity and help the tumor cells survive.
“Being able to specifically target this pathway that is dysregulated in a majority of glioblastoma patients could help address the prognosis of patients with recurrent disease,” said UCSF neuro-oncologist Nicholas Butowski, MD, who is the principal investigator for this phase I trial.
RMC-5552 disrupts this signaling by selectively stopping the mTOR protein from forming the mTOR Complex 1 (mTORC1). Previous classes of mTOR inhibitors did not completely block mTORC1 signaling – mediated by the 4EBP1 protein – from increasing production of other proteins and keeping the tumor cells growing.
Although researchers have developed various mTOR inhibitors in the last decade, few of these drugs have made it to clinical trials for glioblastoma. Funding from the Specialized Programs of Research Excellence (SPORE) grant to the Brain Tumor Center supported the research, led by Butowski and neurology professor William Weiss, MD, PhD, that identified the 4EBP1 protein as a promising target for drug development.
The team’s findings indicate that this new generation of so-called bi-steric mTOR inhibitors, which include RMC-5552, potently block both mTORC1 and 4EBP1 activity. These actions stop tumor growth and kill tumor cells in preclinical models of glioblastoma.
Some preliminary evidence indicates that inhibiting mTOR signaling in glioblastoma cells and tumor xenografts may increase sensitivity to the effects of temozolomide and radiation.
Butowski says these studies suggest the drug could also be amenable to be used in combination with the current standard of care therapy in further clinical trials.