Credit: PNAS
Researchers have discovered that a solvent used as a drug delivery vehicle has antimyeloma properties.
The team found that N-methyl-2-pyrrolidone (NMP)—long-regarded a basic, stable, and inactive solvent—affects the growth and survival of multiple myeloma (MM) cells and stimulates the immune system to kill these tumors.
Jake Shortt, MBChB, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia, described these findings in Cell Reports.
“[W]e found NMP effectively ‘reprograms’ myeloma cells by targeting a class of gene-regulating proteins,” Dr Shortt said. “This reprogramming reawakens thousands of genes that have been silenced in the cancer cells, immediately stopping the myeloma cells from growing, while activating the immune system to respond to the cancer.”
The researchers were surprised by this discovery because they had been using NMP as a vehicle to deliver drugs in mouse models of MM.
“In a routine experiment in 2010, Dr Shortt noticed our preclinical models of myeloma were responding to the control dose of NMP, which was surprising, as this control dose contained none of the novel cancer agents we were actually testing,” said study author Ricky Johnstone, PhD, also of the Peter MacCallum Cancer Centre.
Specifically, the researchers were using NMP as a drug delivery vehicle in mice transplanted with Vk*MYC MM tumors. And they consistently observed antitumor activity in vehicle-only control mice.
The team saw responses to NMP in mice transplanted with multiple, independently derived myelomas; namely, delayed paraprotein progression and improved survival in aggressive clones and sustained regressions in more indolent disease.
Further investigation revealed that NMP is an acetylated lysine mimetic and bromodomain ligand. And NMP shares molecular targets with lenalidomide, including cMYC and IRF4.
Unlike lenalidomide, NMP showed CRBN-independent activity. NMP induced similar growth arrest in CRBN-knockdown MM cells and lenalidomide-resistant MM cells.
Based on these findings, the researchers are planning a phase 1 trial of NMP, which is due to start later this year. The team noted that, because safe levels of NMP in humans are already well-established, the study is in the advanced planning stage.
“We’re at an advantage with this trial because we can immediately start at dosage levels within those recommended under occupational health and safety guidelines,” said David Ritchie, MBChB, PhD, a professor at the Peter MacCallum Cancer Centre and chief investigator of the phase 1 trial.
“It is extremely exciting to have this new insight into NMP, which is comparatively cost-effective and plentiful, compared to novel treatments developed by pharmaceutical companies, and hopefully holds promise for new or improved treatments in other cancer types.”
