As the most aggressive type of brain cancer and one with a very poor survival rate, there is a desperate need for new and improved treatments for glioblastoma. Scientists at Virginia Commonwealth University may have uncovered a powerful new tool in this regard, in the form of an already approved malaria drug found to boost the effectiveness of existing treatments in mice.
Today’s standard of care for glioblastoma uses a mix of radiation therapy and a chemotherapy drug called temozolomide, though the effectiveness is very limited. The five-year survival rate for these patients is less than six percent, with the cancer often exhibiting resistance to these treatments to continue its deadly spread through the brain.
The team’s discovery hinges on a new understanding of the role a certain a genetic element, called Fli-1, plays in driving the glioblastoma’s resistance to therapy. More specifically, the team found Fli-1 regulates the expression of a prominent protein in glioblastoma tumors called heat shock protein B1, or HSPB1, thereby presenting researchers with some new possibilities to intervene and limit their growth.
Using advanced screening techniques to search for drugs that could inhibit Fli-1, the team landed on one already approved to treat malaria called lumefantrine. This process identified lumefantrine as a drug that potentially binds to Fli-1 and deactivates it, halting the expression of genes that drive tumor formation. So the team drew up some experiments to put it to the test.
This began with in vitro studies where glioblastoma cells grown in culture were subjected to radiation and temozolomide, with lumefantrine also thrown into the mix. This proved effective in killing off the cancer cells and suppressing tumor cell growth, including those that would otherwise be resistant to the radiation and temozolomide treatment.
The next round of experiments were conducted in mice brains bearing transplanted human glioblastoma. Again the team found the addition of lumefantrine suppressed the growth of tumor cells, including a therapy-resistant variant.
In addition to the targeting of HSPB1, the team’s work revealed that lumefantrine also has an impact on two other mechanisms employed by growing cancer cells, extracellular matrix (ECM) remodeling, and epithelial-mesenchymal transition. These are also regulated by Fli-1 and were found to be inhibited by lumefantrine.
“These preclinical studies provide a solid rationale for Fli-1/HSPB1 inhibition with lumefantrine as a potential novel approach for glioblastoma management,” says principal investigator Paul B. Fisher. “Identification of drugs like lumefantrine from FDA-approved therapeutic agents and from uncommon sources provides opportunities.”
Interestingly, a heightened expression of Fli-1 has been observed in other types of cancers, including melanoma, ovarian cancer, and breast cancer. For this reason, the researchers are hopeful that lumefantrine could play a role in boosting the effectiveness of other cancer therapies, too.
“The present results may have broader implications than just treating glioblastoma,” Fisher says.
The research was published in the journal Proceedings of the National Academy of Sciences.