Researchers from the University of Helsinki have discovered that the cells of glioblastoma, a lethal brain cancer, often depend on fatty acid-binding protein 3 (FABP3), also known as MDGI, for survival. Informed consent was obtained from all participants, whose samples contributed to the study. Using banked samples, the scientists demonstrated that antihistamines can exploit glioblastoma dependence on FABP3, causing the cancer cells to self-destruct. The work was recently published open-access in the journal EMBO Molecular Medicine.
The study built upon the finding that the expression of FABP3 is associated with a poorer prognosis for the patient. This may be causally related to an increased ability of the tumor cells to invade tissues and organs, metastasize, when the protein is abundantly present in the cancer cells.
The present study investigated inhibiting the function or preventing the presence of FABP3 in the tumor cells. They found that this caused lysosomal membrane instability. Tumors generate many damaged or misfolded proteins, which need to be cleared to prevent cell death, and also to recycle the energy trapped within them. Lysosomes are the cleaning organelles of the cell that perform this function. Their disruption in glioblastoma cells resulted in the leakage of acidic and proteolytic enzymes, initiating cancer cell death.
Many drugs, that may kill isolated cancer tissue in the lab, are often blocked from entering the brain, when in the body, by the blood-brain barrier (BBB). Professor Pirjo Laakkonen’s research group used a lysosome disruptor, the antihistamine known as clemastine, which can readily cross the BBB and access the brain in people.
In cell cultures, clemastine preferentially killed glioblastoma cells at concentrations which had no significant effect on healthy cells, demonstrating a synthetic lethal mechanism. In mouse models, clemastine reduced metastasis and increased the survival time of the animals. In one animal model background the administration of clemastine was currative. The work is preclinical, with studies in people (clinical trials), yet to be conducted.
“Our research demonstrates that MDGI [FABP3] is a key factor regulating and maintaining the structure of the lysosomal membrane. This is the first gene found to regulate the stability of the membrane.”
“Our findings demonstrate that antihistamines and other drugs that increase the permeability of the lysosomal membrane can be considered as an enhancing therapy for patients with glioblastoma alongside established treatments.” – Professor Pirjo Laakkonen, Department of Physiology, University of Helsinki