An already approved cancer drug, talazoparib, has demonstrated enhanced effects against cancer cells in specific patient groups by exploiting genetic variation in cancer cells. The study, conducted by researchers at Uppsala University and published in eBiomedicine, highlights the potential for more individually tailored and effective cancer therapies.
Loss of Heterozygosity
During tumor formation, cancer cells can experience loss of heterozygosity, where only a faulty gene is retained. According to Xiaonan Zhang, researcher at the Department of Immunology, Genetics and Pathology and first author of the study, "In cancer cells it is common that larger or smaller parts the chromosomes are lost. If the faulty gene variant is the one that is retained, the cancer cells will lack the protein that was supposed to be produced from this gene... These differences have the potential to inform the development of treatments that specifically target cancer cells."
CYP2D6 and Talazoparib
The researchers analyzed numerous genes and identified one, CYP2D6, located in a DNA region commonly lost in various cancer types. CYP2D6 encodes an enzyme in the liver. Subsequent testing of different drug compounds on engineered cell models revealed that the effect of the compound was influenced by CYP2D6 activity.
"We analyzed drug compounds that are currently in clinical use or undergoing clinical trials. Among the most promising was a clinically approved drug called talazoparib, which consistently showed a heightened cytotoxic effect against liver cancer cells that lacked a functional CYP2D6 enzyme," says Xiaonan Zhang.
Further Research
The researchers' unpublished data also suggests that talazoparib may exhibit CYP2D6-dependent effects on neuroblastoma and ovarian cancer cells. They plan to further analyze drugs that target enzymes in other organs where enzyme activity levels vary.
Precision Medicine
Tobias Sjöblom, professor at the Department of Immunology, Genetics and Pathology, who led the study, stated, "We believe that by leveraging loss of heterozygosity and natural genetic variations in the cancer cells, we can uncover new treatment options that lead to targeted therapies tailored to each patient's unique genetic profile... By aligning treatments with patients' specific genetic characteristics, more effective therapies can be developed and thereby improve disease."
The study was a collaborative effort with researchers from Switzerland and the Chemical Biology Consortium Sweden (CBCS).
