Mitochondria are not only the powerhouses but also the industrial factories of cells, managing energy resources and manufacturing necessary products. They also serve a vital role in monitoring a cell’s health. When mitochondria are damaged, cells either attempt to repair them or recycle their components to make new mitochondria. But if this fails, disabled mitochondria can trigger the death of the entire cell.
A molecular biologist at Rice University hopes to exploit this cellular suicide program to develop new anticancer therapies by deliberately damaging mitochondria in cancer cells in order to cause their death.
Natalia Kirienko was recruited in 2015 from Massachusetts General Hospital and Harvard Medical School, where she was a postdoctoral researcher, with the help of a First-Time Tenure-Track Award from CPRIT.
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Mitochondria are not only the powerhouses but also the industrial factories of cells, managing energy resources and manufacturing necessary products. They also serve a vital role in monitoring a cell’s health. When mitochondria are damaged, cells either attempt to repair them or recycle their components to make new mitochondria. But if this fails, disabled mitochondria can trigger the death of the entire cell.
A molecular biologist at Rice University hopes to exploit this cellular suicide program to develop new anticancer therapies by deliberately damaging mitochondria in cancer cells in order to cause their death.
Natalia Kirienko was recruited in 2015 from Massachusetts General Hospital and Harvard Medical School, where she was a postdoctoral researcher, with the help of a First-Time Tenure-Track Award from CPRIT.
Any given cell may contain tens to thousands of mitochondria, depending on its needs. The most crucial role of mitochondria in cells is making the packets of energy that power all of the other functions. If mitochondria are slightly damaged for any reason, cellular “repairmen” jump into action to fix them. If the damage is irreparable, the mitochondria are engulfed and the components recycled by the cell. But if many mitochondria are damaged, the repair programs are overwhelmed and the contents of the mitochondria can leak into the cytoplasm of the cell, signaling the cell to destroy itself.
“If we specifically inflict damage on mitochondria in cancer cells we could trigger cell death,” Kirienko says.” This wouldn’t work in all cancers, but can be really productive in cancers that don’t have many mitochondria, but are highly metabolically active.”
In cultured cancer cell lines, Kirienko has found particular success in acute myeloid leukemia. Many cancers have poorly functioning mitochondria due to the accumulation of mutations and degradation of repair mechanisms. So they can’t compensate for the damage that Kirienko’s small molecules inflict on them. When she combines mitochondrial damage with a drug that interferes with glucose metabolism, she says about 80% of the cancer cells die while only 15% of normal cells are affected.
She’s seen promising results in cancer cells isolated from patients, and next she hopes to test drug combinations in mice growing patient-derived tumors. Kirienko is applying for additional funding for this research, which she plans to conduct in collaboration with a physician-scientist, Dr. Marina Konopleva, at The University of Texas MD Anderson Cancer Center.
Kirienko and her colleague plan to test her small molecules together with other anticancer therapeutics to find the strongest combination with the lowest toxicity. Meanwhile, Kirienko continues to screen chemical libraries for additional small molecules that specifically cause mitochondrial damage.
In addition to AML, Kirienko hopes to find other cancers that are sensitive to mitochondrial damage. She has seen promising results with glioblastoma, a deadly brain cancer with few treatment options. She is also trying to see which genetic mutations are most closely associated with sensitivity to mitochondrial damage, which might allow doctors to predict which patients have cancers likely to self-destruct from this type of treatment.
“We’re trying to explore existing therapeutics that are synergistic, identify other small molecules, and find a genetic component where this treatment could be even more strongly augmented,” she says.
CPRIT enabled her to buy some essential equipment and hire personnel, and she has leveraged the grant to apply for additional federal and private funding. So far, she’s received over $2.5 million in additional support, and has applied for another $1 million.
Kirienko received her undergraduate and master’s degrees in biochemistry and biology from Southern Federal University in Russia, and her Ph.D. in molecular biology from the University of Wyoming. She was a postdoctoral research fellow at Mass. General and Harvard Medical beginning in 2010.
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