“SPARK really taught me how to execute my research based on a budget, gave me freedom to choose my line of research, and helped me build overall leadership skills that will be necessary as an independent faculty member.”
2024 Tullie and Rickey Families Spark Awards Winner
Isaac López-Moyado, Ph.D.
Can we take advantage of a vulnerability in cancer cells to preferentially kill them?
Funded: January 2024
Funded by: The generosity of LJI Board Director Tom Tullie and the Tullie Family
Cancer cells accumulate more RNA-DNA hybrids than normal cells. My SPARK project explores whether scientists can actually increase these hybrids to kill cancer cells. Cancer cells form RNA-DNA hybrids during gene expression. Normally, a cell’s RNase H enzymes step in to prevent hybrid buildup. I aim to block these enzymes and force cancer cells to accumulate RNA-DNA hybrids.
I began by using bone marrow cells from a mouse model of acute myeloid leukemia, and I found higher levels of RNA-DNA hybrids in these cancer cells. I then used CRISPR gene-editing techniques to delete RNase H genes and increased these hybrids. I found that this change caused the cancer cells to stop growing within six days.
My analysis showed that cancer cells without RNase H enzymes showed more DNA breaks, indicating that RNA-DNA hybrids cause harmful DNA damage—which spells trouble for a cancer cell. Mapping these breaks revealed they occurred at genomic enhancers, which regulate gene expression. Going forward, I am testing two drugs that inhibit RNase H enzymes on cancer cells and in mice with leukemia. This approach could lead to new cancer treatments that take advantage of RNA-DNA hybrids to kill cancer cells.
What was the goal of your SPARK project?
We desperately need more therapeutic options for treating bone marrow cancers and blood cancers, such as acute myeloid leukemia. My goal was to see if I could turn a feature of cancer cells into a fatal flaw. Cancer cells form RNA-DNA hybrids during gene expression. Normally, a cell’s RNase H enzymes step in to prevent hybrid buildup. I aimed to block these enzymes and force cancer cells to accumulate RNA-DNA hybrids. I began by using bone marrow cells from a mouse model of acute myeloid leukemia. I found higher levels of RNA-DNA hybrids in these cancer cells. I then used CRISPR gene-editing techniques to delete RNase H genes and further increased these hybrids, with lethal consequences to cancer cells.
SPARK Project Results
Increasing RNA-DNA hybrids caused cancer cells to stop growing within six days. When I studied why the cells stopped growing, I found that cancer cells without RNase H enzymes showed more DNA breaks. These DNA breaks are a sign that RNA-DNA hybrids are causing DNA damage—which spells trouble for a cancer cell. Mapping these DNA breaks revealed they occurred at sites called “genomic enhancers.” These sites control gene expression. Without normal genomic enhancers, a cell cannot make the proteins it needs to function. The result? Cancer cell death. I discovered that increasing RNA-DNA hybrids in cancer cells even extended survival in a mouse model of acute myeloid leukemia. This discovery gives me hope that future cancer treatments could take advantage of RNA-DNA hybrids to kill cancer cells.
What's next for this project?
We need to study how this approach would work as an actual drug therapy. Going forward, I am working with a mouse model and with cancer cells to test two drugs that inhibit RNase H enzymes. I am interested in examining how these drugs might work in combination with other existing therapeutic approaches.
SPARK funding was fundamental for launching this research direction, and I expect that follow-up research will advance our understanding of RNA-DNA hybrids as a therapeutic vulnerability in many different types of cancer, including solid tumors such as BRCA1-mutant breast cancer.
What’s next for Isaac?
I am currently finishing experiments to get this project ready for publication in a peer-reviewed journal. Additionally, I have applied for funding to continue this work, and I am pleased to announce that I was recently honored with the EvansMDS Young Investigator Award for research into myelodysplastic syndrome, a group of bone marrow cancers. This funding will support me in carrying on this project and establishing my own laboratory in the coming years.
