Empowered Patient Podcast Focusing on Synthetic Lethality and Targeting the DNA Damage Response Pathway to Kill Cancer Cells with Oren Gilad Aprea Therapeutics
Oren Gilad, President and CEO of Aprea Therapeutics, focused on the DNA damage response pathway, specifically targeting the ATR protein. ATR is a master regulator of DNA replication and is hyperactive in cancer cells, making it a potential Achilles heel for cancer therapy. By inhibiting ATR, cancer cells can be selectively targeted, while normal cells can tolerate lower levels of ATR activity. Synthetic lethality is applied when two genetic mutations are combined, leading to cell death, specifically in cancer cells. Aprea is conducting clinical trials for their targeted treatments, focusing on solid tumors with defined genetic mutations.
Oren explains, "DDR, the DNA damage response pathway, is the broader terminology for the regulation of DNA synthesis. In order for cancer to grow, cells have to duplicate. In order for them to duplicate, they have to replicate their DNA. So what happens is that cancer cells get into this DNA replication phase very early and prematurely, causing a single-strand DNA to be exposed which then activates the ATR pathway, where in normal cells, this pathway is very tightly regulated. The normal cell is not going to enter this phase and start DNA replication before the environment is ready because it’s a very fragile phase of the cell cycle."
"Double-strand DNA is a very stable molecule. It is found in mummies, it survives heat, and it survives freezing. When a double-strand DNA molecule is opened, the exposed single-strand DNA can easily break. That’s where ATR comes into play, it protects and responds to single-strand formation. A cancer cell is hyper-sensitive to ATR inhibition, which we identify as the Achilles heel of cancer. Our work showed that normal cells can live with a reduced level of the ATR activity, so it makes it a good target for cancer therapy."
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