Millions with cancer possess DNA markers that may allow us to transform treatment outcomes and save lives with DDR targeted therapeutics.
DDR pathways help minimize damage to DNA under conditions of cellular stress, including the stress caused by out-of-control proliferation. As such, cancer cells rely on DDR pathways to thrive and grow. In addition, when a particular DDR pathway is rendered dysfunctional during cancer initiation or progression, this loss creates an even greater reliance on compensatory DDR pathways for cancer cell survival. Cancer cells rely on DDR pathways to:
Aprea’s approach is to inhibit DDR pathways that cancer cells specifically rely upon to survive. This strategy involves targeting DDR pathway proteins, like WEE1 and ATR, which normally deal with the problems generated by rapid cell proliferation and mutation of other DDR genes in cancer. This therapeutic approach is called synthetic lethality. Using synthetic lethality, Aprea’s drugs are being developed to selectively kill cancer cells while minimizing the effects on normal, unmutated cells, thus increasing cancer cell killing and decreasing damage to normal cells.
Over a decade ago, our team was one of the first to report mutations that cause cancers to grow out-of-control also increase the need for a particular DDR gene in order to survive and proliferate (Ruzankina, Schoppy, et al., Nature Genetics, 2009; Gilad et al, Cancer Research, 2010; Schoppy et al., Journal of Clinical Investigation, 2012). This gene is ATR – a master regulator of DDR.
The two drugs thus far developed, selective small molecule inhibitors of WEE1 and ATR, take advantage of this precision medicine approach. These drugs are in clinical stages and thereby may offer new hope to cancer patients with unmet medical needs.
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