Mutations in the tumor suppressor BRCA1 predispose to pancreatic, prostate, colorectal, and most notably, breast and ovarian cancers. Currently, inhibitors of poly (ADP-ribose) polymerase (PARPi) are used to treat cancer patients with BRCA1 deficiency; however, 40%-60% of these patients do not have a response to PARPi. Thus, novel combination treatments for patients with BRCA1-deficient cancers that are resistant to PARPi are urgently needed. Ferroptosis is an iron-dependent form of nonapoptotic cell death that is induced by a type of lipid damage on cellular membranes called lipid peroxidation. Certain drugs known as ferroptosis inducers can have potent cell killing effects by inducing fer...

Read More

Mutations in the tumor suppressor BRCA1 predispose to pancreatic, prostate, colorectal, and most notably, breast and ovarian cancers. Currently, inhibitors of poly (ADP-ribose) polymerase (PARPi) are used to treat cancer patients with BRCA1 deficiency; however, 40%-60% of these patients do not have a response to PARPi. Thus, novel combination treatments for patients with BRCA1-deficient cancers that are resistant to PARPi are urgently needed. Ferroptosis is an iron-dependent form of nonapoptotic cell death that is induced by a type of lipid damage on cellular membranes called lipid peroxidation. Certain drugs known as ferroptosis inducers can have potent cell killing effects by inducing ferroptosis in cancer cells and hold great potentials in cancer therapy. Recent studies from us and others have shown that some cancer cells appear to be particularly susceptible to ferroptosis, suggesting therapeutic opportunities to target ferroptosis as a vulnerability in cancer. However, our understanding of ferroptosis vulnerabilities in specific cancer or genetic contexts is relatively rudimentary, limiting our ability to therapeutically target this "Achilles' heel" in cancer. In this application, we propose to understand how ferroptosis is controlled at molecular levels in BRCA1-deficient cancer cells and to design and test ferroptosis-inducing combination therapies in treating BRCA1-deficient cancers by using rigorous preclinical models. Our proposed studies will not only have significant impact on our understanding of the fundamental mechanisms of ferroptosis but also provide novel therapeutic strategies to overcome PARPi resistance in BRCA1-deficient cancers.

Read Less