Cancer Therapy: Novel DNA repair inhibitors

Effective cancer treatment depends on achieving a therapeutic window in which there is greater toxicity to the malignant cells than to normal, healthy tissue. We have sought to exploit synthetic lethality by seeking agents that are more toxic to cancer cells deficient in homology-dependent DNA repair. This applies to cancers with genetic defects in genes such as BRCA1, BRCA2, PALB2, and PTEN. But it also applies to hypoxic cancer cells in which there is down-regulation of the HDR genes, BRCA1 and RAD51. Our efforts in this area have focused on a novel lupus-derived, cell-penetrating antibody that functions as a DNA repair inhibitor to radiosensitize cells (Hansen, Science Translational Medicine 2012) and a promising class of natural products (Colis, Nature Chemistry 2014). We have also sought to exploit the acidic tumor microenvironment using a novel pH-dependent trans-membrane delivery peptide (pHLIP) to introduce anti-microRNA peptide nucleic acids (PNAs) antisense agents to disrupt oncomiR addiction (Cheng, Nature 2015). We recently applied this approach to deliver antisense PNAs to inhibit the otherwise undruggable DNA repair factor, Ku80, to sensitize tumors to radiation (Kaplan, Molecular Cancer Research, 2020). Recently, we have shown that the anti-angiogenic agent, cediranib, not only damages tumors by interrupting their blood supply and thereby inducing hypoxia but also directly down-regulates DNA repair, sensitizing cancer cells to PARP inhibitors and suggesting a strategy for targeted treatment that is currently being pursued in several clinical trials at Yale and elsewhere (Kaplan, Science Translational Medicine, 2019).