Next-generation precision medicine for targeting recombination-deficient cancers

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Precision medicine is a revolutionary therapeutic approach in which therapies are designed and selected based on genetic mutations present in certain cancers. For example, treating patients with BRCA-deficient cancers with a medicine that inhibits a particular DNA repair pathway can result in selective killing of these cancer cells. This approach is based upon the concept of synthetic lethality whereby inactivation of a particular gene product selectively kills cells based on their genetic mutation, while sparing normal cells. Synthetic lethality has been used to target cancer cells mutated or deficient in the BRCA1 or BRCA2 tumor suppressor proteins which promote the homologous recombination (HR) DNA double-strand break (DSB) repair pathway. Because BRCA- deficient cancer cells are impaired in HR, they are susceptible to drugs that cause DNA damage and/or block DNA repair. Approximately 5-10% of breast cancers and ~50% of epithelial ovarian cancers are defective in the BRCA pathway. Thus, these cancer types have been used to develop first-generation personalized medicines that kill BRCA-deficient cells by inactivating Poly-ADP ribose polymerase 1 (PARP1) which promotes base excision repair. Despite the initial success of PARP inhibitors (PARPi), drug resistance has become a major problem in the clinic. Thus, it is important to identify and develop alternative drug targets involved in DNA repair as next-generation personalized medicines for BRCA-deficient cancers that increase patient survival rates and potentially reduce drug resistance. Recent studies have identified DNA polymerase theta (Polq) as a promising new precision medicine drug target in BRCA-deficient breast and ovarian cancers. We have identified selective Polq inhibitors (Polqi) that preferentially kill BRCA-deficient breast cancer cells and BRCA-deficient leukemia cells. These data demonstrate proof of concept that selective Polqi can be developed as pre-clinical drug leads that target BRCA-deficient cancer cells for killing. In Phase I research, we plan to optimize the potency and drug-like properties of our leading Polqi via structure-activity relationship (SAR) studies, and test the efficacy of our lead drug candidate as monotherapy and as combination therapy with PARPi in BRCA-deficient breast cancer xenografts in vivo. In summary, we anticipate that optimized Polqi will preferentially kill BRCA-mutated breast cancer cells in vitro and in vivo, while having little or no effects in normal cells.