Homologous recombination (HR) is the principal pathway for the error-free repair of DNA double-strand breaks and for DNA replication fork maintenance. Mutations in BRCA1, BRCA2 and other HR genes are responsible for half of hereditary breast and ovarian cancers and increase the risk of prostate, pancreatic, and other cancers. Dysfunction in HR genes renders tumor cells addictive to alternative DNA repair pathways such that inactivation of these pathways induces synthetic lethality. Thus, development of inhibitors of PARP (PARPi) has revolutionized therapy of BRCA-deficient cancers. However, the majority of cancer patients treated with PARPi eventually develop resistance to these agents, stre...

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Homologous recombination (HR) is the principal pathway for the error-free repair of DNA double-strand breaks and for DNA replication fork maintenance. Mutations in BRCA1, BRCA2 and other HR genes are responsible for half of hereditary breast and ovarian cancers and increase the risk of prostate, pancreatic, and other cancers. Dysfunction in HR genes renders tumor cells addictive to alternative DNA repair pathways such that inactivation of these pathways induces synthetic lethality. Thus, development of inhibitors of PARP (PARPi) has revolutionized therapy of BRCA-deficient cancers. However, the majority of cancer patients treated with PARPi eventually develop resistance to these agents, stressing the need for new therapeutics.

Our goal is to exploit new synthetically lethal relationships between DNA repair proteins for cancer drug development. While mutations in the human RAD52 gene cause no discernible phenotype, in BRCA-deficient cancer cells, RAD52 inactivation becomes lethal. We have successfully developed a series of highly specific RAD52i that are the most potent yet reported. Our collaboration with a superb UT Health San Antonio DNA repair and drug discovery team will lead to deep mechanistic understanding of BRCA/RAD52 synthetic lethality and will also set the stage for bringing RAD52i into the clinic to treat incalcitrant and relapsed cancers. In collaboration with our UT Health San Antonio colleagues, we will also investigate newly emerging synthetic lethality of BRCA-deficient cells induced by extinguishing the HR proteins RAD54 and RAD51AP1.

Our efforts will provide the foundation for developing new chemical inhibitors targeting a range of HR-deficient cancers. Our holistic, transdisciplinary program underpins our efforts in elucidating the mechanisms of HR and the development of novel cancer therapies to improve cancer care in our unique South Texas catchment area, which has a large Hispanic population with high incidence of BRCA1-deficient cancers.

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