Temple researchers: Small molecule inhibitor shows promise in precision cancer targeting
(Philadelphia, PA) – Cancer cells with mutations in BRCA1 or BRCA2 genes, which serve a vital role in preserving the integrity of the genetic code, are key targets for cancer therapeutics. Yet, few agents can selectively eliminate cells deficient in BRCA, and none can do so without the risk of inducing drug resistance. But scientists at the Lewis Katz School of Medicine at Temple University (LKSOM) now think they can help overcome that problem, thanks to their discovery of a small molecule that selectively kills BRCA-deficient cancer cells by blocking the activity of an alternative DNA repair pathway.
According to Richard T. Pomerantz, PhD, Assistant Professor of Medical Genetics and Molecular Biochemistry in the Fels Institute for Cancer Research at LKSOM, and senior investigator of the study, cancer cells deficient in BRCA proteins, which normally promote a major mechanism of DNA repair known as homologous recombination, become dependent on an alternative DNA repair pathway mediated by a protein called RAD52. Dr. Pomerantz and colleagues are the first to show that the selective inhibition of RAD52 with a small molecule known as 6-hydroxy-DL-dopa (6-OH-dopa) can block the growth of BRCA-deficient cancer cells in vitro, including cells obtained from leukemia patients.
The new findings were published online November 5 in the journal Chemistry & Biology.
"Every cell has redundant DNA repair pathways," Dr. Pomerantz explained. "If the main DNA repair pathway, BRCA-mediated homologous recombination, becomes defective, cancer cells adapt and still proliferate."
Previous studies had shown that the suppression of RAD52 in cells that already harbor mutations in BRCA1 or BRCA2 causes the cells to die. Cells with normally functioning BRCA proteins, on the other hand, are unaffected by the loss of RAD52 activity, because the primary BRCA-mediated DNA repair mechanism is intact.
Prior to the new study, however, no one had identified a small molecule inhibitor of RAD52. RAD52 works by forming a large ring structure that binds to single strands of DNA, and similar to many other DNA-binding proteins, it lacks enzymatic activity. Those features present significant challenges in drug discovery, and in fact, DNA-binding proteins traditionally have been considered to be beyond the reach of even small molecule inhibitors.
Dr. Pomerantz and colleagues screened more than 18,000 compounds before finding 6-OH-dopa, the only small molecule that consistently prevented RAD52 from binding to single-stranded DNA. Experiments in cells showed that 6-OH-dopa is specific for RAD52 and acts by disrupting RAD52 ring structures. In BRCA-deficient cells, treatment with the molecule resulted in reduced cell growth and viability. In contrast, BRCA-proficient cells were mostly unaffected, demonstrating the potential for a new form of precision medicine.
"The effect is like knocking out two legs of a table that normally is supported by four legs. One leg is lost to BRCA mutations and another to RAD52 inhibition. With only two legs left, the table collapses," Dr. Pomerantz explained. "Normal cells are left on three legs, due to only RAD52 inhibition, so they survive."
The discovery of 6-OH-dopa has therapeutic implications for more than just breast and ovarian cancer – the diseases most widely associated with BRCA mutations. Cancers of the lung, prostate, and pancreas, as well as leukemia, also exhibit BRCA deficiencies.
Dr. Pomerantz is moving forward with plans to further develop the small molecule and to identify additional RAD52 inhibitors for testing in BRCA-deficient animal models. With support from the National Institutes of Health (NIH) and the Department of Defense (DoD) and collaborations with Dr. Tomasz Skorski of the Department of Microbiology and Immunology and Fels Institute for Cancer Research at LKSOM, with researchers at the Moulder Center for Drug Discovery at LKSOM, and with scientists at the Rockefeller University, Dr. Pomerantz is hopeful that this line of research will eventually lead to clinical trials.
Other researchers who contributed to the study include Guru Chandramouly, Shane McDevitt, and Tatiana Kent in the Department of Medical Genetics and Molecular Biochemistry at the Fels Institute for Cancer Research, LKSOM; Katherine Sullivan and Tomasz Skorski in the Department of Microbiology and Immunology at the Fels Institute for Cancer Research, LKSOM; Mark Andrake at Fox Chase Cancer Center; and Antonio Luz and J. Fraser Glickman at the Rockefeller University, High-Throughput and Spectroscopy Resource Center, New York.
The research was funded by DoD Breast Cancer Breakthrough Award W81XWH-14-1-0344 and in part by NIH grant 1R01CA190237-01, LKSOM start-up funds, and NIH grant 1R01CA186238.
About Temple Health
Temple University Health System (TUHS) is a $1.6 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the "Best Hospitals" in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with the Lewis Katz School of Medicine at Temple University.
The Lewis Katz School of Medicine (LKSOM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 840 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, the Katz School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, LKSOM is among the top 10 most applied-to medical schools in the nation.
Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System (TUHS) and by the Katz School of Medicine. TUHS neither provides nor controls the provision of health care. All health care is provided by its member organizations or independent health care providers affiliated with TUHS member organizations. Each TUHS member organization is owned and operated pursuant to its governing documents.