Development of Inhibitors of RAD52 Protein Against BRCA-Deficient Breast Cancer
Abstract
Breast cancer is the most common malignancy among women, accounting for nearly a quarter of all women’s cancers. In men, breast cancer is rare but deadlier. In the US, in 2019, 268,600 women and 2,670 men will be diagnosed with breast cancer. Military active duty females (1 out of 7 active duty individuals) have a 20% to 40% higher risk of breast cancer compared to the general population; the cost of breast cancer care is the highest among all cancers ($16.5 billion in 2010) and is expected to rise ($20.5 billion in 2020). About 10% of breast cancers are hereditary with nearly 50% of them caused by mutations in the BRCA1 and BRCA2 genes. Mutations in these genes also cause ovarian cancer and increase the risk of other cancers, including prostate, pancreatic, lung cancers, melanomas, and leukemias. The breast cancers caused by mutations in the BRCA1/2 genes are deadlier than other types of breast cancer. The current standard of care of these patients is inefficient, and the prognosis for their survival is the poorest among all breast cancer types. Radiation therapy coupled with breast conserving surgery shows only a 9% decrease in breast cancer deaths. Combination chemotherapy shows an absolute improvement of only 7%-11% in a 10-year survival for younger women and only of 2%-3% for women ages 50-69, when the majority of breast cancers are diagnosed. Recently, inhibitors of the enzyme, known as PARP1, were developed against BRCA-deficient cancers. However, they show response only in a limited fraction of patients by merely extending their lifespan by several months, and resistance to these inhibitors has already been reported. The goal of this proposal is to develop novel, more effective, less toxic treatment that will impact survival of breast cancer patients carrying mutations in BRCA genes. Recently, it was discovered that mutations in another gene, RAD52, cause death of the cancerous human cells that carry mutations in BRCA1 and BRCA2 genes. Importantly, in normal cells, RAD52 mutations are harmless. Based on this discovery, we proposed to develop chemical inhibitors of RAD52, which could kill cancer cells carrying BRCAs mutations without harm to normal tissues. In our previous studies, we synthesized several such inhibitors and demonstrated their efficacy in killing breast cancer cells carrying BRCA mutations both in cell culture and in the mouse model. Moreover, our data demonstrated that RAD52 inhibitors are especially effective, when they are combined with PARP inhibitors. The goal of the current proposal is to improve the efficiency, specificity, and safety of these RAD52 inhibitors so that they can be used for the therapeutic treatment of cancer patients. In our preliminary studies, we synthesized more than 150 novel analogs of RAD52 inhibitors and demonstrated that 63 of them are up to 15-fold more active in inhibiting RAD52 in the enzymatic assay than our best previous inhibitor. Here, we want to improve their activity 10 times against the BRCA-mutated breast cancer cells in culture and in the mouse model. We also plan to decrease to the minimum the toxicity of these inhibitors against normal tissues. To achieve this goal, the chemistry plan was designed to synthesize new RAD52 inhibitors, and various biochemical, cellular, and animal models were developed to test the activity of these new inhibitors. This work will be assisted by computer modeling of the complexes that the inhibitors form with RAD52 and by crystallographic studies ongoing in our laboratory. We expect that these studies would lead to development of novel efficient therapy against the deadliest type of breast cancer. These RAD52 inhibitors can also be used against other types of cancer that carry mutations in BRCA1 or BRCA2 genes, for instance, ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010408
Entities
People
- Yanming Du
Organizations
- Baruch S. Blumberg Institute
- United States Army