Posted October 5, 2018
Dr. Paul Andreassen, Cincinnati Children's Hospital
Dr. Michael Birrer, University of Alabama at Birmingham
Dr. David Yu, Emory University
Dr. Ralph Scully, Beth Israel Deaconess Medical Center

Breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) encode for critical DNA repair proteins involved in the maintenance of DNA. They facilitate orderly homologous recombination (HR) by stabilizing the DNA, allowing DNA repair enzymes to repair any breaks in the DNA. Normally, these genes protect a person from getting cancer, but mutations in BRCA1 and BRCA2 can lead to nonfunctional proteins that are unable to preserve the genomic integrity of the cells, and any resulting errors in DNA repair can lead to cancerous transformation of the cell. Thus, mutations within these genes predispose individuals to several cancers, including ovarian cancer. While the risk of developing ovarian cancer in a lifetime is a little over 1%, the risk of developing the disease in women with BRCA1 mutations is 44%, and the risk in women with BRAC2 mutations is 17%.

Poly ADP-ribose polymerase (PARP) inhibitors have been particularly effective in treating BRCA1 and BRCA2 mutated ovarian cancers. With the absence of functional BRCA, the cell still has some means of DNA repair, such as by PARP. But adding a PARP inhibitor on top of an already weakened DNA repair pathway due to the BRCA deficiency results in lethality in the cancer cells because they cannot cope with such replication stress.

Since its inception in 1997, the Ovarian Cancer Program (OCRP) has recognized the role BRCA plays in ovarian cancer risk. As such, the program has funded BRCA-focused research throughout the years. To date, 39 OCRP awards have focused on BRCA research. Below are some examples of exciting BRCA-focused research on the horizon that the OCRP is funding.

Novel and Rapid System to Classify BRCA2 Variants in Ovarian Cancer

Dr. Paul Andreassen, Cincinnati Children's Hospital
Fiscal Year 2017 OCRP Investigator-Initiated Research Award

BRCA2 variants can be identified through genetic testing, but the significance of those variants for the patient's health and possible increased risk of disease is often unknown. Dr. Andreassen has developed a system that will allow him to express the full-length human BRCA2 in human cells originating in the ovary. Using this system, he plans to test and reliably predict the pathogenicity of BRCA2 variants with uncertain significance. Moreover, he can use the system to predict the potential effect of particular variants on tumor responsiveness to commonly used ovarian cancer therapies. In addition to BRCA2, Dr. Andreassen plans to use the cell-based system to evaluate other genes that express variants of uncertain significance that are commonly found in ovarian cancer patients, such as variants of PALB2 and RAD51C. Results from this study could dramatically improve genetic screens and have a great clinical impact on the prevention and treatment of ovarian cancer.

Overcoming PARP Inhibitor Resistance in BRCA-Deficient Ovarian Cancers

Dr. Michael Birrer, University of Alabama at Birmingham
Fiscal Year 2017 OCRP Clinical Development Award

Advanced ovarian cancer patients with BRCA mutations are commonly treated with PARP inhibitors. This treatment is initially quite effective, but the vast majority of patients eventually develop resistance and relapse. It is important to understand how these BRCA-deficient ovarian cancer cells develop resistance to PARP inhibitors so that a strategy can be developed to minimize it. Preliminary results suggest that the cell may rewire HR, allowing it to overcome the stress induced by the BRCA deficiency and PARP inhibition, and that an enzyme, ATR, may be central to the HR rewiring process. Dr. Birrer proposes to disrupt the rewiring process by targeting ATR, which will overcome PARP inhibitor resistance in ovarian cancer patients. This study could justify the use of ATR inhibitors in ovarian cancer treatment and improve the response to PARP inhibitor therapy.

Understanding and Exploiting SIRT2/BRCA1 Interplay for Ovarian Cancer Therapy

Dr. David Yu, Emory University
Fiscal Year 2016 OCRP Pilot Award

Recently, Dr. Yu discovered that BRCA1 is regulated by SIRT2, a protein that removes acetyl modifications from proteins and thereby regulates their activity. He found that SIRT2 depletion results in defects in replication that can lead to double-strand breaks in the DNA, and that these breaks need to be repaired by BRCA proteins during HR. In the case of BRCA1 mutations leading to BRCA1 deficiency, this HR repair would not occur and could lead to lethality for the cancer cells. Thus, the potential to utilize SIRT2 inhibitors to selectively destroy BRCA1-dysregulated cancer cells exists. Dr. Yu aims to understand the mechanisms by which BRCA1 is regulated by SIRT2 and how this may be exploited for ovarian cancer treatment. This work could provide a promising therapeutic strategy for ovarian cancer patients with BRCA1 dysregulation.

Analysis of the Tandem Duplicator as a Biomarker of BRCA1-Linked Ovarian Cancer

Dr. Ralph Scully, Beth Israel Deaconess Medical Center
Fiscal Year 2016 OCRP Investigator-Initiated Research Award

It is important to be able to distinguish between different ovarian cancer types, as this is the key to treatment success. For example, ovarian cancers lacking BRCA1 are often responsive to PARP inhibitors; thus, being able to identify BRCA1 mutant ovarian cancers quickly so that patient therapy can be initiated immediately would be ideal. Dr. Scully and his colleagues have developed a new biomarker of BRCA1 inactivation: the formation of small microhomology-mediated tandem duplications. As a potential new tool for characterizing ovarian cancer, it is important to define this novel pathway. Dr. Scully will uncover the mechanism of these microhomology-mediated tandem duplications, thereby validating their use as biomarkers. This would enable efficient characterization of the ovarian cancer, thus facilitating rapid optimization of treatment for the patient.

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