Characterizing Nitro-Fatty Acids as Rad51 Inhibitors and Cotreatment in Triple-Negative Breast Cancer
Abstract
The purpose of our research project is to improve treatment and ultimately survival for triple-?negative breast cancer (TNBC) patients. TNBC is a type of breast cancer that is different from other breast cancers as no targeted therapies currently exist. To date, TNBC therapies include ionizing radiation, surgery, and several different chemotherapies that have toxic side effects. TNBC is associated with poor long?term outcomes compared with other breast cancer subtypes. Many of the TNBC are also basal-like cancers, which are characterized by an aggressive biological behavior with a distant recurrence rate that peaks around 3 years following initial diagnosis. Metastatic TNBC presents have a dismal prognosis with an average survival of 12 months. Clearly, identifying new treatment strategies for TNBC patients is crucial. Research investigating patients that carry genetic aberrations of BRCA1 or BRCA2 genes has led to the discovery that these patients show increased sensitivity to therapies that damage the genome. This is because BRCA genes ensure repair of DNA that is broken on both strands (DNA double-strand break; DNA DSB). Thus, loss of BRCA functions creates a weakness in DNA repair that can be exploited by inducing DNA damage through drugs like cisplatin or doxorubicin. This way, cancer cells, which are genomically unstable to begin with, are killed due to overwhelming DNA damage. Recently, other types of drugs that are less toxic compared to chemotherapy have been found to work better in BRCA mutation carriers. This new class of drugs is called PARP inhibitors. PARP inhibitors stall a type of DNA repair that is different from DNA DSB repair. The PARP inhibitor we have used in our study is called olaparib. Clinical trials using olaparib in metastatic TNBC BRCA carriers have shown that it prolongs life. Based on these findings, the idea has developed to expand the group of patients that benefit from PARP inhibition by chemically inducing a weakness in DNA DSB repair. That way, more TNBC patients can be treated with PARP inhibitors instead of standard chemotherapies. However, suitable compounds that increase the efficacy of PARP inhibitors have yet to be shown to be efficacious enough for entry into Phase 1/2 development for TNBC. We have identified a unique reactivity of a novel class of inhibitors of DNA DSB repair that block activity of Rad51 that like BRCA genes promote DNA DSB repair. These inhibitors are nitro fatty acids (NFAs), which are well-tolerated and readily testable as new drug candidates in humans; NFA derivatives are endogenously present in humans (for example, in olive oil) and their synthetic homologs have been de?risked by preclinical toxicology and five Phase 1 safety evaluations of IV and oral NFAs in healthy and obese volunteers (http://www.complexarx.com), presenting a promising new opportunity for treating TNBC patients, who would otherwise receive standard treatment with chemotherapy. The NFA used in this study is called OA?NO2 and we have shown that it inhibits Rad51 in TNBC cells but not in benign breast cells. We also show that OA-NO2 reduces TNBC in mice and induces signs of DNA DSBs in TNBC tissues compared to a control fatty acid that has not adducted a nitro group. Our overarching working hypothesis is that Rad51 inhibition by nitro fatty acids (NFAs) weaken DSB DNA repair, thereby not only increasing PARPi efficacy and TNBC cell killing but also expanding the group of TNBC patients that benefit from PARPi. Our Research Plan consists of three specific aims. Aim 1 will examine the biochemical details of NFAs in Rad51-mediated DNA repair. Using 10 TNBC cell lines, Aim 2 will determine how NFA is best combined with olaparib (PARP inhibitor) to achieve maximal TNBC killing and a possible dose reduction of olaprib. Aim 3 will then evaluate to what extent NFAs combined with olaparib induce drug synergism in human TNBC ex vivo as well in vivo by utilizing a human-li
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910048XX0
Entities
People
- Carola A. Neumann
Organizations
- United States Army
- University of Pittsburgh