Triple-negative breast cancer (TNBC) makes up 15-20% of breast cancer cases and lacks oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2). TNBC is highly heterogeneous and is associated with poor prognosis. Due to the heterogenous nature of the disease the standard treatment regimen for TNBC patients is combinations of chemotherapy, radiation therapy and surgery. Currently, there are three targeted therapies approved for TNBC patients, poly (ADP-ribose) polymerase inhibitors (PARPi), immune checkpoint inhibitors and antibody-drug conjugates. However, these targeted therapies are only available for subsets of TNBC patients. Resistance to targeted therapies and chemotherapies are a major concern for TNBC patients and is another contributor to poor prognosis. Developing more broadly applicable targeted treatments and overcoming drug resistance would greatly improve patient outcomes.
One approach is through combining long non-coding RNA (lncRNA)-targeting therapies with currently available drugs. LncRNAs are characterised by being longer than 200 nucleotides and not having a significant open reading frame. LncRNAs are an optimal drug target as they are commonly dysregulated in cancers and have cancer-specific expression. Overexpressed lncRNAs can be targeted through different techniques such as CRISPR-cas9, DNA antisense oligonucleotides and small interfering RNA.
A lncRNA driver of cell proliferation in TNBC has been previously identified in the Diermeier lab. We currently have two drugs (ROQ-001 and ROQ-002) developed to specifically target this lncRNA. We combined each of the lncRNA targeting drugs with paclitaxel (chemotherapy) or olaparib (PARPi). We found that both lncRNA-targeting drugs resulted in a further decrease in cell proliferation compared to monotherapy with either paclitaxel or olaparib. Using compusyn analysis, the additional decrease in cell proliferation was confirmed to be due to synergy between the drugs. The next step is to determine the biological significance of these combinations via in vivo experiments.