SiRNA Proteasome Inhibitors for Cancer Theraphy (No. T4-1619)

Lead Researcher: Yosef Shaul


Triple negative breast cancer (TNBC) is an aggressive type of breast cancer, representing over 10% of all breast cancer cases. TNBC is known for its high risk of relapse, poor survival prospects, and near zero survival rates once TNBC metastasizes.
Due to the lack of molecular targets (estrogen, progesterone, and HER2 receptors) common in other forms of breast cancer, there is an absence of specifically targeted therapies available, with systemic (body-wide) chemotherapy given as standard treatment. Though there have been some treatments considered such as a combination of different therapies, there is no specific and effective clinically approved treatments available for TNBC.
The present technology from the group of Prof. Yosef Shaul offers a new innovative mechanism in treating TNBC, using 19S particle disassembly to inhibit the 26S proteasome. The technology offers a unique target in the treatment of triple negative breast cancer.


?  Generating therapeutics towards Triple Negative Breast Cancer.


·         Specific – the technology explicitly targets triple negative breast cancer cells.
·         Unique mechanism – inducing disassembly of the 19S particle, by explicitly knocking down PSMD1 subunit of the 19S complex leads to 26S proteasome inhibition, but leaves 20S activity unperturbed.
·         Flexible drug delivery – system has been shown to be effective using Lentiviral delivery and could possibly use standard RNA interference chemistries.

Technology's Essence

The invention is shRNA knockdown of the PSMD1 subunit of the 19S particle. This causes the disassembly of the 19S complex, which inhibits the 26S proteasome activity leading to cell death in triple negative breast cancer (TNBC). However, what is unique about this mechanism of 26S proteasome inhibition is that the 20S complex is structurally retained and catalytically active, ensuring that proteasomal pathways independent of the 26S particle remain functional. Furthermore drug delivery of the PSMD shRNAs is flexible, as the technology has been effectively demonstrated with lentiviral vector, but could also be performed using other standard techniques related to RNA inhibition.