EpiAxis science in detail
Lysine-specific demethylase 1 (LSD1, also known as KDM1A) is an epigenetic eraser enzyme that can remove methyl groups from lysine residues on histones H3K4me1/2 and H3K9me1/2. LSD1 is known to be aberrantly expressed in many cancers and is associated with inferior prognosis as this aberrant LSD1 expression contributes to impaired cellular differentiation and increased cancer cell proliferation, metastasis and invasiveness.
Importantly, LSD1 is enriched in both chemotherapy and immuno-therapy (IO) resistant cancers, facilitating tumour progression and recurrence.
What is EMT?
Epithelial-to-mesenchymal transition (EMT) is an important cellular event in cancer biology and may be defined as the loss of cell-cell adhesion complexes and cell polarity by an epithelial cell, and the gain of an invasive, migratory, mesenchymal phenotype. EMT is known to play a role in several cancers including prostate, lung, liver, pancreatic, and breast. Importantly, EMT is associated with an increased number of LSD1 sensitive genes.
What has EpiAxis discovered?
Our research indicates that it is a specific phosphorylated form of LSD1 (LSD1p) that is preferentially upregulated in cancer and drives mesenchymal phenotypes. For example, LSD1p expression is higher in IO resistant melanoma patients than in responder patients and also in patients with metastatic brain lesions.
In the 4T1 model of breast cancer metastasis inhibition of LSD1 with EPI-111 monotherapy, has demonstrated:
· Amelioration of EMT with removal of the mesenchymal and stem like cancer cells in primary lesions by day 15: this effect was not seen with anti-PD1 therapy; and
· Enhanced infiltration of CD8+ T-cells into the tumour microenvironment together with removal of checkpoint blockage by day 15 (with a stronger effect than anti-PD1 therapy). We have shown that this is due to LSD1 inhibition releasing the EOMEs brake on CD8+ T-cells.
We have extended these findings into human cancers and have shown that treatment with EPI-111 also reinvigorates CD8+ T cells in IO resistant melanoma and metastatic breast cancer (MBC). Importantly, our in-vitro data indicate that EPI-111 has superior activity compared to other LSD1 inhibitors in development such as GSK2879552 and Oryzon-1001.
As summarised in the diagram below our EPI-1xx peptides are designed to:
1) Prevent the entry of LSD1 into the nucleus by binding to LSD1 nuclear shuttle proteins Importins 1 and 3
2) Then enter the nucleus themselves (instead of LSD1) to disrupt the LSD1/CoREST axis, leading to degradation of existing nuclear LSD1. The net effect is a substantial reduction in the effective LSD1 nuclear pool leading to epigenetic change.