Ovarian cancer is one of the most common and the most lethal gynaecological cancer. Early symptoms of ovarian cancer can be easily confused with less severe conditions, leading to diagnosis at an advanced stage when treatment options are limited. Ovarian cancers often show drug resistance, and thus new effective therapies are needed.
NXP800 was discovered in our Centre for Cancer Drug Discovery at The Institute of Cancer Research by using phenotypic screening designed to find potential Heat Shock Factor 1 (HSF1) inhibitors in cancer cells. HSF1 is a transcription factor that protects cells under stresses, such as heat shock and oncogenic stress. In addition, HSF1 has cancer-specific transcriptional targets, and is associated with cancer progression, invasion, and metastasis. Based on our findings in human tumour xenograft models, NXP800 is currently being tested in a Phase 1b clinical trial of patients with platinum-resistant, ARID1A mutant ovarian cancer. We have made progress on the molecular mechanism of action of NXP800, but this remains to be fully defined.
Our findings show that NXP800 reduces the transcriptional activity of HSF1 and induces the Integrated Stress response (ISR) by activating General Control Nonderepressible 2 (GCN2), a serine/threonine kinase that is known to be activated in response to amino acid deprivation. We found that CRISPR knock-out of GCN2 in SKOV3 ovarian cancer cells blocked the anti-proliferative effect of NXP800, increased the IC50 of NXP800 by more than 20-fold, and antagonized NXP800-induced HSF1 inhibition, indicating that GCN2 plays a crucial role in the biological response to the drug.
We have also shown that ARID1A mutations sensitise cancer cells to NXP800. ARID1A is a subunit of SWI/SNF chromatin remodelling complex and is frequently mutated in ovarian cancer. ARID1A loss-of-function mutations have been shown to promote Epithelial-Mesenchymal Transition (EMT), a process involving dramatic actin cytoskeletal reorganization that enables invasive and migratory properties. Interestingly, our findings show that NXP800 alters actin- and cell migration-related gene expression. In addition, previous studies suggest that actin depolymerization can lead to GCN2 activation. Further studies are underway to explore the potential link between alteration of actin dynamics and GCN2 activation in response to NXP800.