Leveraging novel cryptochrome stabilizers to target GBM
Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain cancer that originates from cells in the brain known as glial cells. The average survival time from diagnosis is 15 months. Treatment usually begins with surgery followed with chemotherapy and radiation. Although aggressive, standard-of-care has not been able to offer a cure for patients. One of the complications of GBM is that these tumours harbor so called cancer stem cells, called GSCs. GSCs are able to support the development and progressive growth of the GBM tumour given that they persist in the tumour microenvironment following surgical resection and are resistant to both chemotherapy and radiation. The laboratories of Drs. Steve Kay and Jeremy Rich have recently discovered that these GSCs harbor a unique dependence of circadian clock components, Brain and Muscle ARNT-Like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK). These findings provide us with a novel therapy paradigm to explore in that we can now leverage small molecule drugs that negatively target the clock to selectively kill GSCs. There are currently two major classes of these compounds: CRY stabilizers and REV-ERB agonists. CRY stabilizers block the degradation of the Cryptochrome1/2 proteins, thereby inhibiting the gene expression effects of BMAL1:CLOCK. REV-ERB agonists suppress the expression of the BMAL1 gene. The Kay laboratory have been leaders in developing CRY stabilizers and we aim to utilise these compounds to target GSCs in cell culture models and GBM tumours in mouse models. Importantly, the CRY stabilizer SHP1705 from Synchronicity Pharma has demonstrated high tolerability and safety in Phase I studies in healthy volunteers. Findings from the proposed project will shed light on the efficacy of SHP1705 as a single agent or in combination with REV-ERB agonists or temozolomide chemotherapy against GBM, thereby providing us with Better Tools for the clinic.