The power of the circadian rhythm in controlling how the body functions is just being understood. For example, it was only in 2017 that the Nobel Prize in Physiology went to scientists finding what controls the circadian rhythm. Now, only a few years later, we’re taking this knowledge, seeing whether it’s the missing link in understanding why targeted treatments are not working in brain cancer and already have a potential drug that may help to treat brain cancer.

GBM is always nearly fatal and even after surgery, chemotherapy and radiation therapy the tumour comes back growing from the stubborn brain cancer stem cells left behind which remain elusive to treat. But if these stem cells could be targeted and made more vulnerable to the different treatments, by shutting down their overactive biological clocks, then once the brain cancer is treated it could be cured.

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.

A new type of small molecule drug is now in phase 1 clinical trials as the first to target circadian clock proteins to treat GBM. This breakthrough research into the most aggressive form of brain cancer was supported by funding from Charlie Teo Foundation.

This research grant came about because Dr Charlie Teo has always been fascinated with the idea that the circadian rhythm may play a role in treating brain cancer. Our research team at the Charlie Teo Foundation sought out Dr Kay and we awarded a grant to him to study this before his research had even been accepted for scientific publication.

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