glioblastomaIt is a common type of brain cancer that is usually treated with a brain scan followed by a medical evaluation for surgery, radiation and chemotherapy, or a combination of treatments. While most cancers shrink after initial treatment, many patients develop metastases that recur and become resistant to chemotherapy or radiation. Factors such as limited treatment options and poor prognosis mean that patients only survive on average 15 months after diagnosis.
A new discovery from the Keck School Institute of Medicine at the University of Southern California indicates that the circadian clock protein is involved in the growth of glioblastoma stem cells and thus activates related proteins such as cryptochrome isoforms. ) CRY2 activity has the effect of treating glioblastoma growth, and the team conducted Phase 1 clinical trials of the investigational small-molecule drug SHP656.
Relationship between circadian clock proteins and glioblastoma
The cryptochrome of the circadian clock protein is an important protein that regulates the biological circadian clock. Common forms in mammals are the isoforms CRY1 and CRY2, which are responsible for the production of CRY1 and CRY2. Mutations in CRY1 and CRY2 can cause disruption of the human biological clock.In addition to participating in the regulation of the circadian rhythm mechanism, the abnormal functioning of the circadian clock protein can also cause certain diseases, such as the generation of Mutations in CRY1 and CRY2 lead to glucose intolerance, produced in the liver Overexpression of the CRY1 gene lowers blood glucose levels.
The Keck School team also found that the functioning of the CRY protein is affected by cancer stem cells.By interfering with the CRY protein, glioblastoma cells can rapidly grow tumors and resist the effects of chemotherapy and radiation.
CRY2 targeting helps inhibit glioblastoma stem cell proliferation
To find small-molecule drugs that can bind to CRY proteins, the research team first analyzed candidate drugs that could bind to mammalian CRY proteins via big data. The results identified a small molecule called SHP656, an oral derivative of the KL001 protein, a protein known to regulate the CRY1, CRY2 diisomer.
The glioblastoma stem cells were then isolated from the patient and treated with SHP656. SHP656 has been shown to selectively bind to the CRY2 protein and activation of the protein effectively inhibits the growth of cancer stem cells, but does not damage normal stem cells in the human body. The research team points out that this finding indicates the important role of the CRY protein isoforms in this therapeutic path. of the CRY1 protein on the growth of glioblastoma, or with other types of cancer.
References:
1. https://www.scienceboard.net/index.aspx?sec=ser&sub=def&pag=dis&ItemID=4773
2. PNAS, 2022; https://www.pnas.org/doi/full/10.1073/pnas.2203936119
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