Preventing brain tumors from repairing themselves by blocking a protein

Glioblastoma multiform (GBM) is a rare and highly invasive brain tumor. The tumor is located under the cortex and grows infiltrated. It often attacks several lobes and deep structures and can spread to the contralateral cerebral hemisphere through the corpus callosum. Frontal lobe was the most common site, followed by temporal lobe and parietal lobe, and occipital lobe and thalamus and basal ganglia.

GBM has a rapid growth rate and a short course of the disease, with the course of 70 percent to 80 percent of patients within 3 to 6 months, and only 10% of patients with the course of more than 1 year. GBM is extremely difficult to treat, and its prognosis is poor. Treatment usually involves a combination of surgical resection, chemotherapy, and radiation therapy, but ultimately it cannot be cured. Radiotherapy and chemotherapy are the criteria for treatment, both of which aim to destroy DNA in cancer cells, but as tumors develop therapeutic resistance, their efficiency declines.

Currently, researchers at the University of California, San Diego, Ludwig Cancer Institute, San Diego, with colleagues across the country reported that inhibiting the activity of a specific protein in GBM increases their sensitivity to radiation and improves treatment prospects of this brain cancer. Their findings were published an online issue of Cancer Cell.

The researchers identified the mechanism by which GBM is used to promote therapeutic resistance: phosphorylation of a protein called phosphatase and tensin homolog, short for PTEN, encoded by the PTEN gene.

PTEN is the first tumor suppressor gene with double specific phosphatase activity, which is also another gene closely related to tumorigenesis after p53 gene. And PTEN is one of the major regulators of cell differentiation, proliferation, and migration in developing brain and adult brain. PTEN is also a classic tumor suppressor in addition to P53 . By inhibiting the activity of the PI3K-Akt signaling pathway and mTOR signaling pathway, PTEN controls a large number of cell processes, including survival, proliferation, energy metabolism and cell structure. Therefore, the expression and function of PTEN regulatory mechanisms, including transcriptional regulation, post-transcriptional regulation by non-coding RNA, post-transcriptional modification and the interaction between proteins, are all changing cancer.

Studies have shown that PTEN also regulates cell proliferation, differentiation, and apoptosis by selectively inhibiting the MAPK signaling pathway. MAPK, also known as a mitogen-activated protein kinase, is a cytoplasmic protein with tyrosine phosphatase activity and is involved in a series of processes including cell growth and differentiation.

However, mutation or modification can have the opposite effect. The researchers found that the phosphorylation of PTEN, the addition of phosphate molecules to an amino acid called tyrosine Y240 in cancer cells promotes DNA repair in tumors, thereby weakening the effects of therapeutic radiation.

When the researchers used inhibitors of fibroblast growth factor receptors to block Y240 phosphorylation in a GBM mouse model, the cancer cells became more sensitive to radiation and died more, prolonging the survival of mice.

These findings are novel and lay the groundwork for further clinical trials. The researchers hope to extend their findings to other types of cancer that use this mechanism to evade treatment.