In many cancers, there exists a type of cancer cell called a cancer stem cell. These are cells that, after chemotherapy or immunotherapy, can cause recurrence of the disease. Glioblastomas, the most common brain cancer type, suffer from this type of recurrence. Temozolomide (TMZ) is a first-line chemotherapy against glioblastoma multiforme (GBM). While it can induce remission, any recurrence tends to lead to a TMZ resistant tumor. Glioblastomas are quite complex tumors, and therefore are troubling to treat.
MicroRNAs (miRNAs) are small segments of non-coding RNA that regulate many genes. These miRNAs have become a target for possible cancer treatments, with many miRNAs found to be associated with one or more cancer types. miR-128-3p is one such miRNA found to inhibit cancer growth and metastasis activities in many cancers when expressed at higher levels. In Glioblastomas, it has been a target as a biomarker. A team out of Zhengzhou University in China hypothesized that miR-128-3p might be able to work synergistically with TMZ and bring about remission while preventing recurrence through. Their hypothesis hinged on whether or not miR-128-3p could act as an inhibitor against GBM stem cells, as seen in other miRNA candidates from other studies.
Their experiments began by taking a general measurement of miR128-3p in a set of GBM cell lines. In all cases, the miRNA was downregulated compared to healthy cells. They then tested how miR128-3p effects GBM lines both in vitro and in mouse models. In vitro experiments showed a clear miR128-3p dependent reduction of cancer cell growth and migration when overexpressed. The mouse model confirmed the trend, with tumor growth being reduced when miR128-3p was upregulated.
The next set of experiments were designed to identify if miR128-3p could synergize with TMZ to treat GBM. Treatment with both TMX and miR-128-3p consistently showed a greater anti-cancer effect compared to TMZ alone. The dual treatment reduced tumor growth and metastasis in mice, as well as increased cancer cell death in in vitro assays. They identified a possible mechanism of miR128-3p in the suppression of the c-MET and PGFRα genes. Both genes are critical for something called epithelial-mesenchymal transition, a process similar to how stem cells work. miR128-3p would prevent the genes expression, thereby preventing the transformation of CSC into full Cancer cells, and increase the effectiveness of TMZ against GBM by preventing recurrence.
The team concludes, “the main finding of this study was that miR-128-3p increased the sensitivity of glioblastoma to TMZ and thus, increased the therapeutic effect of TMZ.” The ability of miR128-3p to enhance TMZs effectiveness agrees with other findings using miRNAs in a similar manner. The possibility of a combination treatment to treat a tumor, and prevent its recurrence, is very attractive and will likely be some of the next first-line therapies for cancer in the next decade.
Sources: Nature, Memorial Sloan Kettering
