Brain cancers called Diffuse Intrinsic Pontine Gliomas (DIPGs) are often a death sentence. These aggressive, fast-growing, drug-resistant tumors are deadly and they originate from glial cells in the brain.
However a recent report published in the journal Cancer Cell details an experimental gene therapy that stops DIPGs in their tracks. This study included researchers from several different institutions, but was led by scientists at Cincinnati Children’s Hospital Medical Center. The study examined human cancer cells and a mouse model of DIPG.
DIPGs seem to require a gene called Olig2 (which encodes a transcription factor) to grow and survive. The majority of gliomas express the protein encoded by the Olig2 gene and removing this gene halts tumor growth and liquidating Olig2-producing cells inhibits tumor formation. This collaborative team designed a technique scientists found a way to use a gene therapy to shut down Olig2 expression.
“We find that elimination of dividing Olig2-expressing cells blocks initiation and progression of glioma in animal models and further show that Olig2 is the molecular arbiter of genetic adaptability that makes high-grade gliomas aggressive and treatment resistant,” said Qing Richard Lu, PhD, lead investigator and scientific director of the Brain Tumor Center at Cincinnati Children’s. “By finding a way to inhibit Olig2 in tumor forming cells, we were able to change the tumor cells’ makeup and sensitize them to targeted molecular treatment. This suggests a proof of principle for stratified therapy in distinct subtypes of malignant gliomas.”
DIPGs originate from supporting brain cells called oligodendrocytes. Oligodendrocytes make the insulation that surrounds the axons of various nerves in the central nervous system. Olig2 expression appears at the early stages of brain cell development, and is also present in the early-stage dividing and replicating cells in tumors. Olig2 also participates in the transformation of normal oligodendrocyte progenitor cells (OPCs) into cancer cells that divide uncontrollably. Olig2 also facilitates the adaptability of gliomas that helps them evade chemotherapeutic regimens. Indeed, clinically speaking, DIPGs may initially respond to chemotherapeutic agents, but they tend to quickly adapt to these drugs and develop high-levels of resistance to them.
Lu and his colleagues and collaborators eliminated Olig2-positive dividing cells from DIPG tumors that were still in the early stages of tumor formation. Lu and his colleagues used an ingenious technique to remove Oligo2 expression: by genetically engineering a herpes simplex virus-based vector, they delivered a suicide gene (Thymidine kinase) into replicating Olig2-positive cancer cells. Since herpes simplex viruses (HSVs) have the ability to grow in neurons that do not divide a great deal, the HSV-vectors are well suited to this purpose. After infecting the early DIPG cells with the HSV vectors, they administered an anti-herpes drug already in clinical use, ganciclovir (GCV), which kills any cells that have the thymidine kinase gene. The Olig2-deleted tumors were not able to grow.
In follow-up work, Lu and his colleagues observed a fascinating fate for the Olig2- tumors. These cells differentiated into astrocyte-like cells that continued to form tumors, but expressed the epidermal growth factor receptor (EGFR) gene at high levels. EGFR is an effective target for several chemotherapy drugs. In repeated tests in mouse models, Olig2 inhibition consistently transformed the glioma-forming cells into EGFR-expressing astrocyte-like cells. Then these tumors were treated with an EGFR-targeted chemotherapy drug called gefitinib. These treatments stopped the growth of new tumor cells and tumor expansion.
According to Dr. Lu, with additional testing, verification, and, of course, refinement, this experimental therapy that he and his colleagues have designed, could help prevent the recurrence of brain cancer in patients who have undergone initial rounds of successful treatment. Lu also added that these new treatments would probably be used in combination with other existing therapies like radiation, surgery, other chemotherapies and targeted molecular treatments.
Lu and his team will continue their research with other human cell lines and “humanized” mouse models of high-grade glioma. Such mouse models use genetically engineered mice that can grow brain tumors derived from the tumor cells of specific human patients. These tumor cells come from the tumors of patients whose families have donated biopsied tumor samples for research. This allows researchers to test different targeted drugs in their therapeutic protocol that may best match the genetic makeup of tumors from specific individuals.
The entire research team cautions the experimental therapeutic approach they describe will require extensive additional research. Therefore, this type of treatment is years away from possible clinical testing. Having said that, Lu said the data are a significant research breakthrough, since this study identifies a definite weakness in these stubborn cancers that almost always relapse and kill the patients who get them.