Uppsala researchers develop Trojan horse approach for medulloblastoma treatment

The malignant pediatric brain tumor medulloblastoma is driven by proteins deep within the cancer cells, for which there are often no effective drugs available. Researchers at Uppsala University have identified a new genetic technique that enables targeting of tumor cells with elevated levels of such proteins. The technique could be used to eliminate cells responsible for tumor relapse. The hope is to develop an effective drug against recurrence of this disease within a few years.

Medulloblastoma is the most common form of malignant brain tumor in children and can often be cured with surgery, radiation, and chemotherapy. However, while this standard treatment can be effective in three out of four cases, it also affects normal cells in the growing brains of children, often leading to lifelong side effects. In some cases, resistance to standard therapy develops, causing relapse, which is strongly associated with increased mortality.

Works like a Trojan horse

Fredrik Swartling, a researcher at Uppsala University, previously identified that the protein SOX9 accumulates at high levels in the cell nucleus during relapse of medulloblastoma. The SOX9 protein binds to specific DNA sequences in our genome and with knowledge of these, Fredrik Swartling's group constructed a virus capable of infecting cancer cells. The virus enters the tumor cells and introduces the SOX9 sequence linked to an enzyme that can kill the tumor.

"Our drug works like a Trojan horse that first infects the tumor cells and introduces our SOX9 sequence linked to an enzyme that acts like efficient mercenaries. For a few days, we lie low and wait for SOX9 to bind to the sequence in the cells where SOX9 has accumulated, which are the ones we want to eliminate. When that happens, we begin treatment with our antiviral drug, which gives the order to the Trojan horse's soldiers to effectively kill the dividing cancer cells," says Fredrik Swartling, who led the study.

In cells from patients with medulloblastoma and in animal models, the treatment worked well, and the antiviral drug ganciclovir effectively reached the brain tumors. The treatment also worked synergistically with the radiation therapy normally given to these patients.

"If our treatment enhances the effectiveness of radiation, it may be possible to use lower radiation doses to eliminate the children's tumors. This would hopefully mean fewer side effects for these patients in future treatments," says researcher Tina Lin, who conducted the treatment studies in the lab.

The hope is to develop an effective drug

The technique is still experimental, but the researchers are now working on developing clinically viable versions of their method that could be used as gene therapy in patients. Currently, there are at least eight approved gene therapies based on viruses similar to the one used in the study.

We hope to begin clinical trials within two to three years, but it requires significant funding. Unfortunately, this type of gene therapy is still very expensive. We hope costs will decrease over time, considering that the virus that we used has not only proven safe but also has an amazing ability to penetrate cancer cells located deep within organs or in hard-to-reach places like the brain." 

Fredrik Swartling, researcher, Uppsala University