Telomerase-positive Pediatric Brain Tumors: Possible New Treatment Method

An experimental molecular therapy in has been used in preclinical laboratory tests to effectively treat several types of deadly pediatric brain cancer. The researchers now propose advancing the treatment to clinical testing in children.

The small molecule 6-thio-2’deoxyguanosine (6-thio-dG) was tested in brain cancer stem cells derived from tumor cells donated by patients. Researchers also tested the treatment in humanized mouse models of pediatric brain cancer.

The cancers include diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG) and high-risk medulloblastoma (MB).

6-thio-dG Therapy

In preclinical laboratory tests, the targeted molecular therapy crossed the body’s protective blood-brain barrier in mouse models – causing extensive DNA damage in cancer cells and stopping or slowing two untreatable types of pediatric brain cancer.

The therapy did not affect non-cancerous cells in the animals, according to the scientists. The therapeutic benefits of 6-thio-dG continued in the animals after treatment was ended.

“These findings show that 6-thio-dG is a promising novel approach to treat therapy resistant pediatric brain tumors and they provide a rationale for clinical testing of this treatment in children with brain tumors,”

said Rachid Drissi, PhD, a senior study investigator in the Cincinnati Children’s Hospital Medical Center Division of Oncology.

Although 6-thio-dG does not appear to enter non-cancerous cells, Drissi stressed more research is needed to ensure the compound’s safety before clinical testing in patients. These studies are underway.

Diffuse Intrinsic Pontine Glioma

A diffuse intrinsic pontine glioma (DIPG) is a tumour located in the pons (middle) of the brain stem. The brain stem is the bottommost portion of the brain, connecting the cerebrum with the spinal cord. The majority of brain stem tumours occur in the pons and are diffusely infiltrating (they grow amidst the nerves), and therefore cannot be surgically removed.

Glioma is a general name for any tumour that arises from the supportive tissue called glia, which help keep the neurons in place and functioning well. The brain stem contains all of the afferent (incoming) neurons within the spinal cord, as well as important structures involved in eye movements and in face and throat muscle control and sensation.

The standard treatment for DIPG is 6 weeks of radiation therapy, which often dramatically improves symptoms. However, symptoms usually recur after 6 to 9 months and progress rapidly.

Despite decades of research effort and technological advancements, DIPG and other high-risk pediatric brain cancers have continued to defy effective treatment.

This study shows that after injection, 6-thio-dG worked by first crossing the blood-brain barrier of DIPG mouse models – a significant advancement that eliminates a major hurdle to treating brain cancers with drugs. The blood-brain barrier protects the organ from pathogens passing through the circulatory system, making it pharmacologically impenetrable.

Interrupting Immortality

The compound works by triggering extensive DNA damage in brain cancer cells and cancer stem cells. To accomplish this, the compound disrupts the function of telomeres on the chromosomes of brain cancer cells, according to the researchers.

Telomeres are repeated sequences of DNA at the ends of chromosomes that prevent or minimize genetic instability in cells. As cells age, telomeres normally shorten and genetic instability helps kill off the aging cells.

But brain cancer cells become immortal because their telomere length continue to be maintained by the enzyme telomerase, making the cells difficult or impossible to kill.

Drissi and his colleagues have shown in earlier studies that 73 percent of DIPG tumors and 50 percent of high-grade gliomas have the enzyme telomerase. Essentially, telomerase helps cancer cells maintain the length of their telomeres.

This led the research team to use a treatment protocol with 6-thio-dG, which already is being tested in preclinical research on lung cancer at another institution. The compound 6-thio-dG is manufactured to be like a similar, naturally occurring ingredient in telomeres.

After injection and entrance to the brain, 6-thio-dG is incorporated in cancer cell chromosomes, which causes telomerase-dependent telomere damage.

Satarupa Sengupta, Matthew Sobo, Kyungwoo Lee, Shiva Senthil Kumar, Angela R. White, Ilgen Mender, Christine Fuller, Lionel ML Chow, Maryam Fouladi, Jerry W Shay and Rachid Drissi
Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors
Mol Cancer Ther April 17 2018 DOI: 10.1158/1535-7163.MCT-17-0792

Image: Tumor cell telomeres are shown in red, telomere dysfunction in yellow and genomic damage is evident in green. Credit: Cincinnati Children’s