Children With Brain Cancers Might Find New Hope With Experimental Drug TAK228

Highlights:

• The experimental drug TAK228 is undergoing clinical trials for adult brain tumors
• Researchers have now tried the drug on two types of pediatric brain cancer cells in the laboratory
• It appears to sensitize these cancers to other treatments like radiotherapy and chemotherapy

An experimental drug, currently referred to as TA228, that is being investigated for the treatment of certain adult cancers, might possibly be useful in the treatment of two fatal brain cancers in children. The two studies indicating the same were published in Cancer Letters and Neuro-Oncology.

Tumors within the skull, whether benign or malignant, are particularly dreaded. They cause symptoms like headaches, seizures, nausea and vomiting, behavioral changes and unsteadiness. Benign tumors usually produce symptoms due to the pressure they exert on a part of the brain. Brain cancers, which are the malignant brain tumors, are of two main types. Primary brain cancers arise from the cells of the brain while secondary brain cancers include those cancers that spread to the brain from other parts of the body. Children can also be affected with brain tumors, with gliomas being the most common.

Two pediatric cancers that are particularly difficult to treat are:

• Diffuse intrinsic pontine glioma (DIPG): This tumor appears from a type of supporting cell of the brain called the glial cells. It affects the brainstem, which controls the vital functions of breathing and the beating of the heart. It is a very aggressive cancer. Surgery is difficult in this vital part of the brain, and currently radiation is the main treatment.
• Atypical teratoid/rhabdoid tumors (AT/RTs): The tumor usually arises from the cerebellum or the brainstem, though it may also arise from other parts of the brain or the spinal cord. The cerebellum is involved in important functions of movement, balance and posture. Treatment is through surgery, radiation and chemotherapy, though the outcomes are still not good.

It is thus clear that both these cancers require a discovery that can treat or control these cancers, thereby prolonging the lives of the affected children. Early studies in the laboratory indicate that TAK228 could potentiate the effects of radiation and chemotherapy for these two cancers. TAK28 acts by reducing the production of a protein called mTOR in cancer cells that promotes the growth and invasion of the cancer, and helps it to resist treatment. Since both the above cancers have increased mTOR activity, the scientists predicted its possible usefulness in these cancers.

The researchers tested the drug on cancer cells obtained from both the cancers. They found that, when tested on the DIPG cancer, TAK228 as compared to control:

• Reduced the multiplication of the cancer cells by about 30 percent
• Killed about 6 percent of the cancer cells. This number was increased to almost double when combined with radiation

It also improved survival in mouse models of the cancer.

The drug produced similar effects against AT/RT cancer cells, reducing their proliferation and increasing deaths among cancer cells.

When tested in mice with the AT/RT cancer who were being treated with cisplatin, TAK228 prolonged the life of mice by about 30 days. Around 40 percent lived for even more than 60 days. In contrast, mice that received either chemotherapy or TAK228 lived for no longer than 25 days

Thus, if further research is successful, TAK228 can emerge as an effective additional agent for the treatment of the two serious pediatric cancers.

Reference:

1. Miyahara H et al. The dual mTOR kinase inhibitor TAK228 inhibits tumorigenicity and enhances radiosensitization in diffuse intrinsic pontine glioma. Cancer Letters DOI: http://dx.doi.org/10.1016/j.canlet.2017.04.019
2. Rubens JA et al. The TORC1/2 inhibitor TAK228 sensitizes atypical teratoid rhabdoid tumors to cisplatin-induced cytotoxicity, Neuro Oncol nox067. DOI: https://doi.org/10.1093/neuonc/nox067

Source-Medindia