Personalized drugs for deadliest brain cancers could be on horizon

By Mark Waghorn via SWNS

Personalized drugs for the deadliest brain cancers could be on the horizon after a breakthrough by scientists.

Specific mutations in a gene known as BRAF affect survival, according to new research.

Improved therapies are urgently needed for the tumors, known as gliomas, which are often incurable.

A study of almost 300 people found they behave differently in adults and children - particularly when responding to medications.

"The findings suggest there are distinct biological characteristics that may influence clinical outcomes and these need to be studied further to understand their impact," said lead author Dr. Karisa Schreck, of Johns Hopkins University.

Glioblastoma is the most common type, with around 2,500 cases diagnosed in the UK each year. Just seven percent of patients are cured.

"Drugs have been developed that target specific BRAF mutations, such as dabrafenib and trametinib, which inhibit the BRAFv600E mutation," Schreck said.

"Knowing which mutation or combination of genetic alterations are driving a patient's cancer is crucial to choosing the best therapy that is most likely to prolong survival."

Dabrafenib targets cells with certain BRAF mutations and prevents the altered protein from sending growth signals. Trametinib blocks the activity of proteins that help send these signals.

Glioma can be caused by BRAF variants. Although they are well understood in children, this was not the case for adults, said Schreck.

The first study of its kind will enable her to design better-informed clinical trials for these patients.

It was based on clinical information, including what treatments the patients received and how long they lived, and the structure and molecular make-up of tumor tissues, including genetic alterations.

The US team divided the tumors into three groups, based on how the BRAF alteration activates a chemical called ERK that fuels cancer

They included Class I mutations such as BRAFv600E , in which the gene is able to activate ERK by itself).

In Class II mutations, BRAF needs to pair up with another molecule to activate ERK. With Class III they amplify ERK signaling through a gene named RAS.

Schreck found BRAF-altered gliomas in adults and children had different features.

"There were more Class I BRAFv600E alterations in adults, and more BRAF fusions in childhood glioma," she said.

"Fusion occurs when part of a BRAF gene wrongly attaches or 'fuses' to a different gene, allowing it to cause cancer.

"BRAFv600E alterations were associated with improved overall survival in adults with glioma.

"But for the most aggressive type of glioma - glioblastoma - that improvement disappeared, and increased age was associated with worse survival in these patients."

The researchers also found BRAFv600E conferred sensitivity to targeted therapy in adult patients.

They knew glioma with BRAFv600E alterations could be sensitive to treatment with drugs that inhibit the gene.

"This study showed patients who received these treatments lived longer than those with the same BRAF alteration and tumor grade who did not," Schreck said.

Targeted therapies halted the growth or shrank the glioma in six out of 13 adult patients.

The average time before the cancer progressed was five months and overall survival was nearly 14 years. It was four and a half years in patients with glioblastoma.

The findings were presented at an international symposium organized by EORTC (European Organization for Research and Treatment of Cancer), NCI (National Cancer Institute) and AACR (American Association for Cancer Research) in Barcelona.

Chair Professor Ruth Plummer, from Newcastle University, who was not involved with the research, said: "These results show how gliomas can behave differently in adults and children, potentially including how they respond to targeted therapies.

"The study advances what we know about gliomas in adults and this knowledge will enable us to better match treatments to the cancer, depending on the specific variations in the BRAF gene.

"It will also enable us to develop new and better therapies to target different genetic variations.

"Glioma can be a difficult disease to treat successfully and we urgently need to find new drugs that help us to improve outcomes for these patients."