New target to combat chemotherapy resistance in deadly brain cancer

Standard treatments, including surgery, radiation, and the chemotherapy drug temozolomide, have seen limited success, unchanged over the past five decades. Although temozolomide can initially slow brain tumour progression, most patients experience rapid resistance, reducing the drug’s effectiveness.

However, a breakthrough from Virginia Tech researchers at the Fralin Biomedical Research Institute at VTC offers new hope. Their recent study, published in the journal iScience, identifies a crucial molecular signalling pathway that could be the key to overcoming this resistance.

Phosphoinositide 3 Kinase signalling pathway
Dr Zhi Sheng, the study’s senior author and assistant professor at the institute, highlights the urgency of the research. “Since it’s the only currently available approved chemotherapy that can effectively reach the brain, finding ways to restore its effectiveness is crucial in addressing the treatment failure in glioblastoma,” he said.

The researchers focused on the Phosphoinositide 3 Kinase (PI3K) signalling pathway, which controls cell growth, survival, and division.

Traditionally, blocking this pathway was considered a potential cancer treatment strategy, but the results were disappointing. The new study shifts the focus to a specific form of the signalling protein called PI3K-beta.

Slowing cancer cell growth
Analysing brain cancer cell cultures, including stem cells from patient specimens, and mouse models with human cancer cells, the team found elevated levels of PI3K-beta in patients unresponsive to treatment.

Blocking PI3K-beta alone made tumour cells more sensitive to temozolomide. Combining a PI3K-beta inhibitor with temozolomide significantly slowed cancer cell growth.

“This research shows that PI3K-beta is specific to glioblastoma, making it the crucial target for effective treatment,” Dr Sheng explained. The distinct role of PI3K-beta in glioblastoma contrasts with the failure of previous treatments that did not differentiate between various forms of the PI3K protein.

While these findings are promising, the is still a challenge in delivering PI3K-beta inhibitors across the blood-brain obstacle. Overcoming this is essential for translating these laboratory successes into clinical treatments for patients.

Dr. Sheng and his team are optimistic about future studies to address these delivery challenges. The research received support from the National Institutes of Health and uses data from several cancer research networks.