Targeted alpha therapy (TAT) is emerging as a potential additional treatment for glioblastoma (GB), a disease which has confounded oncologists for decades due to its aggressive nature and strong resistance to existing therapies.

The current standard treatment for GB is surgery, followed by external beam radiotherapy and the chemotherapy drug, temozolomide. However, survival rates of less than 5-10% at five years have prompted researchers to explore alternative options.

University of South Australia scientists are conducting their own experiments with TAT and have reviewed existing clinical studies to assess the viability of targeted alpha therapy as a treatment option for recurrent glioblastoma.

In a new paper published in Targeted Oncology, UniSA PhD candidate Maram El Sabri, medical radiation physicist Professor Eva Bezak and oncologist Professor Frank Saran outline the evidence supporting TAT.

“Unlike external beam radiotherapy, which delivers radiation more diffusely over a larger volume, TAT delivers high amounts of lethal radiation to the tumour at very short range, hitting its target without significantly affecting surrounding healthy tissue,” says Maram.

“Alpha particles are up to 10 times more potent, when compared to standard photon radiation therapy, killing the cancer cells or at the very least slowing their future growth by damaging their DNA.”

Glioblastomas are problematic because they grow very quickly and spread beyond the easy visible tumour into normal brain tissue, making it difficult for oncologists to deliver the optimal dosage of radiation needed to kill the cancer.

Animal studies demonstrate that only a few targeting agents can effectively cross the blood brain barrier (BBB) to reach cancerous tissue, and those that do cause unwanted side effects in surrounding healthy tissue.

In pre-clinical experiments, TAT has been shown to increase survival rates by 16.1% in newly diagnosed glioblastoma cases and by 36.4% in recurrent tumours. Furthermore, the studies suggest that it has minimal adverse effects for the patient.

Co-author Professor Bezak says TAT was first proposed for cancer therapy more than 20 years ago by internationally acclaimed Australian research scientist, Professor Barry Allen, who died in 2019 from cancer.

“He was ahead of his time. It has taken this long for TAT to be gradually accepted by clinicians and for animal (pre-clinical) and human (clinical) studies to be undertaken,” Prof Bezak says.

“Pre-clinical studies show very promising results. Alpha emitters are up to 10 times more toxic to cells than gamma radiation, which are used in external beam radiation. Also, compared to the cost of current immunotherapy or molecular targeting drugs, targeted alpha therapy is relatively cheap.”

Professor Frank Saran, an Adjunct Clinical Professor at UniSA and experienced radiation oncologist, says very little progress has been made in the treatment of glioblastoma in recent decades, sparking a renewed interest in TAT.

“The most exciting development was the discovery of the chemotherapy drug temozolomide in the 1980s but that has only improved the expected median survival by around three months,” he says.

“Research into this area is very low for several reasons. First, glioblastoma is a rare cancer so does not affect large swathes of the population. It also has extremely low survival rates and there is a long-standing history of failed studies in this area. Unfortunately, pharmaceutical companies are often not willing to invest money in GB because it has a low probability of success and is not commercially viable.”

In her PhD, Maram is developing a computational model to calculate how TAT can be delivered most effectively to the brain after surgery, and in combination with conventional radiation treatment and chemotherapies, specifically targeting residual cancer cells and delivering more effective radiation to the tumour.

“I am excited to find out if we can find the right dosing and radiation range by adding TAT to the conventional treatment options. If this is successful, we might see some significant results in terms of extending a patient’s life,” she says.