Some tumors grow so fast that their cells become oxygen-starved from inability to hook up to the body’s
blood supply. Oxygen-starvation usually triggers signals that cause cell suicide, but in some cancers with a
faulty p53 tumor suppressor gene – which is found in around half of cancers – the cells carry on growing because
the cell-suicide signals fails.
Drugs already being trialed could boost the effectiveness of radiotherapy treatment for many types of cancer.
Now, researchers have discovered that giving a class of drugs called AKT inhibitors in combination with
radiotherapy may boost the effectiveness of the treatment on tumors with the faulty p53 gene by restoring cell
suicide in oxygen-starved cancer cells and making them more radiation-sensitive.
The team – from Cancer Research UK – reports the findings in the Journal of Clinical
Investigation.
Dr. Ester Hammond, study leader and Cancer Research UK scientist based at the University of Oxford, says:
“This exciting discovery sheds light on the role of oxygen-starvation in cancer development and
suggests that drugs already being trialed in cancer patients could potentially boost the effectiveness of
radiotherapy across a range of cancers.”
In their study, Dr. Hammond and colleagues found that six genes that normally protect the body against cancer
are less active in oxygen-starved cancer cells with a faulty p53 gene.
They found the six genes from analyzing lab-grown cancer cells, and then showed they were also affected by
p53 in a range of human cancers, including breast, brain, colorectal, kidney, bladder and melanoma cancers.
Active AKT prevents cell suicide even under oxygen-starvation
The team also found that when two of the genes are inactivated – PHLDA3 and INPP5D – another gene called AKT
becomes permanently switched on, which prevents cell suicide, even though the cancer cells are oxygen-starved.
They then tested the effect of AKT inhibitors in lab-grown cancer cells and mice lacking the p53
gene when treated with radiotherapy. The results showed the radiotherapy killed more tumor cells.
The researchers conclude that their results identify a number of factors that influence cell suicide via the
p53 gene, and suggest “AKT inhibition may improve radiotherapy response in p53-deficient tumors.” Dr. Hammond
adds:
“We hope that this important piece of the jigsaw will support ongoing efforts to develop drugs
that enhance radiotherapy, so that even more patients can benefit from this cornerstone of cancer
treatment.”
As more than half of cancer patients receive radiotherapy as part of their treatment, says Eleanor Barrie, senior
science information manager for Cancer Research UK, anything that improves the effectiveness of
radiotherapy is “great news for patients.”
In their discussion of the results, the researchers suggest it is likely that under oxygen-starvation, p53
also has other anticancer roles, other than driving cells to commit suicide, and note it “would be interesting
to investigate” whether any of the targets they identified in their study affect other anticancer cell
functions under oxygen starvation.
Meanwhile, MNT recently reported how a form of permanent radiotherapy
may prolong prostate cancer survival. For that study, researchers compared low-dose-rate prostate
brachytherapy (LDR-PB), where seeds of radioactive material are implanted in the prostate – to dose-escalated
external beam radiotherapy (EBRT), where beams of radiation are focused on the prostate gland from outside the
body.
Five years after treatment, they found that the men treated with LDR-PB were more than twice as likely to be
free of prostate cancer as those treated with DE-EBRT.