A cellular chemical “switch” that triggers resistance to the most commonly used drug treatment for ovarian cancer has been identified, reveals an Ovarian Cancer Action funded study.
The discovery, details of which are published this month in the journal Cancer Research*, opens up the prospect, for the first time, of targeted treatment to turn off the switch and prolong the survival of women with advanced disease.
Six out of 10 women with ovarian cancer are diagnosed when their disease is already advanced (stage 3 and above), making it much harder to treat successfully.
Surgery and platinum based chemotherapy with carboplatin or cisplatin are initially very effective in these cases. But around two out of three women will become resistant to chemotherapy and stop responding to treatment, prompting a recurrence of their cancer.
The research team, from the Ovarian Cancer Action Research Centre at Imperial College London, analysed tissue samples from three women with ovarian cancer before and after they had stopped responding to platinum, in a bid to pinpoint genes that might be responsible for either boosting or curbing resistance.
Platinum works by entering the cancer cell and locking on to its essential DNA. The resulting damage usually prompts the cell to “commit suicide,” a process known as apoptosis. But in resistant disease, cancer cells are able to fend off apoptosis.
The researchers were particularly interested in the STAT1 gene, which is a known transcription factor, meaning that it triggers activity in other genes within cancer cells, which helps keep them alive.
STAT1 was very active in cells that had become resistant to platinum. But no such activity was seen in cells that were still sensitive to platinum.
Furthermore, the researchers discovered that an enzyme called HDAC4 was the cellular chemical prompt that spurred STAT1 into action.
Disrupting production of this enzyme not only stopped STAT1 activity in resistant cells but restored their sensitivity to platinum treatment.
Further analysis of ovarian cancer cells taken from 16 women before and after they had stopped responding to platinum based treatment confirmed significantly higher levels of HDAC4 in almost half (7 out of 16; 44%) of resistant tumours.
“Our research has identified how ovarian cancer cells stimulate platinum resistance in patients, opening up the real possibility of developing targeted treatment to reverse that process,” comments lead author, Dr Euan Stronach.
Professor Hani Gabra, Director of the Ovarian Cancer Action Research Centre adds: “The Centre is now working with chemists at Imperial College London to develop powerful agents that will specifically block the action of HDAC4 and extend the survival of women with ovarian cancer.
Previous research has suggested that ovarian cancer cells may have inbuilt resistance to chemotherapy rather than acquiring it as a result of treatment, and further research will uncover the most appropriate screening test to identify those women who are most likely to become resistant to treatment.”
Allyson Kaye, Chair of Ovarian Cancer Action, says: “In the UK alone, ovarian cancer kills a woman every two hours, every day, so this discovery could make a significant difference to the lives of the 6500 women who are diagnosed every year with the disease, and their families.”
She continues: “The Ovarian Cancer Action Research Centre is making real headway in the battle against this devastating disease, by making it a disease that women will live with rather than die of. So it’s vital that this type of research can continue.”
Notes for editors:
*HDAC4-regulated STAT1 activation mediates platinum resistance in ovarian cancer. Stronach EA, Alfraidi AM, Rama NR, Datler C, Studd JB, Agarwal R, Guney TG, Gourley C, Hennessy BT, Mills GB, Mai A, Brown R, Dina R, Gabra H.
Cancer Research 2011; doi: 10.1158/0008-5472.CAN-10-4111.
About Ovarian Cancer Action:
Ovarian Cancer Action is the UK’s leading ovarian cancer charity, dedicated to improving survival rates for women with the disease, by funding innovative research, campaigning to raise awareness of the symptoms, and influencing health policy at national and local levels
www.ovarian.org.uk; +44 (0)300 456 4706
For further information/copy of the research, please contact:
Tania Pearson, head of communications at Ovarian Cancer Action
Tel: (direct line) +44 (0)300 456 4706