The discovery that a cellular enzyme switches on a gene that makes ovarian cancer cells resist the most commonly used chemotherapy drugs, is being heralded as a significant breakthrough, with the hope it will lead to new treatments that prolong survival for women in the advanced stages of a disease that currently has a very poor outlook. The research team, from Imperial College London in the UK, write about their discovery in the journal Cancer Research this month.
Lead author Dr Euan Stronach, who runs the Oncogenomics and Drug Resistance team within the Ovarian Cancer Action Research Centre at Imperial College London, told the press that:
“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.”
In six out of ten women diagnosed with ovarian cancer, the prognosis is poor because unfortunately the disease, which is notoriously difficult to spot in the early stages, has already advanced to stage 3 and beyond (cancer has spread beyond the pelvis). This makes it harder to treat successfully.
One of the most common treatments is chemotherapy based on platinum, such as carboplatin and cisplatin.
The platinum works by entering the cancer cell and binding to its DNA, causing sufficient damage to trigger apoptosis or cell suicide.
However, after an initial period, when treatment appears to be going well, in about two thirds of patients, their cancer becomes resistant to platinum-based drugs: the cancer cells are able to fend off apoptosis and tumors start growing again.
However, recent studies suggest resistance to platinum is not triggered by the drugs, but is already present in a minority of cancer cells, which gradually increase in prevalence as the platinum kills off the non-resistant ones.
Thus “resistance is selected for rather than generated by treatment”, write the researchers.
For their Ovarian Cancer Action funded study, the team analyzed tissue samples taken from three women with ovarian cancer before and after they stopped responding to treatment with platinum drugs. This was to find genes that were either boosting (upregulating) or curbing (downregulating) resistance to platinum.
They eventually “identified 91 up- and 126 downregulated genes common to acquired resistance”.
They then experimented with “knocking down” these genes and found that with 4 of them, including one called STAT1 and another called HDAC4, this restored cell suicide capability in the resistant cancer cells, that is it “significantly enhanced apoptotic response to platinum treatment”.
They were particularly interested in the STAT1 gene, because it is already known to trigger activity in other genes inside cancer cells, which helps keep them alive.
They found that STAT1 was very active in cells that were resistant to platinum, but was inactive in cells that were sensitive to platinum.
And they also found that STAT1 and HDAC4 seemed to interact with each other.
When they disrupted production of the cellular enzyme coded by HDAC4, the researchers found it not only stopped STAT1 activity in the resistant cells, but it restored their sensitivity to platinum.
And in a further analysis, when they compared tumor biopsies taken from another 16 women with ovarian cancer before and after they developed resistance to platinum drugs, they found an increased expression of the HDAC4 gene in seven of the 16 resistant tumors.
It would appear, they suggest, that the HDAC4 enzyme, behaves like a chemical “switch” that prompts STAT1 into action and this promotes cancer cell survival.
“Together, our findings identify HDAC4 as a novel, therapeutically tractable target to counter platinum resistance in ovarian cancer,” conclude the researchers.
Senior author Professor Hani Gabra, Director of the Ovarian Cancer Action Research Centre, said:
“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.”
He said because we know from previous studies that some ovarian cancer cells have inbuilt resistance to chemotherapy and don’t acquire it after exposure to them, then further research will find the best screening test to identify those patients who are most likely to become resistant to treatment.
Allyson Kaye, Chair of Ovarian Cancer Action, said in the UK alone, every two hours a woman dies of ovarian cancer:
“… so this discovery could make a significant difference to the lives of the 6,500 women who are diagnosed every year with the disease, and their families.”
She also underscored the importance of this kind of research that is helping to create a future where more and more women will live with rather than die of ovarian cancer.
“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.
Additional source: Ovarian Cancer Action.
Written by: Catharine Paddock, PhD