A research team led by scientists at the Oregon Health & Science University has identified a panel of proteins linked to DNA repair pathways and platinum chemotherapy resistance in sporadic ovarian cancer.
According to Tanja Pejovic, a gynecological oncologist at OHSU and a researcher on the study, the panel could offer clinicians new approaches for testing for DNA repair dysfunction and expand the population of ovarian cancer patients who might benefit from poly-ADP ribose polymerase, or PARP, inhibitor therapy.
PARP inhibitors – which are under development at a number of pharma firms including Abbott, AstraZeneca, Sanofi-Aventis, Clovis Oncology, and BioMarin – have been shown to sensitize cells with homologous recombination deficiencies to chemotherapy-induced DNA injury. Specifically, patients with mutations in the DNA repair genes BRCA1 and BRCA2 have shown strong response to combined PARP inhibitor/platinum chemotherapy treatment.
Myriad Genetics is the leader in BRCA1/2 mutation testing, and, as reported by ProteoMonitor sister publication PGx Reporter, has in the past two years inked three agreements – with Abbott, AstraZeneca, and BioMarin – to develop companion diagnostics to test for germline BRCA1/2 mutations in support of clinical trials of PARP inhibitors (PGx Reporter 4/13/2011).
Germline BRCA1/2 mutations, however, are present in only 10 percent to 15 percent of ovarian cancer patients, which has limited the number of women eligible to participate in such trials. In recent years, research has identified a number of proteins beyond BRCA1/2 that may contribute to PARP sensitivity and disease recurrence, Pejovic told ProteoMonitor, leading the researchers to investigate whether it might be possible to define this so-called "BRCAness" profile via the expression levels of these proteins.
"We thought, why don't we test women for these [other] proteins and see if we can find a much bigger proportion of women who could benefit from these drugs," she said.
In the study, which was published this month in PLoS One, the researchers used protein microarrays to measure the expression levels of seven proteins – PARP, FANCD2, BRCA1, PTEN, HSAX, ATM, and p53 – in tumor samples from 186 patients with advanced stage III or IV and grade 3 ovarian cancer.
They identified a signature, consisting of concomitant high levels of PARP, FANCD2, and p53, that was tied to early recurrence of the disease, which characterizes platinum-resistant ovarian cancer.
Patients with heightened expression of these three proteins were twice as likely to have recurrence within three years, and over half the patients who recurred in the first year after platinum treatment – which the authors defined as early recurrence – had significantly elevated levels of these proteins.
"We think that over-expression of these three proteins perhaps occurs in response to platinum [chemotherapy]," Pejovic said. "That it is a kind of compensatory mechanism" designed to increase the capacity of cells to repair DNA damage caused by the platinum therapy.
This, she said, suggests that patients with this triple-positive protein profile could perhaps benefit from treatment with PARP inhibitors, even without evidence of germline BRCA1/2 mutations. She noted that the study did not identify which of the patients were BRCA1/2 mutation carriers, but instead focused exclusively on protein expression.
One potential limitation of the study, Pejovic acknowledged, was the reliability of the antibodies used for these expression measurements. In particular, measurement of BRCA1 expression levels in ovarian cancer samples has varied significantly across different studies.
For instance, the authors noted, while the PLoS One paper found that 86.7 percent of the cases had negative BRCA1 immunohistochemistry, a recent paper in Acta Obstetricia et Gynecologica Scandinavica showed negative BRCA1 IHC in only 20 percent of its samples.
"That is one of the limitations of our study, and certainly there is a concern there," Pejovic said. She added that, in fact, several of the first antibodies they tried in the study didn't work at all. "We used the best antibodies that we could [find], but certainly it's something that needs to be repeated one way or another."
She added that there were a number of other DNA repair proteins that might be useful in predicting recurrence and platinum resistance, noting that while the researchers limited themselves to looking at seven proteins, "this is by no means comprehensive. There are a number of [DNA repair] proteins that we didn't look at that could be looked at – more than 130."
The researchers have no plans to expand their panel, however, she said. Instead, they are moving to perform functional confirmation of their results, testing to see if the triple-positive cells do, in fact, exhibit problems with homologous recombination.
They also plan to test the results in an additional set of patient samples, and are in the process of obtaining another 154 samples from a well-defined set of stage III and IV serous ovarian cancer tumor samples with which they plan to perform the same analysis, Pejovic said.
The study's findings, she added, are not specific to ovarian cancer, "but should be highly applicable to breast cancer," as well. The researchers hope to contact pharma firms making PARP inhibitors about the work, she said, but have yet to do so.
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