Fewer than half of women diagnosed with ovarian cancer live for five years or more. Sarah Adams, MD, a cancer doctor at the UNM Comprehensive Cancer Center, hopes a new therapy that delivers a one-two punch to cancer cells will change this outcome.
In a new clinical trial Adams is treating women whose ovarian cancer results from mutated BRCA genes with a drug that kills the ovarian cancer cells and another that boosts the immune system in response to the dying cancer cells.
Ovarian cancer has unclear symptoms and no screening tests that catch it in its early stages. Often, it spreads to other organs before a woman even knows she has it. Surgery and chemotherapy can help women at the beginning of their treatment, and this gave Adams the idea for her new approach.
As a gynecologic oncologist, Adams performs surgery and prescribes chemotherapy for women with cancers of the female reproductive organs. Adams has also conducted research suggesting that women with BRCA-related ovarian cancer respond better to some chemotherapy drugs.
Previous research has shown that other chemotherapy drugs not only kill cancer cells but also make the immune system more sensitive to them. Adams’ new treatment combines these approaches into what she thinks may be a powerful way to win against ovarian cancer.
Everyone carries a set of genes for BRCA, each of which contains the instructions to produce a protein. BRCA proteins help DNA to repair itself when both of its strands break and split the molecule in two. But if the BRCA genes are mutated the resulting proteins don’t work properly and the cell can’t repair its DNA. It will die unless it can resort to other repair methods.
Cells with mutated BRCA genes turn to a DNA-repair protein called PARP. Adams’ therapy uses a PARP inhibitor, a drug that keeps the PARP protein from its repair work. “If you knock out BRCA,” Adams says, “the cell can still live. If you knock out PARP, the cell can still live. But if you knock out both, the cell dies.”
The PARP inhibitor does not affect non-cancerous cells because they have working BRCA proteins to repair DNA. “It’s specific to cancer cells, so it’s nicely targeted and there’s minimal toxicity,” Adams says. The therapy is also easy to dispense. “It’s a pill that people take orally,” she says.
Adams’ therapy combines the PARP inhibitor with a specific antibody (a protein that attaches to a target cell). The antibody helps an immune cell, called a T-cell, to find and devour ovarian tumor cells. Untreated ovarian tumors often produce chemical signals that keep T-cells away. But the antibody-PAPR inhibitor combination alerts the entire immune system to the ovarian cancer cells.
Once the immune system finds ovarian cancer cells, it can rid the body of them – if the PARP inhibitor doesn’t kill them first. And because the immune system can remember how to respond to ovarian cancer cells, it continues to rid the body of them if the cancer tries to come back. Adams hopes that this will provide women long-lasting protection.
The clinical trial is currently open to women with BRCA1 or BRCA2 mutations who have a higher risk of getting breast and ovarian cancers and may have relatives who had these cancers at young ages.
In pre-clinical studies, this combination therapy eliminated tumors and helped mice to live longer. The clinical trial now makes the therapy available to women with BRCA gene mutations whose ovarian cancer has returned.
“I’m very excited about the results we’ve seen so far,” Adams says. “I hope that this regimen can achieve long-term benefit for women with ovarian cancer.”