A one-two punch against ovarian cancer

Sarah Adams, MD, hopes to change this outcome. Adams cares for women with ovarian cancer and studies ways to treat them more effectively. She is using a grant from the Oxnard Foundation to study a combination therapy she developed to help women with ovarian cancer.

Adams' therapy takes the dual approach of killing cancerous ovarian cells and teaching the immune system to find them. At the moment, the therapy works very well for tumors resulting from mutated BRCA genes. She has tested it on animals and is preparing for human clinical trials. She hopes to expand the therapy to help all women with ovarian cancer.

BRCA is a set of genes we all carry. Each gene contains the instructions to produce a protein. BRCA proteins help DNA to repair itself when both of its strands break and completely split the molecule in two. If the BRCA genes are mutated, or changed, the resulting proteins do not work properly and the cell cannot repair its DNA. It dies unless it can resort to other repair methods.

Cells with mutated BRCA genes resort to using a DNA-repair protein called PARP. Adams' therapy uses a type of drug called a PARP inhibitor, which keeps the PARP protein from its repair work. "If you knock out BRCA," says Adams, "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 good BRCA proteins to repair DNA. "It's specific to cancer cells so it's nicely targeted," says Adams. The therapy is also easy to dispense. "It's a pill that people take orally and there's very minimal toxicity," she says.

Adams' therapy, based on her team's previous work, combines the PARP inhibitor with a particular antibody. An antibody is a protein that specifically binds a target cell. The antibody Adams' therapy uses helps one type of immune cell, called a T-cell, to recognize and devour tumor cells.

Without treatment, tumors often produce chemical signals that keep T-cells away. By combining the PARP inhibitor with the antibody, Adams' therapy not only kills the cancer cells but alerts the entire immune system to the tumor. So if the PARP inhibitor doesn't kill the tumor cells, the immune system does.

Adams and her team were excited by the results in animals. Post doctoral fellows Dallas Flies, PhD, and Tomoe Higuchi, MD, PhD, carried out the studies. Animals that received the therapy survived longer and the scientists could not find tumors in most of them even months after treatment. Now, Adams and her team will try to expand the therapy to women without BRCA mutations, who are the majority of women with ovarian cancer. The team will also work towards clinical trials for women with these mutations.

To expand the therapy, Adams thinks the initial step of killing the tumor cells must be carried out in some other way. "We don't get that cell death so we never get the signals that start the immune response," she says of tumors that don't have BRCA mutations. "We just need a different stimulus to get the cell death going to then combine with the antibody treatment."

The team will study how PARP works in a cell and whether they can start tumor cell death in some other way using the PARP inhibitor. The team will also study whether lower doses of chemotherapy and whether simply timing chemotherapy differently during treatment can start tumor cell death. "What's unique about ovarian cancer is that we operate on people even when they have cancer that's metastasized because we know it makes the chemotherapy work better. This gives us the opportunity to treat patients when their tumor burden is low after surgical resection -- when there aren't bulky tumors that are sending out inhibitory signals."

Ultimately, the team hopes to boost the immune system of women with ovarian cancer so that their bodies keep the cancer at bay once the tumor is removed or killed. "I've never been this excited about research before," says Adams. "These results have been really exciting."