Dana-Farber scientists recently uncovered a potential vulnerability in a form of ovarian cancer notoriously resistant to chemotherapy. Now they’ve opened a clinical trial involving a drug that targets that susceptibility in patients with the disease.
The impetus for their research is a type of ovarian cancer with excess copies of the cyclinE1 gene (abbreviated CCNE1). Accounting for about 10% of ovarian cancer cases, it is the deadliest form of the disease largely because of a lack of responsiveness to chemotherapy.
Dana-Farber’s Panos Konstantinopoulos, MD, PhD, director of translational research, Gynecologic Oncology, and Dipanjan Chowdhury, PhD, along with Rugang Zhang, PhD, of the Wistar Institute, discovered that a cell protein known as heat shock protein 90 (HSP90) is a useful therapeutic target for this type of ovarian cancer. (Heat shock proteins are produced in response to stressful conditions such as heat, cold, ultraviolet light, or wound healing. They act as “chaperones” to other proteins to make sure they fold and assemble properly and help alert the immune system when infection or cancer is present.)
In ovarian cancer, a surplus of CCNE1 genes enables tumor cells to repair DNA damage caused by chemotherapy drugs, allowing them to weather the treatment and keep growing. The CCNE1 protein is escorted through the cell by HSP90. The researchers hypothesized that drugs able to block HSP90 would hamper CCNE1 and thus interfere with DNA repair. Such drugs, alone or in combination with agents that promote DNA damage, could be lethal to ovarian cancer cells with an oversupply of CCNE1.
Laboratory studies showed that an HSP90-blocking compound called AT13387 worked in concert with DNA damage-inducing drugs such as PARP inhibitors to kill CCNE1-laden ovarian cancer cells. When they tested the combination in animal models, investigators found it inhibited tumor growth and was more effective than either treatment alone.
Encouraged by these findings, researchers have launched a phase I clinical trial of the PARP inhibitor olaparib and AT13387 in women with recurrent ovarian cancer and other metastatic solid tumors.