Dana-Farber Science Inspires Trial of Drug Combo for Ovarian Cancer

As a post-doctoral fellow, Elizabeth Stover, MD, PhD, wanted to understand how ovarian cancer cells become resistant to chemotherapy. Chemotherapy becomes less effective over time for most patients with metastatic ovarian cancer.  

She ran an unbiased screen – a way to look at every gene in the human genome and see which ones protect ovarian cancer cells from dying and which speed them to an end. A set of genes related to programmed cell death stood out. When these genes were present, cancer cells were less likely to die after treatment with platinum or taxane chemotherapy. When absent, cancer cells were more likely to die.  

“It was striking because this pathway was the strongest mediator of resistance and sensitivity to chemotherapy,” says Stover, who published these findings in 2019 and is now a Dana-Farber physician-scientist. “More importantly, these genes were just beginning to become targetable with drugs.” 

Acting on these and other findings, Stover and close collaborator Kris Sarosiek, PhD, of the Harvard T.H. Chan School of Public Health, designed and launched a Dana-Farber clinical trial to determine if targeting one of the proteins in this pathway – called BCL-XL – could help patients with ovarian cancer. The trial is the first to combine standard-of-care paclitaxel chemotherapy with a BCL-XL targeted therapy.  

The trial is backed not only by Stover’s collaborative research but also by decades of science at Dana-Farber that has uncovered the power of targeting programmed cell death to treat cancer.  

Targeting programmed cell death 

A mechanism for programmed cell death (also called apoptosis) is built into every human cell to induce death when the cell is infected or damaged. Cells also have a safety net system that helps protect them from dying prematurely. Cancer cells are known to exploit this safety net to keep tumor cells alive. 

The idea of targeting cell death safety net proteins to treat cancer was originally brought forward by the late Stanley Korsmeyer, MD, of Dana-Farber, more than twenty years ago. His team and the research of others at Dana-Farber led to the development of venetoclax, which targets the cell death safety net protein BCL-2 for the treatment of leukemia. 

Stover worked in Korsmeyer’s lab in 2002 as a graduate student. When she saw cell death safety net proteins as hits in her screens in 2019, she knew she was onto something. 

“I knew there were drugs being developed that were targeting apoptosis and that they could potentially be used to benefit patients with ovarian cancer,” she says. 

The drugs being developed were small molecule inhibitors of the BCL-XL protein. These inhibitors, however, acted on both ovarian cancer cells and on healthy blood cells called platelets. When treated with BCL-XL inhibitors, patients experienced low platelet levels that were difficult to manage. 

A new possibility emerged a few years ago with a drug, DT2216, that degrades BCL-XL. Rather than blocking the protein’s activity, the drug tags it for recycling via the cell’s built-in recycling system. The tagging mechanism used by the drug isn’t very active in platelets, and an early phase clinical trial has shown that the drug is safe, with manageable drops in platelet levels. 

Laboratory studies support a clinical trial 

Sarosiek began testing the activity of DT2216 in patient-derived models of ovarian cancer, with stunning results. In some cases, cancer cells were completely eradicated in animal models after treatment with a combination of DT2216 and chemotherapy.  

“These were some of the strongest effects we’ve seen in drug studies in ovarian cancer models over the years,” says Stover. “The vast majority of the cancer cell lines were sensitive to the degrader, and even more so when combined with paclitaxel, one of our standard-of-care drugs for recurrent ovarian cancer.”  

The researchers observed these strong results in models of high grade serous ovarian cancer. In a separate study, Stover showed that a combination of DT2216 and paclitaxel chemotherapy was effective against models of a rare form of ovarian cancer, clear cell ovarian cancer, that typically does not respond to paclitaxel chemotherapy.  

“Evidence is emerging that this dependency on BCL-XL might arise as early as the formation of ovarian cancer and may be part of the fundamental character that persists throughout the lifespan of that cancer,” says Stover. 

Towards patient benefit 

Stover and Sarosiek shared their data with the makers of DT2216 and worked together with Ursula Matulonis, MD, and Joyce Liu, MD, MPH, of the Dana-Farber Division of Gynecologic Oncology to design a clinical trial to test combining the BCL-XL degrader with standard paclitaxel chemotherapy in patients with recurrent ovarian cancer. The phase 1b trial at Dana-Farber is open to patients with all forms of recurrent ovarian cancer, regardless of previous therapy. 

“It’s a nice study for patients because they’re basically receiving standard-of-care paclitaxel plus a second drug we hope will improve efficacy,” says Stover, who is also exploring whether BCL-XL degraders could be combined with targeted therapies to treat ovarian cancer.

Written by: Beth Dougherty
Medically Reviewed By: Elizabeth Stover, MD, PhD