New Target for Recurrent Ovarian Cancer Identified

Despite recent breakthroughs, ovarian cancer remains the sixth biggest cause of cancer-related deaths among women, and new therapeutic options are desperately needed, particularly for advanced tumors that recur after standard-of-care treatment. A preclinical study headed by researchers at the University of Pennsylvania’s Perelman School of Medicine confirmed a new target for drug-resistant ovarian cancer and provided data to support a therapy method that is already in clinical trials.
The findings will be presented (Abstract #1133) by Sarah Gitto, Ph.D., an instructor of Pathology and Laboratory Medicine, at the American Association for Cancer Research (AACR) Annual Meeting 2023.

“Unfortunately the majority of ovarian cancers recur and become resistant to standard platinum chemotherapy,” said senior author Fiona Simpkins, MD, a professor of Obstetrics and Gynecology. “Platinum-resistant ovarian cancer is the most challenging type of ovarian cancer to treat, and developing new therapies in this area is an urgent priority.”

PARP inhibitors (PARPi), a novel type of targeted standard of care treatment, have extended survival for ovarian cancer patients; nevertheless, these medicines, like chemotherapy, eventually stop functioning for many patients, leaving them without treatment choices.

To address these issues, this study focused on the protein B7-H4, which has been shown in pivotal work by co-author and collaborator Daniel J. Powell Jr., Ph.D., an associate professor of Pathology and Laboratory Medicine, to be a potentially high-impact target found in the majority of breast and ovarian cancers at diagnosis. Because cancer treatment can influence which proteins are expressed on cells, the researchers wanted to see if B7-H4 was still expressed at high levels after numerous treatments in the recurrent context, and if so, if it would be an acceptable therapeutic target.

The researchers examined matched samples from the Penn Ovarian Cancer Research Center Tumor BioTrust Collection to investigate if B7-H4 was detected in tumor tissue from the same patients before, during, and after treatment—and, in some cases, in the setting of end-stage metastatic disease. They discovered that B7-H4 was overexpressed in 92 percent of high-grade serous ovarian carcinoma (HGSOC) tumors at diagnosis and remained high throughout cancer treatment, even after chemotherapy or PARPi. Importantly, the protein was constantly present on the outside of the cells (rather than exclusively within), where it could be easily bound to by a medication.

The researchers evaluated an antibody-drug combination in several cell lines and more than 20 patient-derived xenografts (PDX) cancer models of breast and ovarian cancer after confirming B7-H4 as a feasible target. Antibody-drug conjugates are a novel type of highly targeted immunotherapy medications with considerably lower toxicity than standard chemotherapy.

Tumors shrank after just one dosage in 61 percent of PDX models that had not previously received PARPi or chemotherapy treatment. The medication resulted in considerable tumor shrinkage and enhanced survival in treatment-resistant PDX models when administered every 28 days to better resemble clinical dosage.

“We’re excited about the potential for antibody-drug conjugates to overcome drug resistance, and this work shows they merit further development in ovarian cancer,” Simpkins said. “This type of progress is possible thanks to the patients who participate in research, including biospecimen banking programs that allow scientists to learn about how their disease changes over time.”

Gitto presented the findings during the Innovative Therapeutic Approaches Minisymposium on Sunday, April 16.

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