A preclinical study by a team of oncologists and pharmacologists at Penn Medicine identifies a new target for recurrent ovarian cancer, a difficult-to-treat cancer. The work which was presented at the 2023 meeting of the American Association for Cancer Research (AACR), shows that targeting a protein (B7-H4) found at high levels in all stages of development of this cancer with an antibody-drug conjugate can induce long-lasting responses in tumor models.
Ovarian Cancer seen on CT. Credit: James Heilman, MD
Despite recent progress, ovarian cancer still ranks as the fifth leading cause of cancer-related deaths among women. Consequently, there is a pressing need for new treatment options, particularly for advanced cancers that relapse after initial standard treatment. This preclinical study, led by researchers at the Perelman School of Medicine, confirms a new target for drug-resistant ovarian cancer and supports a treatment approach already tested in previous clinical trials.
Platinum-resistant ovarian cancer
“Unfortunately, most ovarian cancers recur and become resistant to standard platinum-based chemotherapy,” says lead author Dr. Fiona Simpkins, MD, Ph.D., Professor of Obstetrics and Gynecology. “Platinum-resistant ovarian cancer is the most difficult type of ovarian cancer to treat and the development of new therapies in this area is an urgent priority,” adds co-author Dr. Sarah Gitto, Professor of Pathology and Laboratory Medicine, who is presenting the study results at the congress.
PARP inhibitors (PARPi), a new type of standard targeted therapy, have increased survival for ovarian cancer patients, but like chemotherapy, these treatments eventually stop working for many patients, leaving them without treatment options.
The Study
The study focused on the B7-H4 protein, which, as previous studies by the same team have shown, is found at high levels in most breast and ovarian cancers at diagnosis. Although cancer treatment can affect the proteins expressed in the cells, the researchers sought to determine whether B7-H4 is still expressed at high levels after multiple treatments in cases of relapse and whether the protein might be a suitable target for patients who have already received chemotherapy or PARP inhibitors.
The team analyzed samples from the Penn Ovarian Cancer Research Center’s Tumor BioTrust database and examined whether B7-H4 was found in the tumor tissue of the same patients before, during, and after treatment, and in some cases at the end metastatic stage. That analysis showed that :
- B7-H4 is overexpressed in 92% of high-grade serous ovarian carcinoma (HGSOC) tumors at diagnosis, throughout cancer treatment, and even after chemotherapy or PARPi treatment.
- The protein is always outside the cells (rather than inside them), making it accessible to drugs.
Antibody-drug conjugate successfully targets B7-H4
After confirming that B7-H4 is a viable target, researchers tested an antibody-drug conjugate in several cell lines and in more than 20 xenograft models derived from breast and ovarian cancer patients. Antibody-drug conjugates are a new class of immunotherapeutic drugs that are highly selective and much less toxic than traditional chemotherapy. These in vitro experiments show that:
- In 61% of samples that had not received prior treatment with PARPi or chemotherapy, tumor size was significantly reduced after a single dose.
- Continuous treatment every 28 days, to better mimic clinical dosing, produces significant tumor regression and increased survival in treatment-resistant animal models of cancer.
“We have confirmed excellent and stable antitumor activity over a long period in these drug-resistant models, which is rare. We have shown that B7-H4 is a very robust and widespread target that can be used at different stages of the disease.”
Trials already underway
An antibody-drug conjugate targeting B7-H4 is currently being tested in a multicenter Phase I clinical trial (NCT05123482).
The study not only opens up a new therapeutic option for these difficult-to-treat cancers but also illustrates the promise of antibody-drug conjugates in overcoming treatment resistance.
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