Developing Precision Therapies for Ovarian Cancer

Article Published on May 27, 2020

Translational studies of novel antibody-drug conjugates (ADCs) for ovarian cancers hold promise for improved outcomes and progress toward personalized treatments for gynecologic cancers
Researchers use patient-derived xenographs from the Mass General's vast patient base to identify specific tumor molecular fingerprints
Targeting overexpressed molecular fingerprints aids translation of preclinical research into novel clinical treatments
ADCs are one novel ovarian cancer therapy in preclinical testing at Mass General focused on the Sialyl-Thomsen-nouveau antigen as an especially promising target

Historically, women's ovarian cancers have been treated the same way, regardless of each patient's unique molecular makeup. But in the era of precision medicine, this one-treatment-fits-all approach is being replaced by novel therapies tailored to each patient's unique biology.

Researchers at Massachusetts General Hospital, including Whitfield Growdon, MD, a specialist in the Division of Gynecologic Oncology and the Mass General Cancer Center and a researcher in the Vincent Center for Reproductive Biology, and his collaborator Bo Rueda, PhD, director of the Vincent Center for Reproductive Biology, are working to develop next-generation tailored treatment protocols for ovarian cancer. These innovative, tailored approaches are now in preclinical stages. The researchers seek a level of precision treatment for ovarian malignancies never before possible.

"The thought is if you can understand what drives any tumor," says Dr. Growdon, "you can design the optimal therapy tailored to that patient."

Antibody-Drug Conjugates (ADCs)

One highly productive strategy the Mass General team excels in is based on patient-derived xenografts of donated ovarian-tumor tissue. The approach identifies molecular "fingerprints," or technically named tumor signatures.

Researchers use that information to design a novel class of drugs called antibody-drug conjugates (ADCs). This approach targets tumor cell overexpression by delivering a specifically designed antibody to the tumor cell surface to thwart tumor cell overexpression and carcinogenesis.

"We are looking for molecular fingerprints that appear to be overexpressed in tumors so we can design the exact treatment to fit it," Dr. Growdon says.

Reducing Cytotoxicity

At this preclinical stage, the Mass General team is working in mouse models to test tumor molecular fingerprints and ADC drug candidates designed to match those fingerprints. For example, if protein A is overexpressed in a tumor, researchers armed with molecular fingerprint information can design a biologically active ADC drug to counter protein A, delivering it to the tumor by linking it to an antibody. Importantly, the ADC approach enables researchers to deliver nano-level doses of the drug specifically to protein A cells, thus avoiding cytotoxicity damage to healthy cells and eliminating an undesirable side effect of many current cancer treatments.

Early, robust, preclinical testing of ADC-targeted therapies is key, according to Dr. Growdon.

"Tumors are very sneaky. They have many ways of outsmarting treatments very quickly," he says. "The advantage of the antibody-drug conjugate is that with it, we can give nano-quantity of a drug that tracks to the tumor surface."

The team's goal is to translate their findings into ADC therapy suitable for clinical trials in humans in the next several years.

A Role for STn Antigen

In cancers that resist chemotherapy, recurrence is often driven by surviving cells that function as quiescent cancer stem cells.

To fully inhibit ovarian cancer growth and recurrence, one of the team's most promising projects involves the tumor-associated Sialyl-Thomsen-nouveau antigen (STn). This antigen, commonly found on sugars that rest on ovarian tumor cell surfaces, is overexpressed in ovarian cancer cells, as well as in many other types of cancers.

Early results suggest targeting STn through ADCs not only inhibits tumor cell proliferation, but also induces cell death. From their work with rare ovarian mucinous cancers, Dr. Growdon and colleagues observed that STn might be a way that tumors become evasive to conventional therapy.

Their data show that the more STn a tumor expresses, the better it responds to their ADC therapy. To validate this dose-setting finding, they created three models (low, medium and high) and are currently in the discovery stage to find the optimal dose-response for ovarian cancers.

A Tipping Point

The researchers attribute their encouraging progress toward clinical trials to the complementary expertise of interdisciplinary teams.

"This wouldn't be possible without a high-functioning system," says Dr. Growdon. "That's the tag phrase: you have to have a good idea, a good target and a high-functioning system for the validation phase in translational discovery to succeed. That's hard legwork."

Driven by a three-prong collaborative ethic of discovery, translation and application, their shared focus to optimize patient outcomes energizes their work. "We're sort of at a tipping point in the treatment of ovarian cancers, and it's really exciting," he says.

Learn more about the Vincent Center for Reproductive Biology

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