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Fighting Breast and Ovarian Cancer With a Lupus Antibody

September 26, 2022

Of the 1.5 million people living with lupus in the United States, 90% are women. This disease turns the body’s immune system against itself, potentially causing extreme pain, fatigue, difficulty thinking clearly, and cardiovascular disease.

Officially known as systemic lupus erythematosus, lupus is distinct among autoimmune diseases in the way circulating antibodies — proteins that when functioning properly help to protect against disease — react against DNA, the body’s instructions for building cells and passing traits from parents to children.

Drs. Peter M. Glazer and James Hansen discovered that one specific lupus antibody, known as 3E10, can penetrate cancer cells and make them sensitive to and killed by standard radiation and chemotherapy methods. Notably, this technique has shown significant effectiveness in killing cancer cells with DNA repair deficiencies, such as those with mutations in the tumor-suppressing BRCA2 gene that lead to higher rates of breast and ovarian cancer.

Now, nearly a decade since this discovery and with he help of a grant from Women’s Health Research at Yale, researchers are close to advancing a treatment toward clinical trials while learning more about how this lupus antibody penetrates and kills cancer cells.

“This discovery has unlocked promising new pathways for treatment of BRCA-related cancers that affect so many women around the world,” said Glazer, the Robert E. Hunter Professor of Therapeutic Radiology, professor of genetics, and chair of the Department of Therapeutic Radiology. “We have learned a great deal about how 3E10 interacts with DNA, and we continue to explore how this knowledge could be used to create therapies for other types of difficult-to-treat cancers.”

Dr. Glazer and his colleague Dr. James E. Hansen, associate professor of therapeutic radiology, licensed the rights for their antibody discovery to a company, Patrys, Ltd., that has validated the work and developed 3E10 as a cancer therapy for human use. An earlier human study in Switzerland attempting to use 3E10 as a vaccine for lupus had already demonstrated that it is nontoxic. Phase 1 clinical trials could begin as early as next year, Dr. Glazer said, likely for patients with cancers related to mutations of BRCA1/2 genes or of another tumor suppressing gene known as PTEN.

“This is very promising,” Glazer said. “I think it will be important to identify the right subgroup of patients for which this is most effective.”

After publishing the results, Dr. Glazer and his colleagues leveraged the data to obtain a pair of large multiyear grants from the National Institutes of Health. With this funding and the help of Yale graduate student Audrey Turchick, the team has discovered that inside a cancer cell, 3E10 sticks to a DNA repair protein called RAD51. This causes the lethality for cancer cells that are deficient in BRCA1 and BRCA2 genes by preventing the cells from conducting the routine DNA repair necessary to sustain themselves.

With ongoing funding from the NIH, Dr. Glazer’s team, including structural biologist Dr. Franziska Bleichert, is building on these findings to enhance the anti-cancer potency of 3E10 and develop therapeutic strategies by identifying ways for the antibody to stick more strongly to RAD51.

In addition, an MD/PhD student in the lab, Elias Quijano, helped identify the capacity of 3E10 to bind with RNA — a type of molecule used to carry out DNA instructions — and carry RNA into a cancer cell, potentially with instructions that can kill the cell. Quijano and Drs. Glazer, Stephen Squinto, and Bruce Turner co-founded Gennao Bio, a company seeking to develop this method of cancer-fighting therapy.

“This was an unexpected discovery that turns out may be very useful,” Glazer said. “We have some data showing the efficacy of this method against tumors in a laboratory model. It is a versatile platform, because it can deliver different types of RNA in a similar way to how the COVID-19 mRNA vaccines work.”

The research continues, thanks in large part to the investment WHRY made so many years ago.

“I think that type of funding is extremely valuable,” Glazer said of his WHRY grant. “It allowed us to do the sets of exploratory experiments we needed to do to demonstrate our approach was viable and get the larger grants. We showed this is feasible, this is promising.”

Submitted by Jessica Quistorff on September 07, 2022