Jessica St. Laurent, MD, was sure something had gone wrong. The results of an experiment she’d run showed that the cancer cells she was studying had abnormally high levels of a specific collection of proteins of interest to her team.
“I remember seeing the gradient and thinking, This can’t be right,” says St. Laurent, who is a gynecologic oncologist at Dana-Farber Brigham Cancer Center now, but at the time in 2020 was initiating a study in the Dana-Farber lab of Cigall Kadoch, PhD.
The results turned out not only to be right, but also, they held the keys to unlocking the biology underpinning an aggressive and difficult-to-treat form of endometrial cancer. Understanding that biology has led Kadoch and St. Laurent to find and preclinically validate a potential targeted therapy for the disease.
The work is emblematic of Dana-Farber research, which involves a long history of making discoveries that help drive forward advances in cancer.
“It was amazing to have a clinician-scientist come into our lab with an interest in this disease and apply the very intricate basic biology we work on to discover something totally new that could potentially benefit patients,” says Kadoch. “This work embodies the kind of science we support here at Dana-Farber.”
St. Laurent and Kadoch published their findings in Nature Genetics and for next steps plan to test the therapy in clinical trials.
Cigall Kadoch, PhD
Finding a focus: The genetics of endometrial cancers
Back in 2020, St. Laurent was working the night shift taking care of obstetrics and gynecology patients. In her spare time, she was reading research papers trying to find a focus for her Gynecologic Oncology fellowship at Dana-Farber and Brigham and Women’s Hospital.
She homed in on a form of endometrial cancer called dedifferentiated endometrial carcinomas. Patients with these cancers do not respond well to chemotherapy and tend to live less than a year after diagnosis.
“There is a real need to understand more about the biology of these cancers so that we can find better treatments,” says St. Laurent, who worked with co-second authors Alexander Ying, BS, and Grace Xu, BSE, in the Kadoch lab.
By reviewing tumor genetic sequencing data from Dana-Farber and elsewhere, she found that this specific type of endometrial carcinoma, which accounts for 8% of all cases, frequently has genetic aberrations in genes encoding protein complexes called SWI/SNF complexes. Kadoch’s lab has studied these complexes extensively.
SWI/SNF complexes are large molecular machines called chromatin remodelers that regulate the “openness” of our DNA. They govern the levels to which genes are turned on in cells. Specifically, they unwind tightly coiled DNA in the nuclei of our cells to expose gene sequences. When these complexes aren’t working correctly, which is the case in about 20 percent of all human cancers, cells can become malignant.
St. Laurent reached out to see if Kadoch might want to explore the connection between these complexes and endometrial cancer.
“It was kind of a fan girl email,” says St. Laurent, who proposed a project in which she could work with tumor samples from patients at Dana-Farber and elsewhere to study the role of these complexes in the disease.
Finding a target: Unraveling the biology behind the cancer
Kadoch saw the potential in the idea immediately. Not long after that, St. Laurent had her first, rather unexpected results.
She was studying cells with mutations that result in the loss of two genes, ARID1A and ARID1B, which are required for the formation of one subtype of SWI/SNF complex, called cBAF. When these genes are lost, a dramatic imbalance of the three SWI/SNF subtypes results. The cBAF complex is no longer functional, and the other two complexes, ncBAF and PBAF, become overabundant, revealing the steep and unexpected increase in protein expression St. Laurent observed in her experiments.
Further investigation showed that the imbalance of these complexes results in a shift in the gene regulatory programs run by the cells. This shift causes the cells to stop acting like endometrial cells and instead to grow aggressively and resist treatment.
St. Laurent devised a way to restore the ARID1A and ARID1B genes in these cells. Remarkably, this restored the balance of SWI/SNF complexes, and the cells began acting like endometrial cells again.
“These cancers have amazing plasticity,” says St. Laurent. “When the right balance of SWI/SNF complex function is restored, the cells can revert more closely to their normal state.”
Jessica St. Laurent, MD
Photo: Ken Richardson
Vetting a therapy: Testing new clinical-grade agents in models of endometrial cancer
While the restoration of ARID1A and ARID1B was revealing, it is not a realistic therapeutic intervention for patients. The team came up with an alternative approach that would involve breaking down the overabundant complexes.
The agent FHD-286 is a SWI/SNF ATPase inhibitor that is under evaluation in early-stage clinical trials. It is made by Foghorn Therapeutics, founded by Kadoch in 2016. This potent small molecule inhibits the “engines” of SWI/SNF complexes.
Kadoch and St. Laurent tested this agent and two related inhibitors that target these complexes in both cell lines and in patient-derived xenograft models of this form of cancer. They found that the agents slowed the growth of the endometrial cancers. When paired with platinum chemotherapy, the anti-cancer effect was even stronger.
“This is a tumor type that progresses exceptionally rapidly and typically overwhelms the models very quickly. But for the first time, we were able to meaningfully slow that process,” says Kadoch. “It’s a really promising foothold on this disease, and more broadly, speaks to the importance of targeting immediate direct mechanistic consequences of driver genetic mutations in cancer.”
Written by: Beth Dougherty